Datasets:

laion

/

biorxiv_metadata

like 0

Follow

LAION eV 50

DCL1, a Protein that Produces Plant MicroRNA, Coordinates Meristem Activity

10.1101/001438

Stephen E. Schauer;Teresa A. Golden;Delwin S. Merchant;Biranchi N. Patra;Jean D. Lang;Sumita Ray;Bulbul Chakravarti;Deb N. Chakravarti;Animesh Ray;

Abstract Abstract Introduction Results Discussion Materials and Methods Authors' contributions Funding References The ubiquity and importance of short duplex RNAs, termed microRNA (miRNA), for normal development in higher eukaryotes are becoming increasingly clear. We had previously shown that reduction-of-function mutations in Arabidopsis thaliana DCL1 (DICER-LIKE1) gene, affecting the nucleus-localized protein that produces 19-25 nucleotides long miRNA species from longer double stranded RNA precursors, cause a delay in flowering by prolonging the period of juvenile organ development. Here we show that DCL1 transcription is increased at the critical phase of juvenile to reproductive developmental transition, and that DCL1 protein is localized in meri ...

2013-12-21

An XA21-Associated Kinase (OsSERK2) regulates immunity mediated by the XA21 and XA3 immune receptors

10.1101/000950

Xuewei Chen;Shimin Zuo;Benjamin Schwessinger;Mawsheng Chern;Patrick Canlas;Deling Ruan;Arsalan Daudi;Xiaogang Zhang;Jing Wang;Christopher Petzold;Joshua Heazlewood;Pamela C Ronald;

The rice XA21 immune receptor kinase and the structurally related XA3 receptor, confer immunity to Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial leaf blight. Here we report the isolation of OsSERK2 (rice somatic embryogenesis receptor kinase 2) and demonstrate that OsSERK2 positively regulates immunity mediated by XA21 and XA3 as well as the rice immune receptor FLS2 (OsFLS2). Rice plants silenced for OsSerk2 display altered morphology and reduced sensitivity to the hormone brassinolide. OsSERK2 interacts with the intracellular domains of each immune receptor in the yeast-two-hybrid system in a kinase activity dependent manner. OsSERK2 undergoes bidirectional trans-phosphorylation with XA21 in vitro and forms a constitutive complex with XA21 in vivo. These results demonstrate an essential role for OsSERK2 in the function of three rice immune receptors and suggest that direct interaction with the rice immune receptors is critical for their function. Taken together, our findings suggest that the mechanism of OsSERK2-meditated regulation of rice XA21, XA3 and FLS2 differs from that of AtSERK3/BAK1-mediated regulation of Arabidopsis FLS2 and EFR.

2013-11-26

An XA21-Associated Kinase (OsSERK2) regulates immunity mediated by the XA21 and XA3 immune receptors

10.1101/000950

Xuewei Chen;Shimin Zuo;Benjamin Schwessinger;Mawsheng Chern;Patrick Canlas;Deling Ruan;Arsalan Daudi;Xiaogang Zhang;Jing Wang;Christopher Petzold;Joshua Heazlewood;Pamela C Ronald;

The rice XA21 immune receptor kinase and the structurally related XA3 receptor, confer immunity to Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial leaf blight. Here we report the isolation of OsSERK2 (rice somatic embryogenesis receptor kinase 2) and demonstrate that OsSERK2 positively regulates immunity mediated by XA21 and XA3 as well as the rice immune receptor FLS2 (OsFLS2). Rice plants silenced for OsSerk2 display altered morphology and reduced sensitivity to the hormone brassinolide. OsSERK2 interacts with the intracellular domains of each immune receptor in the yeast-two-hybrid system in a kinase activity dependent manner. OsSERK2 undergoes bidirectional trans-phosphorylation with XA21 in vitro and forms a constitutive complex with XA21 in vivo. These results demonstrate an essential role for OsSERK2 in the function of three rice immune receptors and suggest that direct interaction with the rice immune receptors is critical for their function. Taken together, our findings suggest that the mechanism of OsSERK2-meditated regulation of rice XA21, XA3 and FLS2 differs from that of AtSERK3/BAK1-mediated regulation of Arabidopsis FLS2 and EFR.

2013-12-25

Simultaneous optogenetic manipulation and calcium imaging in freely moving C. elegans

10.1101/000943

Frederick B. Shipley;Christopher M. Clark;Mark J. Alkema;Andrew M. Leifer;

Editor:\n\nA fundamental goal of systems neuroscience is to probe the dynamics of neural activity that generate behavior. Here we present an instrument to simultaneously manipulate and monitor neural activity and behavior in the freely moving nematode Caenorhabditis elegans. We use the instrument to directly observe the relationship between sensory neuron activation, interneuron dynamics and locomotion in the mechanosensory circuit.\n\nPreviously in this journal, we presented an optogenetic illumination system capable of real-time light delivery with high spatial resolution to stimulate or inhibit specified targets in freely moving C. elegans [1]. This \"Colbert\" system and others like it [2] have been instrumental in defining neural coding of several behaviors in C. elegans including chemotaxis [3], nociception [4] and the escape response [5]. Here we integrate the Colbert s ...

2013-11-27

Simultaneous optogenetic manipulation and calcium imaging in freely moving C. elegans

10.1101/000943

Frederick B. Shipley;Christopher M. Clark;Mark J. Alkema;Andrew M. Leifer;

Editor:\n\nA fundamental goal of systems neuroscience is to probe the dynamics of neural activity that generate behavior. Here we present an instrument to simultaneously manipulate and monitor neural activity and behavior in the freely moving nematode Caenorhabditis elegans. We use the instrument to directly observe the relationship between sensory neuron activation, interneuron dynamics and locomotion in the mechanosensory circuit.\n\nPreviously in this journal, we presented an optogenetic illumination system capable of real-time light delivery with high spatial resolution to stimulate or inhibit specified targets in freely moving C. elegans [1]. This \"Colbert\" system and others like it [2] have been instrumental in defining neural coding of several behaviors in C. elegans including chemotaxis [3], nociception [4] and the escape response [5]. Here we integrate the Colbert s ...

2013-12-01

Simultaneous optogenetic manipulation and calcium imaging in freely moving C. elegans

10.1101/000943

Frederick B. Shipley;Christopher M. Clark;Mark J. Alkema;Andrew M. Leifer;

Editor:\n\nA fundamental goal of systems neuroscience is to probe the dynamics of neural activity that generate behavior. Here we present an instrument to simultaneously manipulate and monitor neural activity and behavior in the freely moving nematode Caenorhabditis elegans. We use the instrument to directly observe the relationship between sensory neuron activation, interneuron dynamics and locomotion in the mechanosensory circuit.\n\nPreviously in this journal, we presented an optogenetic illumination system capable of real-time light delivery with high spatial resolution to stimulate or inhibit specified targets in freely moving C. elegans [1]. This \"Colbert\" system and others like it [2] have been instrumental in defining neural coding of several behaviors in C. elegans including chemotaxis [3], nociception [4] and the escape response [5]. Here we integrate the Colbert s ...

2014-04-02

Analysis of the study of the cerebellar pinceau by Korn and Axelrad

10.1101/001123

Antonin Blot;Boris Barbour;

The axon initial segment of each cerebellar Purkinje cell is ensheathed by basket cell axons in a structure called the pinceau, which is largely devoid of chemical synapses and gap junctions. These facts and ultrastructural similarities with the axon cap of the teleost Mauthner cell led to the conjecture that the pinceau mediates ephaptic (via the extracellular field) inhibition. Korn and Axelrad published a study in 1980 in which they reported confirmation of this conjecture. We have analysed their results and show that most are likely to be explained by an artefactual signal arising from the massive stimulation of parallel fibres they employed. We reproduce their experiments and confirm that all of their results are consistent with this artefact. Their data therefore provide no evidence regarding the operation of the pinceau.

2013-12-03

Influence of walking speed on locomotor time production

10.1101/001156

Fabrice MEGROT;Carole MEGROT;

The aim of the present study was to determine whether or not walking speed affects temporal perception. It was hypothesized that fast walking would reduce the perceived length of time while slow walking increase production estimates. 16 healthy subjects were included. After a first << calibration >> phase allowing the determination of different walking speeds, the subjects were instructed to demonstrate periods of time or << target times >> of 3s and 7s, by a walking movement. Then, subjects were asked to simulate walking by raising one foot after the other without advancing. Finally, a third condition, Motionless, involved producing the target times while standing without movement. The results of this study suggest that movement does influence the perception of time, causing an overestimation of time. In agreement with the results of Denner et al. (1963) the subjects produced times which were longer than the target times.

2013-12-04

Genomic architecture of human neuroanatomical diversity

10.1101/001198

Roberto Toro;Jean-Baptiste Poline;Guillaume Huguet;Eva Loth;Vincent Frouin;Tobias Banaschewski;Gareth J Barker;Arun Bokde;Christian Büchel;Fabiana Carvalho;Patricia Conrod;Mira Fauth-Bühler;Herta Flor;Jürgen Gallinat;Hugh Garavan;Penny Gowloan;Andreas Heinz;Bernd Ittermann;Claire Lawrence;Hervé Lemaître;Karl Mann;Frauke Nees;TomᚠPaus;Zdenka Pausova;Marcella Rietschel;Trevor Robbins;Michael Smolka;Andreas Ströhle;Gunter Schumann;Thomas Bourgeron;

Human brain anatomy is strikingly diverse and highly inheritable: genetic factors may explain up to 80% of its variability. Prior studies have tried to detect genetic variants with a large effect on neuroanatomical diversity, but those currently identified account for <5% of the variance. Here we show, based on our analyses of neuroimaging and whole-genome genotyping data from 1,765 subjects, that up to 54% of this heritability is captured by large numbers of single nucleotide polymorphisms of small effect spread throughout the genome, especially within genes and close regulatory regions. The genetic bases of neuroanatomical diversity appear to be relatively independent of those of body size (height), but shared with those of verbal intelligence scores. The study of this genomic architecture should help us better understand brain evolution and disease.

2013-12-10

Conneconomics: The Economics of Dense, Large-Scale, High-Resolution Neural Connectomics

10.1101/001214

Adam H Marblestone;Evan R Daugharthy;Reza Kalhor;Ian D Peikon;Justus M Kebschull;Seth L Shipman;Yuriy Mishchenko;Je Hyuk Lee;David A Dalrymple;Bradley M Zamft;Konrad P Kording;Edward S Boyden;Anthony M Zador;George M Church;

We analyze the scaling and cost-performance characteristics of current and projected connectomics approaches, with reference to the potential implications of recent advances in diverse contributing fields. Three generalized strategies for dense connectivity mapping at the scale of whole mammalian brains are considered: electron microscopic axon tracing, optical imaging of combinatorial molecular markers at synapses, and bulk DNA sequencing of trans-synaptically exchanged nucleic acid barcode pairs. Due to advances in parallel-beam instrumentation, whole mouse brain electron microscopic image acquisition could cost less than $100 million, with total costs presently limited by image analysis to trace axons through large image stacks. Optical microscopy at 50-100 nm isotropic resolution could potentially read combinatorially multiplexed molecular information from individual synapses, which could indicate the identifies of the pre-synaptic and post-synaptic cells without relying on axon tracing. An optical approach to whole mouse brain connectomics may be achievable for less than $10 million and could be enabled by emerging technologies to sequence nucleic acids in-situ in fixed tissue via fluorescent microscopy. Novel strategies relying on bulk DNA sequencing, which would extract the connectome without direct imaging of the tissue, could produce a whole mouse brain connectome for $100k-$1 million or a mouse cortical connectome for $10k-$100k. Anticipated further reductions in the cost of DNA sequencing could lead to a $1000 mouse cortical connectome.

2013-12-10

Conneconomics: The Economics of Dense, Large-Scale, High-Resolution Neural Connectomics

10.1101/001214

Adam H Marblestone;Evan R Daugharthy;Reza Kalhor;Ian D Peikon;Justus M Kebschull;Seth L Shipman;Yuriy Mishchenko;Je Hyuk Lee;David A Dalrymple;Bradley M Zamft;Konrad P Kording;Edward S Boyden;Anthony M Zador;George M Church;

We analyze the scaling and cost-performance characteristics of current and projected connectomics approaches, with reference to the potential implications of recent advances in diverse contributing fields. Three generalized strategies for dense connectivity mapping at the scale of whole mammalian brains are considered: electron microscopic axon tracing, optical imaging of combinatorial molecular markers at synapses, and bulk DNA sequencing of trans-synaptically exchanged nucleic acid barcode pairs. Due to advances in parallel-beam instrumentation, whole mouse brain electron microscopic image acquisition could cost less than $100 million, with total costs presently limited by image analysis to trace axons through large image stacks. Optical microscopy at 50-100 nm isotropic resolution could potentially read combinatorially multiplexed molecular information from individual synapses, which could indicate the identifies of the pre-synaptic and post-synaptic cells without relying on axon tracing. An optical approach to whole mouse brain connectomics may be achievable for less than $10 million and could be enabled by emerging technologies to sequence nucleic acids in-situ in fixed tissue via fluorescent microscopy. Novel strategies relying on bulk DNA sequencing, which would extract the connectome without direct imaging of the tissue, could produce a whole mouse brain connectome for $100k-$1 million or a mouse cortical connectome for $10k-$100k. Anticipated further reductions in the cost of DNA sequencing could lead to a $1000 mouse cortical connectome.

2013-12-13

Conneconomics: The Economics of Dense, Large-Scale, High-Resolution Neural Connectomics

10.1101/001214

Adam H Marblestone;Evan R Daugharthy;Reza Kalhor;Ian D Peikon;Justus M Kebschull;Seth L Shipman;Yuriy Mishchenko;Je Hyuk Lee;David A Dalrymple;Bradley M Zamft;Konrad P Kording;Edward S Boyden;Anthony M Zador;George M Church;

We analyze the scaling and cost-performance characteristics of current and projected connectomics approaches, with reference to the potential implications of recent advances in diverse contributing fields. Three generalized strategies for dense connectivity mapping at the scale of whole mammalian brains are considered: electron microscopic axon tracing, optical imaging of combinatorial molecular markers at synapses, and bulk DNA sequencing of trans-synaptically exchanged nucleic acid barcode pairs. Due to advances in parallel-beam instrumentation, whole mouse brain electron microscopic image acquisition could cost less than $100 million, with total costs presently limited by image analysis to trace axons through large image stacks. Optical microscopy at 50-100 nm isotropic resolution could potentially read combinatorially multiplexed molecular information from individual synapses, which could indicate the identifies of the pre-synaptic and post-synaptic cells without relying on axon tracing. An optical approach to whole mouse brain connectomics may be achievable for less than $10 million and could be enabled by emerging technologies to sequence nucleic acids in-situ in fixed tissue via fluorescent microscopy. Novel strategies relying on bulk DNA sequencing, which would extract the connectome without direct imaging of the tissue, could produce a whole mouse brain connectome for $100k-$1 million or a mouse cortical connectome for $10k-$100k. Anticipated further reductions in the cost of DNA sequencing could lead to a $1000 mouse cortical connectome.

2013-12-16

Conneconomics: The Economics of Dense, Large-Scale, High-Resolution Neural Connectomics

10.1101/001214

Adam H Marblestone;Evan R Daugharthy;Reza Kalhor;Ian D Peikon;Justus M Kebschull;Seth L Shipman;Yuriy Mishchenko;Je Hyuk Lee;David A Dalrymple;Bradley M Zamft;Konrad P Kording;Edward S Boyden;Anthony M Zador;George M Church;

We analyze the scaling and cost-performance characteristics of current and projected connectomics approaches, with reference to the potential implications of recent advances in diverse contributing fields. Three generalized strategies for dense connectivity mapping at the scale of whole mammalian brains are considered: electron microscopic axon tracing, optical imaging of combinatorial molecular markers at synapses, and bulk DNA sequencing of trans-synaptically exchanged nucleic acid barcode pairs. Due to advances in parallel-beam instrumentation, whole mouse brain electron microscopic image acquisition could cost less than $100 million, with total costs presently limited by image analysis to trace axons through large image stacks. Optical microscopy at 50-100 nm isotropic resolution could potentially read combinatorially multiplexed molecular information from individual synapses, which could indicate the identifies of the pre-synaptic and post-synaptic cells without relying on axon tracing. An optical approach to whole mouse brain connectomics may be achievable for less than $10 million and could be enabled by emerging technologies to sequence nucleic acids in-situ in fixed tissue via fluorescent microscopy. Novel strategies relying on bulk DNA sequencing, which would extract the connectome without direct imaging of the tissue, could produce a whole mouse brain connectome for $100k-$1 million or a mouse cortical connectome for $10k-$100k. Anticipated further reductions in the cost of DNA sequencing could lead to a $1000 mouse cortical connectome.

2014-04-21

Functional connectivity networks with and without global signal correction

10.1101/000968

Satoru Hayasaka;

In functional connectivity analyses in BOLD (blood oxygenation level dependent) fMRI data, there is an ongoing debate on whether to correct global signals in fMRI time series data. Although the discussion has been ongoing in the fMRI community since the early days of fMRI data analyses, this subject has gained renewed attention in recent years due to the surging popularity of functional connectivity analyses, in particular graph theory-based network analyses. However, the impact of correcting (or not correcting) for global signals has not been systematically characterized in the context of network analyses. Thus, in this work, I examined the effect of global signal correction on an fMRI network analysis. In particular, voxel-based resting-state fMRI networks were constructed with and without global signal correction. The resulting functional connectivity networks were compared. Without global signal correction, the distributions of the correlation coefficients were positively biased. I also found that, without global signal correction, nodes along the interhemisphic fissure were highly connected whereas some nodes and subgraphs around white-matter tracts became disconnected from the rest of the network. These results from this study show differences between the networks with or without global signal correction.

2013-11-26

Functional connectivity networks with and without global signal correction

10.1101/000968

Satoru Hayasaka;

In functional connectivity analyses in BOLD (blood oxygenation level dependent) fMRI data, there is an ongoing debate on whether to correct global signals in fMRI time series data. Although the discussion has been ongoing in the fMRI community since the early days of fMRI data analyses, this subject has gained renewed attention in recent years due to the surging popularity of functional connectivity analyses, in particular graph theory-based network analyses. However, the impact of correcting (or not correcting) for global signals has not been systematically characterized in the context of network analyses. Thus, in this work, I examined the effect of global signal correction on an fMRI network analysis. In particular, voxel-based resting-state fMRI networks were constructed with and without global signal correction. The resulting functional connectivity networks were compared. Without global signal correction, the distributions of the correlation coefficients were positively biased. I also found that, without global signal correction, nodes along the interhemisphic fissure were highly connected whereas some nodes and subgraphs around white-matter tracts became disconnected from the rest of the network. These results from this study show differences between the networks with or without global signal correction.

2013-12-19

Embodied cognition, embodied regulation, and the Data Rate Theorem

10.1101/001586

Rodrick Wallace;

The Data Rate Theorem carries deep implications for theories of embodied cognition, extensions providing a spectrum of necessary conditions dynamic statistical models useful in empirical studies. A large deviations argument, however, implies that the regulation and stabilization of such systems is itself an interpenetrating phenomenon necessarily convoluted with embodied cognition. For humans, the central regulatory role of culture has long been known. Although a ground-state collapse analogous to generalized anxiety appears ubiquitous to such systems, lack of cultural modulation in real-time automatons or distributed cognition man-machine cockpits makes them subject to a pathology under which all possible targets are enemies.

2013-12-23

Embodied cognition, embodied regulation, and the Data Rate Theorem

10.1101/001586

Rodrick Wallace;

The Data Rate Theorem carries deep implications for theories of embodied cognition, extensions providing a spectrum of necessary conditions dynamic statistical models useful in empirical studies. A large deviations argument, however, implies that the regulation and stabilization of such systems is itself an interpenetrating phenomenon necessarily convoluted with embodied cognition. For humans, the central regulatory role of culture has long been known. Although a ground-state collapse analogous to generalized anxiety appears ubiquitous to such systems, lack of cultural modulation in real-time automatons or distributed cognition man-machine cockpits makes them subject to a pathology under which all possible targets are enemies.

2014-01-13

Hippocampal Motifs

10.1101/001636

Zahra Aghajan;Lavanya Acharya;Jesse Cushman;Cliff Vuong;Jason Moore;Mayank Mehta;

Dorsal Hippocampal neurons provide an allocentric map of space1, characterized by three key properties. First, their firing is spatially selective1-3, termed a rate code. Second, as animals traverse through place fields, neurons sustain elevated firing rates for long periods, however this has received little attention. Third the theta-phase of spikes within this sustained activity varies with animals location, termed phase-precession or a temporal code4-10. The precise relationship between these properties and the mechanisms governing them are not understood, although distal visual cues (DVC) are thought to be sufficient to reliably elicit them2,3. Hence, we measured rat CA1 neurons activity during random foraging in two-dimensional VR--where only DVC provide consistent allocentric location information-- and compared it with their activity in real world (RW). Surprisingly, we found little spatial selectivity in VR. This is in sharp contrast to robust spatial selectivity commonly seen in one-dimensional RW and VR7-11, or two-dimensional RW1-3. Despite this, neurons in VR generated approximately two-second long phase precessing spike sequences, termed \"hippocampal motifs\". Motifs, and \"Motif-fields\", an aggregation of all motifs of a neuron, had qualitatively similar properties including theta-scale temporal coding in RW and VR, but the motifs were far less spatially localized in VR. These results suggest that intrinsic, network mechanisms generate temporally coded hippocampal motifs, which can be dissociated from their spatial selectivity. Further, DVC alone are insufficient to localize motifs spatially to generate a robust rate code.

2013-12-31

Water and the biology of *prions* and plaques

10.1101/000224

Graham K Steel;Phillippa M Wiggins;n/a n/a;

This is an attempt to account for the insolubility and/or aggregation of prions and plaques in terms of a model of water consisting of an equilibrium between high density and low density microdomains. Hydrophobic molecules, including proteins, accumulate selectively into stable populations, enriched in high density water, at charged sites on biopolymers. In enriched high density water, proteins are probably partially unfolded and may precipitate out when released. All extracellular matrices contain such charged polymers. Prions, which have been shown to accumulate in soils and clays containing silicates and aluminates also probably accumulate in extracellular matrices.\n\nRelease of proteins follows hydrolysis of the charged groups by highly reactive high density water. This is normally a slow process but is greatly accelerated by urea. Plaques may form with age and disease because of accumulation of urea and, perhaps, glucose in the blood. This favours precipitation of proteins emerging from matrices, rather than refolding and solution. Dialysis should, therefore, interfere with plaque formation and impede the development of some age-related diseases.

2013-11-12

Differentiation-dependent telomeric long non-coding transcription in a model of skeletal myogenesis

10.1101/000679

Scott Brouilette;Samir Ounzain;Vinit Sawhney;Kenta Yashiro;Yasunori Shintani;Kunihiko Takahashi;Steven Coppen;Takuya Narita;Kelli Torsney;Martin Carrier;Niall Campbell;Ken Suzuki;

Telomeres comprise the distal ends of eukaryotic chromosomes, serve to maintain genomic integrity and are extended by the ribonucleoprotein telomerase. Recent evidence indicates that telomeres are transcribed to generate long non-coding RNAs (lncRNAs) and that these transcripts (TERRA) may inhibit telomerase activity. In this study we assessed telomerase activity and telomeric lncRNA expression in a mouse model of skeletal myogenesis. Using the C2C12 cell line we demonstrated decreased telomerase activity during differentiation into terminally-differentiated skeletal myotubes. Despite existing in a post-mitotic state, residual telomerase activity remained in C2C12 myotubes, indicating a role independent of telomere extension. Telomeric transcripts were detected in both myoblasts and myotubes, with reduced expression during differentiation correlating with reduced telomerase expression. Our data indicate that in a mouse model of skeletal myogenesis TERRA expression does not reduce telomerase activity, suggesting that their relationship is more complex than originally perceived; the role of telomeric derived lncRNAs in relation to telomerase activity may be cell-type specific. These findings raise the possibility for novel non-telomerase regulatory function for TERRA-lncRNAs during skeletal myogenesis.

2013-11-18

Virulence in a Pseudomonas syringae Strain with a Small Repertoire of Predicted Effectors

10.1101/000869

Kevin L Hockett;Marc T Nishimura;Erick Karlsrud;Kevin Dougherty;David A Baltrus;

Both type III effector proteins and non-ribosomal peptide toxins play important roles for Pseudomonas syringae pathogenicity in host plants, but whether and how these virulence pathways interact to promote infection remains unclear. Genomic evidence from one clade of P. syringae suggests a tradeoff between the total number of type III effector proteins and presence of syringomycin, syringopeptin, and syringolin A toxins. Here we report the complete genome sequence from P. syringae CC1557, which contains the lowest number of known type III effectors to date and has also acquired genes similar to sequences encoding syringomycin pathways from other strains. We demonstrate that this strain is pathogenic on Nicotiana benthamiana and that both the type III secretion system and a new type III effector family, hopBJ1, contribute to virulence. We further demonstrate that virulence activity of HopBJ1 is dependent on similar catalytic sites as the E. coli CNF1 toxin. Taken together, our results provide additional support for a negative correlation between type III effector repertoires and the potential to produce syringomycin-like toxins while also highlighting how genomic synteny and bioinformatics can be used to identify and characterize novel virulence proteins.

2013-11-23

Virulence in a Pseudomonas syringae Strain with a Small Repertoire of Predicted Effectors

10.1101/000869

Kevin L Hockett;Marc T Nishimura;Erick Karlsrud;Kevin Dougherty;David A Baltrus;

Both type III effector proteins and non-ribosomal peptide toxins play important roles for Pseudomonas syringae pathogenicity in host plants, but whether and how these virulence pathways interact to promote infection remains unclear. Genomic evidence from one clade of P. syringae suggests a tradeoff between the total number of type III effector proteins and presence of syringomycin, syringopeptin, and syringolin A toxins. Here we report the complete genome sequence from P. syringae CC1557, which contains the lowest number of known type III effectors to date and has also acquired genes similar to sequences encoding syringomycin pathways from other strains. We demonstrate that this strain is pathogenic on Nicotiana benthamiana and that both the type III secretion system and a new type III effector family, hopBJ1, contribute to virulence. We further demonstrate that virulence activity of HopBJ1 is dependent on similar catalytic sites as the E. coli CNF1 toxin. Taken together, our results provide additional support for a negative correlation between type III effector repertoires and the potential to produce syringomycin-like toxins while also highlighting how genomic synteny and bioinformatics can be used to identify and characterize novel virulence proteins.

2014-04-21

High Genetic Diversity and Adaptive Potential of Two Simian Hemorrhagic Fever Viruses in a Wild Primate Population

10.1101/001040

Adam L. Bailey;Michael Lauck;Andrea Weiler;Samuel D. Sibley;Jorge M. Dinis;Zachary Bergman;Chase W. Nelson;Michael Correll;Michael Gleicher;David Hyeroba;Alex Tumukunde;Geoffrey Weny;Colin Chapman;Jens Kuhn;Austin Hughes;Thomas C. Friedrich;Tony L. Goldberg;David H. O'Connor;

Key biological properties such as high genetic diversity and high evolutionary rate enhance the potential of certain RNA viruses to adapt and emerge. Identifying viruses with these properties in their natural hosts could dramatically improve disease forecasting and surveillance. Recently, we discovered two novel members of the viral family Arteriviridae: simian hemorrhagic fever virus (SHFV)-krc1 and SHFV-krc2, infecting a single wild red colobus (Procolobus rufomitratus tephrosceles) in Kibale National Park, Uganda. Nearly nothing is known about the biological properties of SHFVs in nature, although the SHFV type strain, SHFV-LVR, has caused devastating outbreaks of viral hemorrhagic fever in captive macaques. Here we detected SHFV-krc1 and SHFV-krc2 in 40% and 47% of 60 wild red colobus tested, respectively. We found viral loads in excess of 106 - 107 RNA copies per milliliter of blood plasma for each of these viruses. SHFV-krc1 and SHFV-krc2 also showed high genetic diversity at both the inter- and intra-host levels. Analyses of synonymous and non-synonymous nucleotide diversity across viral genomes revealed patterns suggestive of positive selection in SHFV open reading frames (ORF) 5 (SHFV-krc2 only) and 7 (SHFV-krc1 and SHFV-krc2). Thus, these viruses share several important properties with some of the most rapidly evolving, emergent RNA viruses.

2013-12-03

Extensive Phenotypic Changes Associated with Large-scale Horizontal Gene Transfer

10.1101/001362

Kevin Dougherty;Brian A Smith;Autum F Moore;Shannon Maitland;Chris Fanger;Rachel Murillo;David A Baltrus;

Horizontal gene transfer often leads to phenotypic changes within recipient organisms independent of any immediate evolutionary benefits. While secondary phenotypic effects of horizontal transfer (i.e. changes in growth rates) have been demonstrated and studied across a variety of systems using relatively small plasmid and phage, little is known about how size of the acquired region affects the magnitude or number of such costs. Here we describe an amazing breadth of phenotypic changes which occur after a large-scale horizontal transfer event (~1Mb megaplasmid) within Pseudomonas stutzeri including sensitization to various stresses as well as changes in bacterial behavior. These results highlight the power of horizontal transfer to shift pleiotropic relationships and cellular networks within bacterial genomes. They also provide an important context for how secondary effects of transfer can bias evolutionary trajectories and interactions between species. Lastly, these results and system provide a foundation to investigate evolutionary consequences in real time as newly acquired regions are ameliorated and integrated into new genomic contexts.

2013-12-12

Lack of evidence for the presence of an interferon in invertebrate

10.1101/000513

Pei-Hui Wang;

In vertebrates, the interferon (IFN) response is the primary form of innate antiviral defense. Previously (2005), a partial cDNA which could encode an interferon-like protein (IntlP) is reported in shrimp, later Rosa et al. (2008) argue that this partial cDNA should encode a portion of insect mitochondrial ATP synthase (MAS) B-chain. Recently (2009), it is demonstrated IntlP also possess antibacterial activity beside antiviral activity reported before. Lacking of a consensus opinion to the question of whether this gene encodes IntlP or MAS, we try to provide more evidences to identify this gene exactly. Here we obtain the full length cDNAs of IntlP/ MAS in Litopenaeus vannamei, and perform the tissue distribution and induced expression analysis. Our results confirm that IntlP is coded by a mistaken ORF and the actual protein indeed is a L. vannamei mitochondrial ATP synthase (LvMAS) whose function is unknown in antiviral responses.

2013-11-16

Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders

10.1101/000604

Claudiu I Bandea;

Despite decades of research, thousands of studies and numerous advances, the etiologies of Alzheimers Disease (AD), Parkinsons Disease (PD), Huntingtons Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration (FTLD-U), Creutzfeldt-Jakob Disease (CJD), Reactive Systemic Amyloidosis (RSA) and many other neurodegenerative and systemic amyloid diseases have not been defined, nor have the pathogenic mechanisms leading to cellular death and disease. Moreover, the biological functions of APP/amyloid-{beta} (A{beta}), tau, -synuclein, huntingtin, TAR DNA-binding protein 43 (TDP-43), prion protein (PrP), amyloid A (AA) and some of the other primary proteins implicated in amyloid diseases are not known. And, there are no successful preventive or therapeutic approaches. Based on a comprehensive analysis and new interpretation of the existing data in context of an evolutionary framework, it is proposed that: (i) A{beta}, tau, -synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system, (ii) the isomeric conformational changes of these proteins and their assembly into various oligomers, plaques, and tangles are not protein misfolding events as defined for decades, nor are they prion-replication activities, but part of their normal, evolutionarily selected innate immune repertoire, and (iii) the immune reactions and activities associated with the function of these proteins in innate immunity lead to AD, PD, HD, ALS, CJD, RSA and other related diseases, which are innate immunity disorders.

2013-11-18

Genomics via Optical Mapping (I): 0-1 Laws for Mapping with Single Molecules

10.1101/000844

Thomas Anantharaman;Bud (Bhubaneswar) Mishra;

The genomic data that can be collected from a single DNA molecule by the best chemical and optical methods (e.g., using technologies from OpGen, BioNanoGenomics, NABSys, PacBio, etc.) are badly corrupted by many poorly understood noise processes. Thus, single molecule technology derives its utility through powerful probabilistic modeling, which can provide precise lower and upper bounds on various experimental parameters to create the correct map or validate sequence assembly. As an example, this analysis shows how as the number of \"imaged\" single molecules (i.e., coverage) is increased in the optical mapping data, the probability of successful computation of the map jumps from 0 to 1 for fairly small number of molecules.

2013-11-22

The-LHON-Enigma: explaining the behaviour of Leber&amp;#146;s Hereditary Optic Neuropathy by the use of a simple computer model

10.1101/000935

IAN S Logan;

Lebers Hereditary Optic Neuropathy (LHON) appears as an enigmatic condition; affecting only certain families and often causing a severe loss of vision seemingly at random amongst family members. The first breakthrough came in 1988 with the linking of the condition to a mutation in the mitochondrial DNA (mtDNA). Now it is known that about 90% of cases are linked to 3 mutations. In this paper the hypothesis is suggested that a LHON mutation decreases the function of the mitochondrial enzyme, Complex I, by 50% and this alone critically endangers the survival of cells - especially the fragile cells of the optic nerves. A computer model has been written to illustrate how the hypothesis can produce a natural history for the condition of LHON that has features similar to those observed in practice; thereby successfully explaining the behaviour of this enigmatic condition.

2013-11-25

Routes for breaching and protecting genetic privacy

10.1101/000042

Yaniv Erlich;Arvind Narayanan;

We are entering the era of ubiquitous genetic information for research, clinical care, and personal curiosity. Sharing these datasets is vital for rapid progress in understanding the genetic basis of human diseases. However, one growing concern is the ability to protect the genetic privacy of the data originators. Here, we technically map threats to genetic privacy and discuss potential mitigation strategies for privacy-preserving dissemination of genetic data.\n\nAbout the AuthorsYaniv Erlich is a Fellow at the Whitehead Institute for Biomedical Research. Erlich received his Ph.D. from Cold Spring Harbor Laboratory in 2010 and B.Sc. from Tel-Aviv University in 2006. Prior to that, Erlich worked in computer security and was responsible for conducting penetration tests on financial institutes and commercial companies. Dr. Erlichs research involves developing new algorithms for computational human genetics.\n\nArvind Narayanan is an Assistant Professor in the Department of Computer Science and the Center for Information Technology and Policy at Princeton. He studies information privacy and security. His research has shown that data anonymization is broken in fundamental ways, for which he jointly received the 2008 Privacy Enhancing Technologies Award. His current research interests include building a platform for privacy-preserving data sharing.\n\nSummaryO_LIBroad data dissemination is essential for advancements in genetics, but also brings to light concerns regarding privacy.\nC_LIO_LIPrivacy breaching techniques work by cross-referencing two or more pieces of information to gain new, potentially undesirable knowledge on individuals or their families.\nC_LIO_LIBroadly speaking, the main routes to breach privacy are identity tracing, attribute disclosure, and completion of sensitive DNA information.\nC_LIO_LIIdentity tracing exploits quasi-identifiers in the DNA data or metadata to uncover the identity of an unknown genetic dataset.\nC_LIO_LIAttribute disclosure techniques work on known DNA datasets. They use the DNA information to link the identity of a person with a sensitive phenotype.\nC_LIO_LICompletion techniques also work on known DNA data. They try to uncover sensitive genomic areas that were masked to protect the participant.\nC_LIO_LIIn the last few years, we have witnessed a rapid growth in the range of techniques and tools to conduct these privacy-breaching attacks. Currently, most of the techniques are beyond the reach of the general public, but can be executed by trained persons with varying degrees of effort.\nC_LIO_LIThere is considerable debate regarding risk management. One camp supports a pragmatic, ad-hoc approach of privacy by obscurity and the other supports a systematic, mathematically-backed approach of privacy by design.\nC_LIO_LIPrivacy by design algorithms include access control, differential privacy, and cryptographic techniques. So far, data custodians of genetic databases mainly adopted access control as a mitigation strategy.\nC_LIO_LINew developments in cryptographic techniques may usher in an additional arsenal of security by design techniques.\nC_LI

2013-11-07

Routes for breaching and protecting genetic privacy

10.1101/000042

Yaniv Erlich;Arvind Narayanan;

We are entering the era of ubiquitous genetic information for research, clinical care, and personal curiosity. Sharing these datasets is vital for rapid progress in understanding the genetic basis of human diseases. However, one growing concern is the ability to protect the genetic privacy of the data originators. Here, we technically map threats to genetic privacy and discuss potential mitigation strategies for privacy-preserving dissemination of genetic data.\n\nAbout the AuthorsYaniv Erlich is a Fellow at the Whitehead Institute for Biomedical Research. Erlich received his Ph.D. from Cold Spring Harbor Laboratory in 2010 and B.Sc. from Tel-Aviv University in 2006. Prior to that, Erlich worked in computer security and was responsible for conducting penetration tests on financial institutes and commercial companies. Dr. Erlichs research involves developing new algorithms for computational human genetics.\n\nArvind Narayanan is an Assistant Professor in the Department of Computer Science and the Center for Information Technology and Policy at Princeton. He studies information privacy and security. His research has shown that data anonymization is broken in fundamental ways, for which he jointly received the 2008 Privacy Enhancing Technologies Award. His current research interests include building a platform for privacy-preserving data sharing.\n\nSummaryO_LIBroad data dissemination is essential for advancements in genetics, but also brings to light concerns regarding privacy.\nC_LIO_LIPrivacy breaching techniques work by cross-referencing two or more pieces of information to gain new, potentially undesirable knowledge on individuals or their families.\nC_LIO_LIBroadly speaking, the main routes to breach privacy are identity tracing, attribute disclosure, and completion of sensitive DNA information.\nC_LIO_LIIdentity tracing exploits quasi-identifiers in the DNA data or metadata to uncover the identity of an unknown genetic dataset.\nC_LIO_LIAttribute disclosure techniques work on known DNA datasets. They use the DNA information to link the identity of a person with a sensitive phenotype.\nC_LIO_LICompletion techniques also work on known DNA data. They try to uncover sensitive genomic areas that were masked to protect the participant.\nC_LIO_LIIn the last few years, we have witnessed a rapid growth in the range of techniques and tools to conduct these privacy-breaching attacks. Currently, most of the techniques are beyond the reach of the general public, but can be executed by trained persons with varying degrees of effort.\nC_LIO_LIThere is considerable debate regarding risk management. One camp supports a pragmatic, ad-hoc approach of privacy by obscurity and the other supports a systematic, mathematically-backed approach of privacy by design.\nC_LIO_LIPrivacy by design algorithms include access control, differential privacy, and cryptographic techniques. So far, data custodians of genetic databases mainly adopted access control as a mitigation strategy.\nC_LIO_LINew developments in cryptographic techniques may usher in an additional arsenal of security by design techniques.\nC_LI

2013-11-11

Routes for breaching and protecting genetic privacy

10.1101/000042

Yaniv Erlich;Arvind Narayanan;

We are entering the era of ubiquitous genetic information for research, clinical care, and personal curiosity. Sharing these datasets is vital for rapid progress in understanding the genetic basis of human diseases. However, one growing concern is the ability to protect the genetic privacy of the data originators. Here, we technically map threats to genetic privacy and discuss potential mitigation strategies for privacy-preserving dissemination of genetic data.\n\nAbout the AuthorsYaniv Erlich is a Fellow at the Whitehead Institute for Biomedical Research. Erlich received his Ph.D. from Cold Spring Harbor Laboratory in 2010 and B.Sc. from Tel-Aviv University in 2006. Prior to that, Erlich worked in computer security and was responsible for conducting penetration tests on financial institutes and commercial companies. Dr. Erlichs research involves developing new algorithms for computational human genetics.\n\nArvind Narayanan is an Assistant Professor in the Department of Computer Science and the Center for Information Technology and Policy at Princeton. He studies information privacy and security. His research has shown that data anonymization is broken in fundamental ways, for which he jointly received the 2008 Privacy Enhancing Technologies Award. His current research interests include building a platform for privacy-preserving data sharing.\n\nSummaryO_LIBroad data dissemination is essential for advancements in genetics, but also brings to light concerns regarding privacy.\nC_LIO_LIPrivacy breaching techniques work by cross-referencing two or more pieces of information to gain new, potentially undesirable knowledge on individuals or their families.\nC_LIO_LIBroadly speaking, the main routes to breach privacy are identity tracing, attribute disclosure, and completion of sensitive DNA information.\nC_LIO_LIIdentity tracing exploits quasi-identifiers in the DNA data or metadata to uncover the identity of an unknown genetic dataset.\nC_LIO_LIAttribute disclosure techniques work on known DNA datasets. They use the DNA information to link the identity of a person with a sensitive phenotype.\nC_LIO_LICompletion techniques also work on known DNA data. They try to uncover sensitive genomic areas that were masked to protect the participant.\nC_LIO_LIIn the last few years, we have witnessed a rapid growth in the range of techniques and tools to conduct these privacy-breaching attacks. Currently, most of the techniques are beyond the reach of the general public, but can be executed by trained persons with varying degrees of effort.\nC_LIO_LIThere is considerable debate regarding risk management. One camp supports a pragmatic, ad-hoc approach of privacy by obscurity and the other supports a systematic, mathematically-backed approach of privacy by design.\nC_LIO_LIPrivacy by design algorithms include access control, differential privacy, and cryptographic techniques. So far, data custodians of genetic databases mainly adopted access control as a mitigation strategy.\nC_LIO_LINew developments in cryptographic techniques may usher in an additional arsenal of security by design techniques.\nC_LI

2013-12-01

Generation of high-resolution a priori Y-chromosome phylogenies using &amp;#147;next-generation&amp;#148; sequencing data

10.1101/000802

Gregory R Magoon;Raymond H Banks;Christian Rottensteiner;Bonnie E Schrack;Vincent O Tilroe;Terry Robb;Andrew J Grierson;

An approach for generating high-resolution a priori maximum parsimony Y-chromosome (chrY) phylogenies based on SNP and small INDEL variant data from massively-parallel short-read (next-generation) sequencing data is described; the tree-generation methodology produces annotations localizing mutations to individual branches of the tree, along with indications of mutation placement uncertainty in cases for which \"no-calls\" (through lack of mapped reads or otherwise) at particular site precludes a precise placement of the mutation. The approach leverages careful variant site filtering and a novel iterative reweighting procedure to generate high-accuracy trees while considering variants in regions of chrY that had previously been excluded from analyses based on short-read sequencing data. It is argued that the proposed approach is also superior to previous region-based filtering approaches in that it adapts to the quality of the underlying data and will automatically allow the scope of sites considered to expand as the underlying data quality improves (e.g. through longer read lengths). Key related issues, including calling of genotypes for the hemizygous chrY, reliability of variant results, read mismappings and \"heterozygous\" genotype calls, and the mutational stability of different variants are discussed and taken into account. The methodology is demonstrated through application to a dataset consisting of 1292 male samples from diverse populations and haplogroups, with the majority coming from low-coverage sequencing by the 1000 Genomes Project. Application of the tree-generation approach to these data produces a tree involving over 120,000 chrY variant sites (about 45,000 sites if singletons are excluded). The utility of this approach in refining the Y-chromosome phylogenetic tree is demonstrated by examining results for several haplogroups. The results indicate a number of new branches on the Y-chromosome phylogenetic tree, many of them subdividing known branches, but also including some that inform the presence of additional levels along the trunk of the tree. Finally, opportunities for extensions of this phylogenetic analysis approach to other types of genetic data are examined.

2013-11-22

Generation of high-resolution a priori Y-chromosome phylogenies using &amp;#147;next-generation&amp;#148; sequencing data

10.1101/000802

Gregory R Magoon;Raymond H Banks;Christian Rottensteiner;Bonnie E Schrack;Vincent O Tilroe;Terry Robb;Andrew J Grierson;

An approach for generating high-resolution a priori maximum parsimony Y-chromosome (chrY) phylogenies based on SNP and small INDEL variant data from massively-parallel short-read (next-generation) sequencing data is described; the tree-generation methodology produces annotations localizing mutations to individual branches of the tree, along with indications of mutation placement uncertainty in cases for which \"no-calls\" (through lack of mapped reads or otherwise) at particular site precludes a precise placement of the mutation. The approach leverages careful variant site filtering and a novel iterative reweighting procedure to generate high-accuracy trees while considering variants in regions of chrY that had previously been excluded from analyses based on short-read sequencing data. It is argued that the proposed approach is also superior to previous region-based filtering approaches in that it adapts to the quality of the underlying data and will automatically allow the scope of sites considered to expand as the underlying data quality improves (e.g. through longer read lengths). Key related issues, including calling of genotypes for the hemizygous chrY, reliability of variant results, read mismappings and \"heterozygous\" genotype calls, and the mutational stability of different variants are discussed and taken into account. The methodology is demonstrated through application to a dataset consisting of 1292 male samples from diverse populations and haplogroups, with the majority coming from low-coverage sequencing by the 1000 Genomes Project. Application of the tree-generation approach to these data produces a tree involving over 120,000 chrY variant sites (about 45,000 sites if singletons are excluded). The utility of this approach in refining the Y-chromosome phylogenetic tree is demonstrated by examining results for several haplogroups. The results indicate a number of new branches on the Y-chromosome phylogenetic tree, many of them subdividing known branches, but also including some that inform the presence of additional levels along the trunk of the tree. Finally, opportunities for extensions of this phylogenetic analysis approach to other types of genetic data are examined.

2013-11-24

Generation of high-resolution a priori Y-chromosome phylogenies using &amp;#147;next-generation&amp;#148; sequencing data

10.1101/000802

Gregory R Magoon;Raymond H Banks;Christian Rottensteiner;Bonnie E Schrack;Vincent O Tilroe;Terry Robb;Andrew J Grierson;

An approach for generating high-resolution a priori maximum parsimony Y-chromosome (chrY) phylogenies based on SNP and small INDEL variant data from massively-parallel short-read (next-generation) sequencing data is described; the tree-generation methodology produces annotations localizing mutations to individual branches of the tree, along with indications of mutation placement uncertainty in cases for which \"no-calls\" (through lack of mapped reads or otherwise) at particular site precludes a precise placement of the mutation. The approach leverages careful variant site filtering and a novel iterative reweighting procedure to generate high-accuracy trees while considering variants in regions of chrY that had previously been excluded from analyses based on short-read sequencing data. It is argued that the proposed approach is also superior to previous region-based filtering approaches in that it adapts to the quality of the underlying data and will automatically allow the scope of sites considered to expand as the underlying data quality improves (e.g. through longer read lengths). Key related issues, including calling of genotypes for the hemizygous chrY, reliability of variant results, read mismappings and \"heterozygous\" genotype calls, and the mutational stability of different variants are discussed and taken into account. The methodology is demonstrated through application to a dataset consisting of 1292 male samples from diverse populations and haplogroups, with the majority coming from low-coverage sequencing by the 1000 Genomes Project. Application of the tree-generation approach to these data produces a tree involving over 120,000 chrY variant sites (about 45,000 sites if singletons are excluded). The utility of this approach in refining the Y-chromosome phylogenetic tree is demonstrated by examining results for several haplogroups. The results indicate a number of new branches on the Y-chromosome phylogenetic tree, many of them subdividing known branches, but also including some that inform the presence of additional levels along the trunk of the tree. Finally, opportunities for extensions of this phylogenetic analysis approach to other types of genetic data are examined.

2013-12-12

Generation of high-resolution a priori Y-chromosome phylogenies using &amp;#147;next-generation&amp;#148; sequencing data

10.1101/000802

Gregory R Magoon;Raymond H Banks;Christian Rottensteiner;Bonnie E Schrack;Vincent O Tilroe;Terry Robb;Andrew J Grierson;

An approach for generating high-resolution a priori maximum parsimony Y-chromosome (chrY) phylogenies based on SNP and small INDEL variant data from massively-parallel short-read (next-generation) sequencing data is described; the tree-generation methodology produces annotations localizing mutations to individual branches of the tree, along with indications of mutation placement uncertainty in cases for which \"no-calls\" (through lack of mapped reads or otherwise) at particular site precludes a precise placement of the mutation. The approach leverages careful variant site filtering and a novel iterative reweighting procedure to generate high-accuracy trees while considering variants in regions of chrY that had previously been excluded from analyses based on short-read sequencing data. It is argued that the proposed approach is also superior to previous region-based filtering approaches in that it adapts to the quality of the underlying data and will automatically allow the scope of sites considered to expand as the underlying data quality improves (e.g. through longer read lengths). Key related issues, including calling of genotypes for the hemizygous chrY, reliability of variant results, read mismappings and \"heterozygous\" genotype calls, and the mutational stability of different variants are discussed and taken into account. The methodology is demonstrated through application to a dataset consisting of 1292 male samples from diverse populations and haplogroups, with the majority coming from low-coverage sequencing by the 1000 Genomes Project. Application of the tree-generation approach to these data produces a tree involving over 120,000 chrY variant sites (about 45,000 sites if singletons are excluded). The utility of this approach in refining the Y-chromosome phylogenetic tree is demonstrated by examining results for several haplogroups. The results indicate a number of new branches on the Y-chromosome phylogenetic tree, many of them subdividing known branches, but also including some that inform the presence of additional levels along the trunk of the tree. Finally, opportunities for extensions of this phylogenetic analysis approach to other types of genetic data are examined.

2013-12-13

Bayesian inference of infectious disease transmission from whole genome sequence data

10.1101/001388

Xavier Didelot;Jennifer Gardy;Caroline Colijn;

Genomics is increasingly being used to investigate disease outbreaks, but an important question remains unanswered - how well do genomic data capture known transmission events, particularly for pathogens with long carriage periods or large within-host population sizes? Here we present a novel Bayesian approach to reconstruct densely-sampled outbreaks from genomic data whilst considering within-host diversity. We infer a time-labelled phylogeny using BEAST, then infer a transmission network via a Monte-Carlo Markov Chain. We find that under a realistic model of within-host evolution, reconstructions of simulated outbreaks contain substantial uncertainty even when genomic data reflect a high substitution rate. Reconstruction of a real-world tuberculosis outbreak displayed similar uncertainty, although the correct source case and several clusters of epidemiologically linked cases were identified. We conclude that genomics cannot wholly replace traditional epidemiology, but that Bayesian reconstructions derived from sequence data may form a useful starting point for a genomic epidemiology investigation.

2013-12-16

Massively differential bias between two widely used Illumina library preparation methods for small RNA sequencing

10.1101/001479

Jeanette Baran-Gale;Michael R Erdos;Christina Sison;Alice Young;Emily E Fannin;Peter S Chines;Praveen Sethupathy;

Recent advances in sequencing technology have helped unveil the unexpected complexity and diversity of small RNAs. A critical step in small RNA library preparation for sequencing is the ligation of adapter sequences to both the 5 and 3 ends of small RNAs. Two widely used protocols for small RNA library preparation, Illumina v1.5 and Illumina TruSeq, use different pairs of adapter sequences. In this study, we compare the results of small RNA-sequencing between v1.5 and TruSeq and observe a striking differential bias. Nearly 100 highly expressed microRNAs (miRNAs) are >5-fold differentially detected and 48 miRNAs are >10-fold differentially detected between the two methods of library preparation. In fact, some miRNAs, such as miR-24-3p, are over 30-fold differentially detected. The results are reproducible across different sequencing centers (NIH and UNC) and both major Illumina sequencing platforms, GAIIx and HiSeq. While some level of bias in library preparation is not surprising, the apparent massive differential bias between these two widely used adapter sets is not well appreciated. As increasingly more laboratories transition to the newer TruSeq-based library preparation for small RNAs, researchers should be aware of the extent to which the results may differ from previously published results using v1.5.

2013-12-19

The causal meaning of genomic predictors and how it affects the construction and comparison of genome-enabled selection models

10.1101/001511

Bruno D Valente;Gota Morota;Guilherme JM Rosa;Daniel Gianola;Kent Weigel;

The additive genetic effect is arguably the most important quantity inferred in animal and plant breeding analyses. The term effect indicates that it represents causal information, which is different from standard statistical concepts as regression coefficient and association. The process of inferring causal information is also different from standard statistical learning, as the former requires causal (i.e. non-statistical) assumptions and involves extra complexities. Remarkably, the task of inferring genetic effects is largely seen as a standard regression/prediction problem, contradicting its label. This widely accepted analysis approach is by itself insufficient for causal learning, suggesting that causality is not the point for selection. Given this incongruence, it is important to verify if genomic predictors need to represent causal effects to be relevant for selection decisions, especially because applying regression studies to answer causal questions may lead to wrong conclusions. The answer to this question defines if genomic selection models should be constructed aiming maximum genomic predictive ability or aiming identifiability of genetic causal effects. Here, we demonstrate that selection relies on a causal effect from genotype to phenotype, and that genomic predictors are only useful for selection if they distinguish such effect from other sources of association. Conversely, genomic predictors capturing non-causal signals provide information that is less relevant for selection regardless of the resulting predictive ability. Focusing on covariate choice decision, simulated examples are used to show that predictive ability, which is the criterion normally used to compare models, may not indicate the quality of genomic predictors for selection. Additionally, we propose using alternative criteria to construct models aiming for the identification of the genetic causal effects.

2013-12-21

A Population Genetic Signature of Polygenic Local Adaptation

10.1101/000026

Jeremy J Berg;Graham Coop;

Adaptation in response to selection on polygenic phenotypes occurs via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that have undergone local adaptation. Using GWAS data, we estimate the mean additive genetic value for a give phenotype across many populations as simple weighted sums of allele frequencies. We model the expected differentiation of GWAS loci among populations under neutrality to develop simple tests of selection across an arbitrary number of populations with arbitrary population structure. To find support for the role of specific environmental variables in local adaptation we test for correlations with the estimated genetic values. We also develop a general test of local adaptation to identify overdispersion of the estimated genetic values values among populations. This test is a natural generalization of QST /FST comparisons based on GWAS predictions. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles. We apply our tests to the human genome diversity panel dataset using GWAS data for six different traits. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results.

2013-11-07

A Population Genetic Signature of Polygenic Local Adaptation

10.1101/000026

Jeremy J Berg;Graham Coop;

Adaptation in response to selection on polygenic phenotypes occurs via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that have undergone local adaptation. Using GWAS data, we estimate the mean additive genetic value for a give phenotype across many populations as simple weighted sums of allele frequencies. We model the expected differentiation of GWAS loci among populations under neutrality to develop simple tests of selection across an arbitrary number of populations with arbitrary population structure. To find support for the role of specific environmental variables in local adaptation we test for correlations with the estimated genetic values. We also develop a general test of local adaptation to identify overdispersion of the estimated genetic values values among populations. This test is a natural generalization of QST /FST comparisons based on GWAS predictions. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles. We apply our tests to the human genome diversity panel dataset using GWAS data for six different traits. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results.

2014-09-08

Matchmaker, Matchmaker, Make Me a Match: Migration of Populations via Marriages in the Past

10.1101/000257

Sang Hoon Lee;Robyn Ffrancon;Daniel M. Abrams;Beom Jun Kim;Mason A. Porter;

The study of human mobility is both of fundamental importance and of great potential value. For example, it can be leveraged to facilitate efficient city planning and improve prevention strategies when faced with epidemics. The newfound wealth of rich sources of data--including banknote flows, mobile phone records, and transportation data--have led to an explosion of attempts to characterize modern human mobility. Unfortunately, the dearth of comparable historical data makes it much more difficult to study human mobility patterns from the past. In this paper, we present such an analysis: we demonstrate that the data record from Korean family books (called \"jokbo\") can be used to estimate migration patterns via marriages from the past 750 years. We apply two generative models of long-term human mobility to quantify the relevance of geographical information to human marriage records in the data, and we find that the wide variety in the geographical distributions of the clans poses interesting challenges for the direct application of these models. Using the different geographical distributions of clans, we quantify the \"ergodicity\" of clans in terms of how widely and uniformly they have spread across Korea, and we compare these results to those obtained using surname data from the Czech Republic. To examine population flow in more detail, we also construct and examine a population-flow network between regions. Based on the correlation between ergodicity and migration patterns in Korea, we identify two different types of migration patterns: diffusive and convective. We expect the analysis of diffusive versus convective effects in population flows to be widely applicable to the study of mobility and migration patterns across different cultures.

2013-11-12

Matchmaker, Matchmaker, Make Me a Match: Migration of Populations via Marriages in the Past

10.1101/000257

Sang Hoon Lee;Robyn Ffrancon;Daniel M. Abrams;Beom Jun Kim;Mason A. Porter;

The study of human mobility is both of fundamental importance and of great potential value. For example, it can be leveraged to facilitate efficient city planning and improve prevention strategies when faced with epidemics. The newfound wealth of rich sources of data--including banknote flows, mobile phone records, and transportation data--have led to an explosion of attempts to characterize modern human mobility. Unfortunately, the dearth of comparable historical data makes it much more difficult to study human mobility patterns from the past. In this paper, we present such an analysis: we demonstrate that the data record from Korean family books (called \"jokbo\") can be used to estimate migration patterns via marriages from the past 750 years. We apply two generative models of long-term human mobility to quantify the relevance of geographical information to human marriage records in the data, and we find that the wide variety in the geographical distributions of the clans poses interesting challenges for the direct application of these models. Using the different geographical distributions of clans, we quantify the \"ergodicity\" of clans in terms of how widely and uniformly they have spread across Korea, and we compare these results to those obtained using surname data from the Czech Republic. To examine population flow in more detail, we also construct and examine a population-flow network between regions. Based on the correlation between ergodicity and migration patterns in Korea, we identify two different types of migration patterns: diffusive and convective. We expect the analysis of diffusive versus convective effects in population flows to be widely applicable to the study of mobility and migration patterns across different cultures.

2014-05-27

Matchmaker, Matchmaker, Make Me a Match: Migration of Populations via Marriages in the Past

10.1101/000257

Sang Hoon Lee;Robyn Ffrancon;Daniel M. Abrams;Beom Jun Kim;Mason A. Porter;

The study of human mobility is both of fundamental importance and of great potential value. For example, it can be leveraged to facilitate efficient city planning and improve prevention strategies when faced with epidemics. The newfound wealth of rich sources of data--including banknote flows, mobile phone records, and transportation data--have led to an explosion of attempts to characterize modern human mobility. Unfortunately, the dearth of comparable historical data makes it much more difficult to study human mobility patterns from the past. In this paper, we present such an analysis: we demonstrate that the data record from Korean family books (called \"jokbo\") can be used to estimate migration patterns via marriages from the past 750 years. We apply two generative models of long-term human mobility to quantify the relevance of geographical information to human marriage records in the data, and we find that the wide variety in the geographical distributions of the clans poses interesting challenges for the direct application of these models. Using the different geographical distributions of clans, we quantify the \"ergodicity\" of clans in terms of how widely and uniformly they have spread across Korea, and we compare these results to those obtained using surname data from the Czech Republic. To examine population flow in more detail, we also construct and examine a population-flow network between regions. Based on the correlation between ergodicity and migration patterns in Korea, we identify two different types of migration patterns: diffusive and convective. We expect the analysis of diffusive versus convective effects in population flows to be widely applicable to the study of mobility and migration patterns across different cultures.

2014-08-16

Matchmaker, Matchmaker, Make Me a Match: Migration of Populations via Marriages in the Past

10.1101/000257

Sang Hoon Lee;Robyn Ffrancon;Daniel M. Abrams;Beom Jun Kim;Mason A. Porter;

The study of human mobility is both of fundamental importance and of great potential value. For example, it can be leveraged to facilitate efficient city planning and improve prevention strategies when faced with epidemics. The newfound wealth of rich sources of data--including banknote flows, mobile phone records, and transportation data--have led to an explosion of attempts to characterize modern human mobility. Unfortunately, the dearth of comparable historical data makes it much more difficult to study human mobility patterns from the past. In this paper, we present such an analysis: we demonstrate that the data record from Korean family books (called \"jokbo\") can be used to estimate migration patterns via marriages from the past 750 years. We apply two generative models of long-term human mobility to quantify the relevance of geographical information to human marriage records in the data, and we find that the wide variety in the geographical distributions of the clans poses interesting challenges for the direct application of these models. Using the different geographical distributions of clans, we quantify the \"ergodicity\" of clans in terms of how widely and uniformly they have spread across Korea, and we compare these results to those obtained using surname data from the Czech Republic. To examine population flow in more detail, we also construct and examine a population-flow network between regions. Based on the correlation between ergodicity and migration patterns in Korea, we identify two different types of migration patterns: diffusive and convective. We expect the analysis of diffusive versus convective effects in population flows to be widely applicable to the study of mobility and migration patterns across different cultures.

2014-10-16

The evolution of sex differences in disease genetics

10.1101/000414

William P Gilks;Jessica K Abbott;Edward H Morrow;

There are significant differences in the biology of males and females, ranging from biochemical pathways to behavioural responses, which are relevant to modern medicine. Broad-sense heritability estimates differ between the sexes for many common medical disorders, indicating that genetic architecture can be sex-dependent. Recent genome-wide association studies (GWAS) have successfully identified sex-specific and sex-biased effects, where in addition to sex-specific effects on gene expression, twenty-two medical traits have sex-specific or sex-biased loci. Sex-specific genetic architecture of complex traits is also extensively documented in model organisms using genome-wide linkage or association mapping, and in gene disruption studies. The evolutionary origins of sex-specific genetic architecture and sexual dimorphism lie in the fact that males and females share most of their genetic variation yet experience different selection pressures. At the extreme is sexual antagonism, where selection on an allele acts in opposite directions between the sexes. Sexual antagonism has been repeatedly identified via a number of experimental methods in a range of different taxa. Although the molecular basis remains to be identified, mathematical models predict the maintenance of deleterious variants that experience selection in a sex-dependent manner. There are multiple mechanisms by which sexual antagonism and alleles under sex-differential selection could contribute toward the genetics of common, complex disorders. The evidence we review clearly indicates that further research into sex-dependent selection and the sex-specific genetic architecture of diseases would be rewarding. This would be aided by studies of laboratory and wild animal populations, and by modelling sex-specific effects in genome-wide association data with joint, gene-by-sex interaction tests. We predict that even sexually monomorphic diseases may harbour cryptic sex-specific genetic architecture. Furthermore, empirical evidence suggests that investigating sex-dependent epistasis may be especially rewarding. Finally, the prevalent nature of sex-specific genetic architecture in disease offers scope for the development of more effective, sex-specific therapies.\n\nFundingThis work was supported by the European Research Council (WPG and EHM; Starting Grant #280632), a Royal Society University Research Fellowship (EHM), the Swedish Research Council (JKA), and the Volkswagen Foundation (JKA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nCompeting interestsThe authors declare that they have no competing financial interests.

2013-11-14

Human genetics and clinical aspects of neurodevelopmental disorders

10.1101/000687

Gholson J Lyon;Jason O'Rawe;

Introduction Introduction Clinical classifications and the... De novo mutations, germline... Rare and compensatory mutations Current ability / approaches Prenatal diagnosis,... Implications for acceptance,... Conclusions References \"our incomplete studies do not permit actual classification; but it is better to leave things by themselves rather than to force them into classes which have their foundation only on paper\" -- Edouard Seguin (Seguin, 1866)\n\n\"The fundamental mistake which vitiates all work based upon Mendels method is the neglect of ancestry, and the attempt to regard the whole effect upon offspring, produced by a particular parent, as due to the existence in the parent of particular structural c ...

2013-11-18

Human genetics and clinical aspects of neurodevelopmental disorders

10.1101/000687

Gholson J Lyon;Jason O'Rawe;

Introduction Introduction Clinical classifications and the... De novo mutations, germline... Rare and compensatory mutations Current ability / approaches Prenatal diagnosis,... Implications for acceptance,... Conclusions References \"our incomplete studies do not permit actual classification; but it is better to leave things by themselves rather than to force them into classes which have their foundation only on paper\" -- Edouard Seguin (Seguin, 1866)\n\n\"The fundamental mistake which vitiates all work based upon Mendels method is the neglect of ancestry, and the attempt to regard the whole effect upon offspring, produced by a particular parent, as due to the existence in the parent of particular structural c ...

2014-02-20

Human genetics and clinical aspects of neurodevelopmental disorders

10.1101/000687

Gholson J Lyon;Jason O'Rawe;

Introduction Introduction Clinical classifications and the... De novo mutations, germline... Rare and compensatory mutations Current ability / approaches Prenatal diagnosis,... Implications for acceptance,... Conclusions References \"our incomplete studies do not permit actual classification; but it is better to leave things by themselves rather than to force them into classes which have their foundation only on paper\" -- Edouard Seguin (Seguin, 1866)\n\n\"The fundamental mistake which vitiates all work based upon Mendels method is the neglect of ancestry, and the attempt to regard the whole effect upon offspring, produced by a particular parent, as due to the existence in the parent of particular structural c ...

2014-06-22

Human genetics and clinical aspects of neurodevelopmental disorders

10.1101/000687

Gholson J Lyon;Jason O'Rawe;

Introduction Introduction Clinical classifications and the... De novo mutations, germline... Rare and compensatory mutations Current ability / approaches Prenatal diagnosis,... Implications for acceptance,... Conclusions References \"our incomplete studies do not permit actual classification; but it is better to leave things by themselves rather than to force them into classes which have their foundation only on paper\" -- Edouard Seguin (Seguin, 1866)\n\n\"The fundamental mistake which vitiates all work based upon Mendels method is the neglect of ancestry, and the attempt to regard the whole effect upon offspring, produced by a particular parent, as due to the existence in the parent of particular structural c ...

2014-10-06

Variational Inference of Population Structure in Large SNP Datasets

10.1101/001073

Anil Raj;Matthew Stephens;Jonathan K Pritchard;

Tools for estimating population structure from genetic data are now used in a wide variety of applications in population genetics. However, inferring population structure in large modern data sets imposes severe computational challenges. Here, we develop efficient algorithms for approximate inference of the model underlying the STRUCTURE program using a variational Bayesian framework. Variational methods pose the problem of computing relevant posterior distributions as an optimization problem, allowing us to build on recent advances in optimization theory to develop fast inference tools. In addition, we propose useful heuristic scores to identify the number of populations represented in a dataset and a new hierarchical prior to detect weak population structure in the data. We test the variational algorithms on simulated data, and illustrate using genotype data from the CEPH-Human Genome Diversity Panel. The variational algorithms are almost two orders of magnitude faster than STRUCTURE and achieve accuracies comparable to those of ADMIXTURE. Furthermore, our results show that the heuristic scores for choosing model complexity provide a reasonable range of values for the number of populations represented in the data, with minimal bias towards detecting structure when it is very weak. Our algorithm, fastSTRUCTURE, is freely available online at http://pritchardlab.stanford.edu/structure.html.

2013-12-02

OTX2 Dosage Sensitivity is Implicated in Hemifacial Microsomia

10.1101/001099

Dina Zielinski;Barak Markus;Mona Sheikh;Melissa Gymrek;Clement Chu;Marta Zaks;Balaji Srinivasan;Jodi D. Hoffman;Dror Aizenbud;Yaniv Erlich;

Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. Here, we investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. We performed whole-exome sequencing and a genome-wide survey of segmental variations. Analysis of the exome sequencing results indicated the absence of a pathogenic coding point mutation. Inspection of segmental variations identified a 1.3Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is concordant with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of our study. Our findings highlight dosage sensitivity of OTX2 in human craniofacial development and suggest a possible shared etiology between a subtype of hemifacial microsomia and medulloblastoma.

2013-12-03

A Tale of Two Hypotheses: Genetics and the Ethnogenesis of Ashkenazi Jewry

10.1101/001354

Aram Yardumian;

The debate over the ethnogenesis of Ashkenazi Jewry is longstanding, and has been hampered by a lack of Jewish historiographical work between the Biblical and the early Modern eras. Most historians, as well as geneticists, situate them as the descendants of Israelite tribes whose presence in Europe is owed to deportations during the Roman conquest of Palestine, as well as migration from Babylonia, and eventual settlement along the Rhine. By contrast, a few historians and other writers, most famously Arthur Koestler, have looked to migrations following the decline of the little-understood Medieval Jewish kingdom of Khazaria as the main source for Ashkenazi Jewry. A recent study of genetic variation in southeastern European populations (Elhaik 2012) also proposed a Khazarian origin for Ashkenazi Jews, eliciting considerable criticism from other scholars investigating Jewish ancestry who favor a Near Eastern origin of Ashkenazi populations. This paper re-examines the genetic data and analytical approaches used in these studies of Jewish ancestry, and situates them in the context of historical, linguistic, and archaeological evidence from the Caucasus, Europe and the Near East. Based on this reanalysis, it appears not only that the Khazar Hypothesis per se is without serious merit, but also the veracity of the Rhineland Hypothesis may also be questionable.

2013-12-12

Selection signatures in worldwide Sheep populations

10.1101/001453

Maria-Ines Fariello;Bertrand Servin;Gwenola Tosser-Klopp;Rachelle Rupp;Carole Moreno;International Sheep Genomics Consortium n.a.;Magali San Cristobal;simon boitard;

The diversity of populations in domestic species offer great opportunities to study genome response to selection. The recently published Sheep Hapmap dataset is a great example of characterization of the world wide genetic diversity in the Sheep. In this study, we re-analyzed the Sheep Hapmap dataset to identify selection signatures in worldwide Sheep populations. Compared to previous analyses, we make use of statistical methods that (i) take account of the hierarchical structure of sheep populations, (ii) make use of Linkage Disequilibrium information and (iii) focus specifically on either recent or older selection signatures. We show that this allows to pinpoint several new selection signatures in the sheep genome and to distinguish those related to modern breeding objectives and to earlier post-domestication constraints. The newly identified regions, together with the one previously identified, reveal the extensive genome response to selection on morphology, color and adaptation to new environments.

2013-12-17

Selection signatures in worldwide Sheep populations

10.1101/001453

Maria-Ines Fariello;Bertrand Servin;Gwenola Tosser-Klopp;Rachelle Rupp;Carole Moreno;International Sheep Genomics Consortium n.a.;Magali San Cristobal;simon boitard;

The diversity of populations in domestic species offer great opportunities to study genome response to selection. The recently published Sheep Hapmap dataset is a great example of characterization of the world wide genetic diversity in the Sheep. In this study, we re-analyzed the Sheep Hapmap dataset to identify selection signatures in worldwide Sheep populations. Compared to previous analyses, we make use of statistical methods that (i) take account of the hierarchical structure of sheep populations, (ii) make use of Linkage Disequilibrium information and (iii) focus specifically on either recent or older selection signatures. We show that this allows to pinpoint several new selection signatures in the sheep genome and to distinguish those related to modern breeding objectives and to earlier post-domestication constraints. The newly identified regions, together with the one previously identified, reveal the extensive genome response to selection on morphology, color and adaptation to new environments.

2014-04-11

Ancient human genomes suggest three ancestral populations for present-day Europeans

10.1101/001552

Iosif Lazaridis;Nick Patterson;Alissa Mittnik;Gabriel Renaud;Swapan Mallick;Karola Kirsanow;Peter H. Sudmant;Joshua G. Schraiber;Sergi Castellano;Mark Lipson;Bonnie Berger;Christos Economou;Ruth Bollongino;Qiaomei Fu;Kirsten Bos;Susanne Nordenfelt;Heng Li;Cesare de Filippo;Kay Prüfer;Susanna Sawyer;Cosimo Posth;Wolfgang Haak;Fredrik Hallgren;Elin Fornander;Nadin Rohland;Dominique Delsate;Michael Francken;Jean-Michel Guinet;Joachim Wahl;George Ayodo;Hamza A. Babiker;Graciela Baillet;Elena Balanovska;Oleg Balanovsky;Ramiro Barrantes;Gabriel Bedoya;Haim Ben-Ami;Judit Bene;Fouad Berrada;Claudio M.

We sequenced genomes from a [~]7,000 year old early farmer from Stuttgart in Germany, an [~]8,000 year old hunter-gatherer from Luxembourg, and seven [~]8,000 year old hunter-gatherers from southern Sweden. We analyzed these data together with other ancient genomes and 2,345 contemporary humans to show that the great majority of present-day Europeans derive from at least three highly differentiated populations: West European Hunter-Gatherers (WHG), who contributed ancestry to all Europeans but not to Near Easterners; Ancient North Eurasians (ANE), who were most closely related to Upper Paleolithic Siberians and contributed to both Europeans and Near Easterners; and Early European Farmers (EEF), who were mainly of Near Eastern origin but also harbored WHG-related ancestry. We model these populations deep relationships and show that EEF had [~]44% ancestry from a \"Basal Eurasian\" lineage that split prior to the diversification of all other non-African lineages.

2013-12-23

Ancient human genomes suggest three ancestral populations for present-day Europeans

10.1101/001552

Iosif Lazaridis;Nick Patterson;Alissa Mittnik;Gabriel Renaud;Swapan Mallick;Karola Kirsanow;Peter H. Sudmant;Joshua G. Schraiber;Sergi Castellano;Mark Lipson;Bonnie Berger;Christos Economou;Ruth Bollongino;Qiaomei Fu;Kirsten Bos;Susanne Nordenfelt;Heng Li;Cesare de Filippo;Kay Prüfer;Susanna Sawyer;Cosimo Posth;Wolfgang Haak;Fredrik Hallgren;Elin Fornander;Nadin Rohland;Dominique Delsate;Michael Francken;Jean-Michel Guinet;Joachim Wahl;George Ayodo;Hamza A. Babiker;Graciela Baillet;Elena Balanovska;Oleg Balanovsky;Ramiro Barrantes;Gabriel Bedoya;Haim Ben-Ami;Judit Bene;Fouad Berrada;Claudio M.

We sequenced genomes from a [~]7,000 year old early farmer from Stuttgart in Germany, an [~]8,000 year old hunter-gatherer from Luxembourg, and seven [~]8,000 year old hunter-gatherers from southern Sweden. We analyzed these data together with other ancient genomes and 2,345 contemporary humans to show that the great majority of present-day Europeans derive from at least three highly differentiated populations: West European Hunter-Gatherers (WHG), who contributed ancestry to all Europeans but not to Near Easterners; Ancient North Eurasians (ANE), who were most closely related to Upper Paleolithic Siberians and contributed to both Europeans and Near Easterners; and Early European Farmers (EEF), who were mainly of Near Eastern origin but also harbored WHG-related ancestry. We model these populations deep relationships and show that EEF had [~]44% ancestry from a \"Basal Eurasian\" lineage that split prior to the diversification of all other non-African lineages.

2014-04-02

Ancient human genomes suggest three ancestral populations for present-day Europeans

10.1101/001552

Iosif Lazaridis;Nick Patterson;Alissa Mittnik;Gabriel Renaud;Swapan Mallick;Karola Kirsanow;Peter H. Sudmant;Joshua G. Schraiber;Sergi Castellano;Mark Lipson;Bonnie Berger;Christos Economou;Ruth Bollongino;Qiaomei Fu;Kirsten Bos;Susanne Nordenfelt;Heng Li;Cesare de Filippo;Kay Prüfer;Susanna Sawyer;Cosimo Posth;Wolfgang Haak;Fredrik Hallgren;Elin Fornander;Nadin Rohland;Dominique Delsate;Michael Francken;Jean-Michel Guinet;Joachim Wahl;George Ayodo;Hamza A. Babiker;Graciela Baillet;Elena Balanovska;Oleg Balanovsky;Ramiro Barrantes;Gabriel Bedoya;Haim Ben-Ami;Judit Bene;Fouad Berrada;Claudio M.

We sequenced genomes from a [~]7,000 year old early farmer from Stuttgart in Germany, an [~]8,000 year old hunter-gatherer from Luxembourg, and seven [~]8,000 year old hunter-gatherers from southern Sweden. We analyzed these data together with other ancient genomes and 2,345 contemporary humans to show that the great majority of present-day Europeans derive from at least three highly differentiated populations: West European Hunter-Gatherers (WHG), who contributed ancestry to all Europeans but not to Near Easterners; Ancient North Eurasians (ANE), who were most closely related to Upper Paleolithic Siberians and contributed to both Europeans and Near Easterners; and Early European Farmers (EEF), who were mainly of Near Eastern origin but also harbored WHG-related ancestry. We model these populations deep relationships and show that EEF had [~]44% ancestry from a \"Basal Eurasian\" lineage that split prior to the diversification of all other non-African lineages.

2014-04-05

Evaluating the use of ABBA-BABA statistics to locate introgressed loci

10.1101/001347

Simon H. Martin;John W. Davey;Chris D. Jiggins;

Several methods have been proposed to test for introgression across genomes. One method tests for a genome-wide excess of shared derived alleles between taxa using Pattersons D statistic, but does not establish which loci show such an excess or whether the excess is due to introgression or ancestral population structure. Several recent studies have extended the use of D by applying the statistic to small genomic regions, rather than genome-wide. Here, we use simulations and whole genome data from Heliconius butterflies to investigate the behavior of D in small genomic regions. We find that D is unreliable in this situation as it gives inflated values when effective population size is low, causing D outliers to cluster in genomic regions of reduced diversity. As an alternative, we propose a related statistic [Formula] a modified version of a statistic originally developed to estimate the genome-wide fraction of admixture. [Formula] is not subject to the same biases as D, and is better at identifying introgressed loci. Finally, we show that both D and [Formula] outliers tend to cluster in regions of low absolute divergence (dXY), which can confound a recently proposed test for differentiating introgression from shared ancestral variation at individual loci.

2013-12-11

Evaluating the use of ABBA-BABA statistics to locate introgressed loci

10.1101/001347

Simon H. Martin;John W. Davey;Chris D. Jiggins;

Several methods have been proposed to test for introgression across genomes. One method tests for a genome-wide excess of shared derived alleles between taxa using Pattersons D statistic, but does not establish which loci show such an excess or whether the excess is due to introgression or ancestral population structure. Several recent studies have extended the use of D by applying the statistic to small genomic regions, rather than genome-wide. Here, we use simulations and whole genome data from Heliconius butterflies to investigate the behavior of D in small genomic regions. We find that D is unreliable in this situation as it gives inflated values when effective population size is low, causing D outliers to cluster in genomic regions of reduced diversity. As an alternative, we propose a related statistic [Formula] a modified version of a statistic originally developed to estimate the genome-wide fraction of admixture. [Formula] is not subject to the same biases as D, and is better at identifying introgressed loci. Finally, we show that both D and [Formula] outliers tend to cluster in regions of low absolute divergence (dXY), which can confound a recently proposed test for differentiating introgression from shared ancestral variation at individual loci.

2014-06-02

Evaluating the use of ABBA-BABA statistics to locate introgressed loci

10.1101/001347

Simon H. Martin;John W. Davey;Chris D. Jiggins;

Several methods have been proposed to test for introgression across genomes. One method tests for a genome-wide excess of shared derived alleles between taxa using Pattersons D statistic, but does not establish which loci show such an excess or whether the excess is due to introgression or ancestral population structure. Several recent studies have extended the use of D by applying the statistic to small genomic regions, rather than genome-wide. Here, we use simulations and whole genome data from Heliconius butterflies to investigate the behavior of D in small genomic regions. We find that D is unreliable in this situation as it gives inflated values when effective population size is low, causing D outliers to cluster in genomic regions of reduced diversity. As an alternative, we propose a related statistic [Formula] a modified version of a statistic originally developed to estimate the genome-wide fraction of admixture. [Formula] is not subject to the same biases as D, and is better at identifying introgressed loci. Finally, we show that both D and [Formula] outliers tend to cluster in regions of low absolute divergence (dXY), which can confound a recently proposed test for differentiating introgression from shared ancestral variation at individual loci.

2014-08-20

The importance of population growth and regulation in human life history evolution

10.1101/001404

Ryan Baldini;

Explaining the evolution of human life history characteristics remains an outstanding problem to evolutionary anthropologists. Progress is hindered by common misunderstandings of how selection works in age-structured populations. I review two important results of life history theory related to demography. First, different life history strategies evolve under density-independent and density-dependent population growth. Second, and more poorly appreciated, different kinds of density-dependence also select for different life history strategies; assuming zero population growth alone is insufficient to determine the optimal strategy. I show that these facts are more than methodological niceties by reanalyzing the model by Kaplan et al. (2000) and showing that the results depend strongly on the form of population regulation assumed. This analysis suggests that progress in human life history theory requires better understanding of the demography of our ancestors. I close with a discussion of empirical implications.

2013-12-14

An Adaptive Threshold in Mammalian Neocortical Evolution

10.1101/001289

Eric Lewitus;Iva Kelava;Alex T Kalinka;Pavel Tomancak;Wieland B Huttner;

Expansion of the neocortex is a hallmark of human evolution. However, it remains an open question what adaptive mechanisms facilitated its expansion. Here we show, using gyrencephaly index (GI) and other physiological and life-history data for 102 mammalian species, that gyrencephaly is an ancestral mammalian trait. We provide evidence that the evolution of a highly folded neocortex, as observed in humans, requires the traversal of a threshold of [~]109 neurons, and that species above and below the threshold exhibit a bimodal distribution of physiological and life-history traits, establishing two phenotypic groups. We identify, using discrete mathematical models, proliferative divisions of pro-genitors in the basal compartment of the developing neocortex as evolutionarily necessary and sufficient for generating a fourteen-fold increase in daily prenatal neuron production and thus traversal of the neuronal threshold. Finally, using RNA-seq data from fetal human neocortical germinal zones, we show a genomic correlate to the neuron threshold in the differential conservation of long intergenic non-coding RNA. (see arXiv:1304.5412)

2013-12-13

An Adaptive Threshold in Mammalian Neocortical Evolution

10.1101/001289

Eric Lewitus;Iva Kelava;Alex T Kalinka;Pavel Tomancak;Wieland B Huttner;

Expansion of the neocortex is a hallmark of human evolution. However, it remains an open question what adaptive mechanisms facilitated its expansion. Here we show, using gyrencephaly index (GI) and other physiological and life-history data for 102 mammalian species, that gyrencephaly is an ancestral mammalian trait. We provide evidence that the evolution of a highly folded neocortex, as observed in humans, requires the traversal of a threshold of [~]109 neurons, and that species above and below the threshold exhibit a bimodal distribution of physiological and life-history traits, establishing two phenotypic groups. We identify, using discrete mathematical models, proliferative divisions of pro-genitors in the basal compartment of the developing neocortex as evolutionarily necessary and sufficient for generating a fourteen-fold increase in daily prenatal neuron production and thus traversal of the neuronal threshold. Finally, using RNA-seq data from fetal human neocortical germinal zones, we show a genomic correlate to the neuron threshold in the differential conservation of long intergenic non-coding RNA. (see arXiv:1304.5412)

2013-12-16

Direct Reciprocity Under Uncertainty Does Not Explain One-Shot Cooperation, But It Can Explain Norm Psychology

10.1101/001446

Matthew Zefferman;

Humans in many societies cooperate in economic experiments at much higher levels than would be expected if their goal was maximizing economic returns even when interactions are anonymous and one-shot. This is a puzzle because paying a cost to benefit another player in one-shot interactions has no direct benefit to the cooperator. This paper explores the logic of two competing evolutionary hypotheses to explain this behavior. The \"norm psychology\" hypothesis holds that a players choice of strategy is heavily influenced by socially-learned cultural norms. Its premise is that over the course of human evolutionary history, cultural norms varied considerably across human societies and through a process of gene-culture co-evolution, humans evolved mechanisms to learn and adopt the norms of their particular society. The \"evolutionary mismatch\" hypothesis holds that pro-social preferences evolved genetically in our hunter-gatherer past where one-shot anonymous interactions were rare and these evolved \"protocols\" for cooperation are misapplied in modern, laboratory, conditions. I compare these hypotheses by adopting a well-known model of the mismatch hypothesis. I show that the cooperation generated by the model is based on a flawed assumption - that the best thing to do is cooperate in a repeated game. I show that repeated games generate a great diversity of behavioral equilibria, in support of the norm psychology hypothesiss premise. When interaction is repeated, adopting local norms is a more evolutionarily successful strategy than automatically cooperating. If various groups are at different behavioral equilibria, then cultural selection between groups tends to select for cooperative behavior.

2013-12-17

Hawkish but helpful: When cultural group selection favors within-group aggression

10.1101/001487

Ben Hanowell;

The origin of cooperation is a central problem in evolutionary biology and social science. Cultural group selection and parochial altruism are popular but controversial evolutionary explanations for large-scale cooperation. Proponents of the cultural group selection hypothesis argue that the human tendency to conform--a consequence of our reliance on social learning--maintained sufficient between-group variation to allow group selection (which favors altruism) to overpower individual selection (which favors selfishness), whereupon large-scale altruism could emerge. Proponents of the parochial altruism hypothesis argue that altruism could emerge in tandem with hostility toward other groups if the combination of the two traits increased success in inter-group contests. Proponents of both hypotheses assume that cooperation is altruistic and that within-group conflict is antithetical to cooperation, implying that group selection for cooperation reduces within-group conflict. Yet within-group conflict need not be antithetical to cooperation. This essay uses a mathematical model to show that selection between groups can lead to greater within-group aggression if within-group aggression enhances the value of individually costly public goods contributions. This model may help to explain cross-cultural associations between warfare, socialization for aggression, aggressive sports, and interpersonal violence among humans. It may also apply to other forms of inter-group conflict among humans. Finally, the model suggests that group selection can lead to disharmony within groups, a caveat to the use of group selection models to inform social policy.

2013-12-20

Revisiting the effect of population size on cumulative cultural evolution

10.1101/001529

Ryan Baldini;

Henrich (2004) argued that larger populations can better maintain complex technologies because they contain more highly skilled people whom others can imitate. His original model, however, did not distinguish the effects of population size from population density or network size; a learners social network included the entire population. Does population size remain important when populations are subdivided and networks are realistically small? I use a mathematical model to show that population size has little effect on equilibrium levels of mean skill under a wide range of conditions. The effects of network size and transmission error rate usually overshadow that of population size. Population size can, however, affect the rate at which a population approaches equilibrium, by increasing the rate at which innovations arise. This effect is small unless innovation is very rare. Whether population size predicts technological complexity in the real world, then, depends on whether technological evolution is innovation-limited and short of equilibrium. The effect of population \"connectedness,\" via migration or trade, is similar. I discuss the results of this analysis in light of the current empirical debate.

2013-12-21

Revisiting the effect of population size on cumulative cultural evolution

10.1101/001529

Ryan Baldini;

Henrich (2004) argued that larger populations can better maintain complex technologies because they contain more highly skilled people whom others can imitate. His original model, however, did not distinguish the effects of population size from population density or network size; a learners social network included the entire population. Does population size remain important when populations are subdivided and networks are realistically small? I use a mathematical model to show that population size has little effect on equilibrium levels of mean skill under a wide range of conditions. The effects of network size and transmission error rate usually overshadow that of population size. Population size can, however, affect the rate at which a population approaches equilibrium, by increasing the rate at which innovations arise. This effect is small unless innovation is very rare. Whether population size predicts technological complexity in the real world, then, depends on whether technological evolution is innovation-limited and short of equilibrium. The effect of population \"connectedness,\" via migration or trade, is similar. I discuss the results of this analysis in light of the current empirical debate.

2013-12-31

Species Delimitation using Genome-Wide SNP Data

10.1101/001172

Adam Leache;Matthew Fujita;Vladimir Minin;Remco Bouckaert;

The multi-species coalescent has provided important progress for evolutionary inferences, including increasing the statistical rigor and objectivity of comparisons among competing species delimitation models. However, Bayesian species delimitation methods typically require brute force integration over gene trees via Markov chain Monte Carlo (MCMC), which introduces a large computation burden and precludes their application to genomic-scale data. Here we combine a recently introduced dynamic programming algorithm for estimating species trees that bypasses MCMC integration over gene trees with sophisticated methods for estimating marginal likelihoods, needed for Bayesian model selection, to provide a rigorous and computationally tractable technique for genome-wide species delimitation. We provide a critical yet simple correction that brings the likelihoods of different species trees, and more importantly their corresponding marginal likelihoods, to the same common denominator, which enables direct and accurate comparisons of competing species delimitation models using Bayes factors. We test this approach, which we call Bayes factor delimitation (*with genomic data; BFD*), using common species delimitation scenarios with computer simulations. Varying the numbers of loci and the number of samples suggest that the approach can distinguish the true model even with few loci and limited samples per species. Misspecification of the prior for population size{theta} has little impact on support for the true model. We apply the approach to West African forest geckos (Hemidactylus fasciatus complex) using genome-wide SNP data data. This new Bayesian method for species delimitation builds on a growing trend for objective species delimitation methods with explicit model assumptions that are easily tested.

2013-12-05

Species Delimitation using Genome-Wide SNP Data

10.1101/001172

Adam Leache;Matthew Fujita;Vladimir Minin;Remco Bouckaert;

The multi-species coalescent has provided important progress for evolutionary inferences, including increasing the statistical rigor and objectivity of comparisons among competing species delimitation models. However, Bayesian species delimitation methods typically require brute force integration over gene trees via Markov chain Monte Carlo (MCMC), which introduces a large computation burden and precludes their application to genomic-scale data. Here we combine a recently introduced dynamic programming algorithm for estimating species trees that bypasses MCMC integration over gene trees with sophisticated methods for estimating marginal likelihoods, needed for Bayesian model selection, to provide a rigorous and computationally tractable technique for genome-wide species delimitation. We provide a critical yet simple correction that brings the likelihoods of different species trees, and more importantly their corresponding marginal likelihoods, to the same common denominator, which enables direct and accurate comparisons of competing species delimitation models using Bayes factors. We test this approach, which we call Bayes factor delimitation (*with genomic data; BFD*), using common species delimitation scenarios with computer simulations. Varying the numbers of loci and the number of samples suggest that the approach can distinguish the true model even with few loci and limited samples per species. Misspecification of the prior for population size{theta} has little impact on support for the true model. We apply the approach to West African forest geckos (Hemidactylus fasciatus complex) using genome-wide SNP data data. This new Bayesian method for species delimitation builds on a growing trend for objective species delimitation methods with explicit model assumptions that are easily tested.

2014-01-04

Sap flow through petioles and petioles reveals leaf-level responses to light and vapor pressure deficit in the tropical tree Tabebuia rosea (Bignoniaceae)

10.1101/000711

Adam Roddy;Klaus Winter;Todd Dawson;

Continuous measurements of sap flow have been widely used to measure water flux through tree stems and branches. However, these measurements lack the resolution necessary for determining fine-scale, leaf-level responses to environmental variables. We used the heat ratio method to measure sap flow rates through leaf petioles and leaflet petiolules of saplings of the tropical tree Tabebuia rosea (Bignoniaceae) to determine how leaf and leaflet sap flow responds to variation in light and vapor pressure deficit (VPD). We found that in the morning sap flow rates to east-facing leaves increased 26 minutes before adjacent west-facing leaves. Although leaves had higher integrated sap flow than their largest leaflet, this difference was not proportional to the difference in leaf area, which could be due to lower conduit area in petiolules than in petioles. In contrast to measurements on main stems, integrated daily sap flow was negatively correlated with daily mean VPD. Furthermore, leaves exhibited previously undescribed patterns of hysteresis in the sap flow-VPD and sap flow-PAR relationships. When hysteresis in the sap flow-PAR relationship was clockwise, the sap flow-VPD relationship was also clockwise; however, when hysteresis in the sap flow-PAR relationship was counterclockwise, the sap flow-VPD relationship displayed an intersected loop. These pattern differences highlight how substantially leaf-level processes may vary within a canopy and how leaf-level processes may not scale predictably to the stem level.

2013-11-19

Linking indices for biodiversity monitoring to extinction risk theory

10.1101/000760

Michael A. McCarthy;Alana L. Moore;Jochen Krauss;John W Morgan;Christopher F. Clements;

Biodiversity indices often combine data from different species when used in monitoring programs. Heuristic properties can suggest preferred indices, but we lack objective ways to discriminate between indices with similar heuristics. Biodiversity indices can be evaluated by determining how well they reflect management objectives that a monitoring program aims to support. For example, the Convention on Biological Diversity requires reporting about extinction rates, so simple indices that reflect extinction risk would be valuable. Here we develop three biodiversity indices that are based on simple models of population viability that relate extinction risk to abundance. The first index is based on the geometric mean abundance of species. A second uses a more general power mean. A third integrates both the geometric mean abundance and trend. These indices require the same data as previous indices, but they also relate directly to extinction risk. Field data for butterflies and woodland plants, and experimental studies of protozoan communities show that the indices correlate with local extinction rates. Applying the index based on the geometric mean to global data on changes in avian abundance suggests that the average extinction probability of birds has increased approximately 1% from 1970 to 2009.

2013-11-21

Linking indices for biodiversity monitoring to extinction risk theory

10.1101/000760

Michael A. McCarthy;Alana L. Moore;Jochen Krauss;John W Morgan;Christopher F. Clements;

Biodiversity indices often combine data from different species when used in monitoring programs. Heuristic properties can suggest preferred indices, but we lack objective ways to discriminate between indices with similar heuristics. Biodiversity indices can be evaluated by determining how well they reflect management objectives that a monitoring program aims to support. For example, the Convention on Biological Diversity requires reporting about extinction rates, so simple indices that reflect extinction risk would be valuable. Here we develop three biodiversity indices that are based on simple models of population viability that relate extinction risk to abundance. The first index is based on the geometric mean abundance of species. A second uses a more general power mean. A third integrates both the geometric mean abundance and trend. These indices require the same data as previous indices, but they also relate directly to extinction risk. Field data for butterflies and woodland plants, and experimental studies of protozoan communities show that the indices correlate with local extinction rates. Applying the index based on the geometric mean to global data on changes in avian abundance suggests that the average extinction probability of birds has increased approximately 1% from 1970 to 2009.

2014-02-07

The Effectiveness of China’s National Forest Protection Program and National-level Nature Reserves, 2000 to 2010: PREPRINT

10.1101/000893

Guopeng Ren;Stephen S. Young;Lin Wang;Wei Wang;Yongcheng Long;Ruidong Wu;Junsheng Li;Jianguo Zhu;Douglas W. Yu;

There is profound interest in knowing the degree to which Chinas institutions are capable of protecting its natural forests and biodiversity in the face of economic and political change. Chinas two most important forest protection policies are its National Forest Protection Program (NFPP) and its National-level Nature Reserves (NNRs). The NFPP was implemented in 17 provinces starting in the year 2000 in response to deforestation-caused flooding. We used MODIS data (MOD13Q1) to estimate forest cover and forest loss across mainland China, and we report that 1.765 million km2 or 18.7% of mainland China was covered in forest (12.3%, canopy cover > 70%) and woodland (6.4%, 40% [&le;] canopy cover < 70%) in 2000. By 2010, a total of 480,203 km2 of forest + woodland was lost, amounting to an annual deforestation rate of 2.7%. The forest-only loss was 127,473 km2, or 1.05% annually. The three most rapidly deforested provinces were outside NFPP jurisdiction, in the southeast. Within the NFPP provinces, the annual forest + woodland loss rate was 2.26%, and the forest-only rate was 0.62%. Because these loss rates are likely overestimates, China appears to have achieved, and even exceeded, its NFPP target of reducing deforestation to 1.1% annually in the target provinces. We also assemble the first-ever polygon dataset for Chinas forested NNRs (n = 237), which covered 74,030 km2 in 2000. Conventional unmatched and covariate-matching analyses both find that about two-thirds of Chinas NNRs exhibit effectiveness in protecting forest cover and that within-NNR deforestation rates are higher in provinces that have higher overall deforestation.

2013-11-25

Mechanism of β-Aminobutyric Acid-Induced Resistance in Wheat to the Grain Aphid, Sitobion avenae

10.1101/001032

He-He Cao;Meng Zhang;Hui Zhao;Yi Zhang;Xing-Xing Wang;Shan-Shan Guo;Zhan-Feng Zhang;Tong-Xian Liu;

The non-protein amino acid {beta}-aminobutyric acid (BABA) could induce plant resistance to a broad spectrum of biotic and abiotic stresses. However, BABA-induced plant resistance to insects is less well-studied, especially its underlying mechanism. In this research, we applied BABA to wheat seedlings and tested its effects on Sitobion avenae. When applied as a soil drench, BABA significantly reduced weight of S. avenae, whereas foliar spray and seed treatment had no such effects. BABA-mediated suppression of S. avenae growth is dose dependent and could last at least for 7 days. The aminobutyric acid concentration in phloem sap of BABA-treated plants accumulated to high levels and increased with BABA concentrations applied. Moreover, after 10 days of treatment, the aminobutyric acid content in BABA-treated plants was still higher than that in control treatment. S. avenae could not discriminate artificial diet containing BABA from standard diet, indicating that BABA itself is not a deterrent to this aphid. Also S. avenae did not show preference for control plants or BABA-treated plants. Consistent with choice test results, S. avenae had similar feeding activities on control and BABA-treated plants, suggesting that BABA did not induce antifeedants in wheat seedlings. In addition, aminobutyric acid concentration in S. avenae feeding on BABA-treated plants was significantly higher than those feeding on control palnts. S. avenae growth rate was reduced on artificial diet containing BABA, indicating direct toxic effects of BABA to this aphid. These results suggest that BABA application could enhance wheat plant resistance to S. avenae and the mechanism is possibly due to direct toxicity of high BABA contents in plant phloem.

2013-12-02

Climate change triggers morphological and life-history evolution in response to predators

10.1101/001263

Edmund Hart;Nicholas Gotelli;

Although climate change is expected to reorganize entire communities, this restructuring might reflect either direct ecological or evolutionary responses to abiotic conditions or indirect effects mediated through altered species interactions. We tested the hypothesis that changes in trophic interaction strength due to altered predator abundance have a cascading evolutionary response in a prey species (Daphnia pulex). Using a multiyear / multigenerational field experiment, we manipulated 12 open aquatic mesocosms to simulate hydrological conditions under climate change. After a three-year press manipulation, we collected Daphnia pulex from each pond and raised them in a common garden. Using quantitative genetic methods, we measured a series of quantitative traits every other day on 108 individuals for eight weeks. There was a significant decrease in tail spine length and population growth rate in groups exposed to the most extreme future climate scenarios. Structural equation models demonstrated that trait changes were best explained as an indirect effect of climate change treatments mediated through changes in predator abundance. Our results suggest climate change can trigger a cascade of ecological and evolutionary forces by reducing predator density, which in turn acts as a selective force leading to evolutionary change in prey morphology and life history.

2013-12-10

Broad-scale spatial patterns of canopy cover and pond morphology affect the structure of a Neotropical amphibian metacommunity

10.1101/001255

Diogo B. Provete;Thiago Gonçalves-Souza;Michel Garey;Itamar A. Martins;Denise Rossa-Feres;

Spatial and environmental processes influence species composition at distinct scales. Previous studies suggested that the landscape-scale distribution of larval anurans is influenced by environmental gradients related to adult breeding site selection, such as pond canopy cover, but not water chemistry. However, the combined effects of spatial, pond morphology, and water chemistry variables on metacommunity structure of larval anurans have not been analyzed. We used a partial redundancy analysis with variation partitioning to analyze the relative influence of pond morphology (e.g., depth, area, and aquatic vegetation), water chemistry, and spatial variables on a tadpole metacommunity from southeastern Brazil. We predict that the metacommunity will be spatially structured at broad spatial scales, while environmental variables, mainly related to adult habitat selection, would play a larger role at fine spatial scales. We found that broad-scale spatial patterns of pond canopy cover and pond morphology strongly influenced metacommunity structure. Additionally, species composition was spatially autocorrelated at short distances. We suggest that the reproductive behavior of adult anurans is driving tadpole metacommunity dynamics, since pond morphology, but not water chemistry affects breeding site selection by adults. Our results contribute to the understanding of amphibian species diversity in tropical environments.

2013-12-10

Broad-scale spatial patterns of canopy cover and pond morphology affect the structure of a Neotropical amphibian metacommunity

10.1101/001255

Diogo B. Provete;Thiago Gonçalves-Souza;Michel Garey;Itamar A. Martins;Denise Rossa-Feres;

Spatial and environmental processes influence species composition at distinct scales. Previous studies suggested that the landscape-scale distribution of larval anurans is influenced by environmental gradients related to adult breeding site selection, such as pond canopy cover, but not water chemistry. However, the combined effects of spatial, pond morphology, and water chemistry variables on metacommunity structure of larval anurans have not been analyzed. We used a partial redundancy analysis with variation partitioning to analyze the relative influence of pond morphology (e.g., depth, area, and aquatic vegetation), water chemistry, and spatial variables on a tadpole metacommunity from southeastern Brazil. We predict that the metacommunity will be spatially structured at broad spatial scales, while environmental variables, mainly related to adult habitat selection, would play a larger role at fine spatial scales. We found that broad-scale spatial patterns of pond canopy cover and pond morphology strongly influenced metacommunity structure. Additionally, species composition was spatially autocorrelated at short distances. We suggest that the reproductive behavior of adult anurans is driving tadpole metacommunity dynamics, since pond morphology, but not water chemistry affects breeding site selection by adults. Our results contribute to the understanding of amphibian species diversity in tropical environments.

2014-04-09

Assessing the Use of Antiviral Treatment to Control Influenza

10.1101/001537

Sarah C Kramer;Shweta Bansal;

Vaccines are the cornerstone of influenza control policy, but can suffer from several drawbacks. Seasonal influenza vaccines are prone to production problems and low efficacies, while pandemic vaccines are unlikely to be available in time to slow a rapidly spreading global outbreak. Antiviral therapy was found to be beneficial during the influenza A(H1N1)pdm09 pandemic even with limited use; however, antiviral use has decreased further since then. We seek to determine the role antiviral therapy can play in pandemic and seasonal influenza control on the population level, and to find optimized strategies for more efficient use of treatment. Using an age-structured contact network model for an urban population, we find that while a conservative antiviral therapy strategy cannot replace a robust influenza vaccine, it can play a role in reducing attack rates and eliminating outbreaks.

2013-12-26

Black rhinoceros demography should be stage, not age, based.

10.1101/001610

Peter R Law;Wayne L Linklater;

Biologically meaningful and standardized definitions of life stages are essential for demographic studies, especially for endangered and intensively managed species such as rhinoceros. Focusing on the black rhinoceros Diceros bicornis, we argue that standardized biological definitions of calf, subadult, and adult, rather than age classes, provide the appropriate basis for black rhinoceros demography. Age classes do not correlate well with the risks of mortality nor characterize, at least for females, the attainment of reproductive maturity. Black rhinoceros demography based on age classes, typical of existing literature, obscures the significance of studies of mortality and fecundity. Comparison of studies also requires standardized definitions. We propose biologically meaningful definitions of life stages appropriate for the demography of the black rhinoceros and encourage the community of rhinoceros researchers to reach consensus on standardized, demographically appropriate definitions for adoption for each rhinoceros species.

2013-12-30

Beyond species: why ecological interaction networks vary through space and time

10.1101/001677

Timothée Poisot;Daniel B Stouffer;Dominique Gravel;

Community ecology is tasked with the considerable challenge of predicting the structure, and properties, of emerging ecosystems. It requires the ability to understand how and why species interact, as this will allow the development of mechanism-based predictive models, and as such to better characterize how ecological mechanisms act locally on the existence of interspecific interactions. Here we argue that the current conceptualization of species interaction networks is ill-suited for this task. Instead, we propose that future research must start to account for the intrinsic variability of species interactions, then scale up from here onto complex networks. This can be accomplished simply by recognizing that there exists intra-specific variability, in traits or properties related to the establishment of species interactions. By shifting the scale towards population-based processes, we show that this new approach will improve our predictive ability and mechanistic understanding of how species interact over large spatial or temporal scales.

2014-01-03

Beyond species: why ecological interaction networks vary through space and time

10.1101/001677

Timothée Poisot;Daniel B Stouffer;Dominique Gravel;

Community ecology is tasked with the considerable challenge of predicting the structure, and properties, of emerging ecosystems. It requires the ability to understand how and why species interact, as this will allow the development of mechanism-based predictive models, and as such to better characterize how ecological mechanisms act locally on the existence of interspecific interactions. Here we argue that the current conceptualization of species interaction networks is ill-suited for this task. Instead, we propose that future research must start to account for the intrinsic variability of species interactions, then scale up from here onto complex networks. This can be accomplished simply by recognizing that there exists intra-specific variability, in traits or properties related to the establishment of species interactions. By shifting the scale towards population-based processes, we show that this new approach will improve our predictive ability and mechanistic understanding of how species interact over large spatial or temporal scales.

2014-01-04

Beyond species: why ecological interaction networks vary through space and time

10.1101/001677

Timothée Poisot;Daniel B Stouffer;Dominique Gravel;

Community ecology is tasked with the considerable challenge of predicting the structure, and properties, of emerging ecosystems. It requires the ability to understand how and why species interact, as this will allow the development of mechanism-based predictive models, and as such to better characterize how ecological mechanisms act locally on the existence of interspecific interactions. Here we argue that the current conceptualization of species interaction networks is ill-suited for this task. Instead, we propose that future research must start to account for the intrinsic variability of species interactions, then scale up from here onto complex networks. This can be accomplished simply by recognizing that there exists intra-specific variability, in traits or properties related to the establishment of species interactions. By shifting the scale towards population-based processes, we show that this new approach will improve our predictive ability and mechanistic understanding of how species interact over large spatial or temporal scales.

2014-04-11

Beyond species: why ecological interaction networks vary through space and time

10.1101/001677

Timothée Poisot;Daniel B Stouffer;Dominique Gravel;

Community ecology is tasked with the considerable challenge of predicting the structure, and properties, of emerging ecosystems. It requires the ability to understand how and why species interact, as this will allow the development of mechanism-based predictive models, and as such to better characterize how ecological mechanisms act locally on the existence of interspecific interactions. Here we argue that the current conceptualization of species interaction networks is ill-suited for this task. Instead, we propose that future research must start to account for the intrinsic variability of species interactions, then scale up from here onto complex networks. This can be accomplished simply by recognizing that there exists intra-specific variability, in traits or properties related to the establishment of species interactions. By shifting the scale towards population-based processes, we show that this new approach will improve our predictive ability and mechanistic understanding of how species interact over large spatial or temporal scales.

2014-07-21

Drosophila embryogenesis scales uniformly across temperature and developmentally diverse species

10.1101/000307

Steven Gregory Kuntz;Michael B Eisen;

Temperature affects both the timing and outcome of animal development, but the detailed effects of temperature on the progress of early development have been poorly characterized. To determine the impact of temperature on the order and timing of events during Drosophila melanogaster embryogenesis, we used time-lapse imaging to track the progress of embryos from shortly after egg laying through hatching at seven precisely maintained temperatures between 17.5{degrees}C and 32.5{degrees}C. We employed a combination of automated and manual annotation to determine when 36 milestones occurred in each embryo. D. melanogaster embryogenesis takes 33 hours at 17.5{degrees}C, and accelerates with increasing temperature to a low of 16 hours at 27.5{degrees}C, above which embryogenesis slows slightly. Remarkably, while the total time of embryogenesis varies over two fold, the relative timing of events from cellularization through hatching is constant across temperatures. To further explore the relationship between temperature and embryogenesis, we expanded our analysis to cover ten additional Drosophila species of varying climatic origins. Six of these species, like D. melanogaster, are of tropical origin, and embryogenesis time at different temperatures was similar for them all. D. mojavensis, a sub-tropical fly, develops slower than the tropical species at lower temperatures, while D. virilis, a temperate fly, exhibits slower development at all temperatures. The alpine sister species D. persimilis and D. pseudoobscura develop as rapidly as tropical flies at cooler temperatures, but exhibit diminished acceleration above 22.5{degrees}C and have drastically slowed development by 30{degrees}C. Despite ranging from 13 hours for D. erecta at 30{degrees}C to 46 hours for D. virilis at 17.5{degrees}C, the relative timing of events from cellularization through hatching is constant across all of the species and temperatures examined here, suggesting the existence of a previously unrecognized timer controlling the progress of embryogenesis that has been tuned by natural selection in response to the thermal environment in which each species lives.\n\nAuthor SummaryTemperature profoundly impacts the rate of development of \"cold-blooded\" animals, which proceeds far faster when it is warm. There is, however, no universal relationship. Closely related species can develop at markedly different speeds at the same temperature, likely resulting from environmental adaptation. This creates a major challenge when comparing development among species, as it is unclear whether they should be compared at the same temperature or under different conditions to maintain the same developmental rate. Facing this challenge while working with flies (Drosophila species), we found there was little data to inform this decision. So, using time-lapse imaging, precise temperature-control, and computational and manual video-analysis, we tracked the complex process of embryogenesis in 11 species at seven different temperatures. There was over a three-fold difference in developmental rate between the fastest species at its fastest temperature and the slowest species at its slowest temperature. However, our finding that the timing of events within development all scaled uniformly across species and temperatures astonished us. This is good news for developmental biologists, since we can induce species to develop nearly identically by growing them at different temperatures. But it also means flies must possess some unknown clock-like molecular mechanism driving embryogenesis forward.

2013-11-12

Lipoproteins carry endocannabinoids that inhibit the Hedgehog pathway

10.1101/000570

Helena Khaliullina;Mesut Bilgin;Julio L. Sampaio;Andrej Shevchenko;Suzanne Eaton;

Hedgehog proteins are lipid-modified secreted signaling molecules that regulate tissue development and homeostasis. Lipids contained in circulating lipoproteins repress the Hedgehog signaling pathway in the absence of Hedgehog ligand, but the identity of these lipids is unknown. Here, using biochemical fractionation and lipid mass spectrometry, we identify these inhibitory lipids as endocannabinoids. Endocannabinoids are present in lipoproteins of both flies and humans, and repress the pathway in both mammalian signaling assays and Drosophila wing imaginal discs. In Drosophila, endocannabinoids are required in vivo to keep the levels of Smoothened and full-length Cubitus interruptus (Ci155) low in the absence of Hedgehog. Furthermore, elevating their endogenous levels inhibits Hedgehog-dependent accumulation of Smoothened and Ci155. Interestingly, cannabis-derived phytocannabinoids are also potent pathway inhibitors in flies and mammals. These findings constitute a novel link between organismal metabolism and local Hedgehog signaling, and suggest previously unsuspected mechanisms for the broad physiological activities of cannabinoids.

2013-11-18

An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells

10.1101/000653

David A Turner;Jamie Trott;Penelope Hayward;Pau Rué;Alfonso Martinez Arias;

Embryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst, retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analyzed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a \"race for fates\" at the level of single cells in which the neuroectodermal fate has an advantage.

2013-11-18

An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells

10.1101/000653

David A Turner;Jamie Trott;Penelope Hayward;Pau Rué;Alfonso Martinez Arias;

Embryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst, retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analyzed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a \"race for fates\" at the level of single cells in which the neuroectodermal fate has an advantage.

2013-11-21

An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells

10.1101/000653

David A Turner;Jamie Trott;Penelope Hayward;Pau Rué;Alfonso Martinez Arias;

Embryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst, retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analyzed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a \"race for fates\" at the level of single cells in which the neuroectodermal fate has an advantage.

2014-01-30

An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells

10.1101/000653

David A Turner;Jamie Trott;Penelope Hayward;Pau Rué;Alfonso Martinez Arias;

Embryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst, retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analyzed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a \"race for fates\" at the level of single cells in which the neuroectodermal fate has an advantage.

2014-06-30

Stem cells in Nanomia bijuga (Siphonophora), a colonial animal with localized growth zones

10.1101/001685

Stefan Siebert;Freya E. Goetz;Samuel H. Church;Pathikrit Bhattacharyya;Felipe Zapata;Steven H.D. Haddock;Casey W. Dunn;

BackgroundSiphonophores (Hydrozoa) have unparalleled colony-level complexity, precision of colony organization, and functional specialization between zooids (i.e., the units that make up colonies) Previous work has shown that, unlike other colonial animals, most growth in siphonophores is restricted to one or two well-defined growth zones that are the sites of both elongation and zooid budding. It remained unknown, however, how this unique colony growth and development is realized at the cellular level.\n\nResultsTo understand the colony-level growth and development of siphonophores at the cellular level, we characterize the distribution of proliferating cells and interstitial stem cells (i-cells) in the siphonophore Nanomia bijuga. Within the colony we find that i-cells are present at the tip of the horn, the structure within the growth zone that gives rise to new zooids. They persist in the youngest zooid buds, but as each zooid matures i-cells become progressively restricted to specific regions within the zooids until they are mostly absent from the oldest zooids. I-cell marker-gene expression remained in gametogenic regions. I-cells are not found in the stem between maturing zooids. Domains of high cell proliferation include regions where i-cells can be found, but also include some areas without i-cells such as the stem within the growth zones. Cell proliferation in regions devoid of marker gene expression indicates the presence of mitotically active epithelial cell lineages and, potentially, progenitor cell populations.\n\nConclusionsRestriction of stem cells to particular regions in the colony may play a major role in facilitating the precision of siphonophore growth, and also lead to a reduced developmental plasticity in other, typically older, parts of the colony. This helps explain why siphonophore colonies have such precise colony-level organization.

2014-01-06

Stem cells in Nanomia bijuga (Siphonophora), a colonial animal with localized growth zones

10.1101/001685

Stefan Siebert;Freya E. Goetz;Samuel H. Church;Pathikrit Bhattacharyya;Felipe Zapata;Steven H.D. Haddock;Casey W. Dunn;

BackgroundSiphonophores (Hydrozoa) have unparalleled colony-level complexity, precision of colony organization, and functional specialization between zooids (i.e., the units that make up colonies) Previous work has shown that, unlike other colonial animals, most growth in siphonophores is restricted to one or two well-defined growth zones that are the sites of both elongation and zooid budding. It remained unknown, however, how this unique colony growth and development is realized at the cellular level.\n\nResultsTo understand the colony-level growth and development of siphonophores at the cellular level, we characterize the distribution of proliferating cells and interstitial stem cells (i-cells) in the siphonophore Nanomia bijuga. Within the colony we find that i-cells are present at the tip of the horn, the structure within the growth zone that gives rise to new zooids. They persist in the youngest zooid buds, but as each zooid matures i-cells become progressively restricted to specific regions within the zooids until they are mostly absent from the oldest zooids. I-cell marker-gene expression remained in gametogenic regions. I-cells are not found in the stem between maturing zooids. Domains of high cell proliferation include regions where i-cells can be found, but also include some areas without i-cells such as the stem within the growth zones. Cell proliferation in regions devoid of marker gene expression indicates the presence of mitotically active epithelial cell lineages and, potentially, progenitor cell populations.\n\nConclusionsRestriction of stem cells to particular regions in the colony may play a major role in facilitating the precision of siphonophore growth, and also lead to a reduced developmental plasticity in other, typically older, parts of the colony. This helps explain why siphonophore colonies have such precise colony-level organization.

2015-03-16

Journey to the Center of the Mitochondria Guided by the Tail Anchor of Protein Tyrosine Phosphatase 1B

10.1101/000836

Julia Fueller;Mikhail Egorov;Kirstin A. Walther;Ola Sabet;Jana Mallah;Markus Grabenbauer;Ali Kinkhabwala;

The canonical protein tyrosine phosphatase PTP1B has traditionally been considered to exclusively reside on the endoplasmic reticulum (ER). Using confocal microscopy, we show that endogenous PTP1B actually exhibits a higher local concentration at the mitochondria in all mammalian cell lines that we tested. Fluorescently labeled chimeras containing full-length PTP1B or only its 35 amino acid tail anchor localized identically, demonstrating the complete dependence of PTP1Bs subcellular partitioning on its tail anchor. Correlative light and electron microscopy using GFP-driven photo-oxidation of DAB revealed that PTP1Bs tail anchor localizes it to the mitochondrial interior and to mitochondrial-associated membrane (MAM) sites along the ER. Heterologous expression of the tail anchor of PTP1B in the yeast S. cerevisiae surprisingly led to its exclusive localization to the ER/vacuole with no presence at the mitochondria. Studies with various yeast mutants of conserved membrane insertion pathways revealed a role for the GET/TRC40 pathway in ER insertion, but also emphasized the likely dominant role of spontaneous insertion. Further studies of modified tail isoforms in both yeast and mammalian cells revealed a remarkable sensitivity of subcellular partitioning to slight changes in transmembrane domain (TMD) length, C-terminal charge, and hydropathy. For example, addition of a single positive charge to the tail anchor was sufficient to completely shift the tail anchor to the mitochondria in mammalian cells and to largely shift it there in yeast cells, and a point mutation that increased TMD hydropathy was sufficient to localize the tail anchor exclusively to the ER in mammalian cells. Striking differences in the subcellular partitioning of a given tail anchor isoform in mammalian versus yeast cells most likely point to fundamental differences in the lipid composition of specific organelles (e.g. affecting membrane charge or thickness) in higher versus lower eukaryotes. Fluorescence lifetime imaging microscopy (FLIM) detection of the Forster Resonance Energy Transfer (FRET)-based interaction of the catalytic domain of PTP1B with the epidermal growth factor receptor (EGFR/ErbB1) at the mitochondria revealed a strong interaction on the cytosolic face of the outer mitochondrial membrane (OMM), suggesting the presence of a significant pool of PTP1B there and a novel role for PTP1B in the regulation of mitochondrial ErbB1 activity. In summary, in addition to its well-established general localization along the ER, our results reveal that PTP1B specifically accumulates at MAM sites along the ER and localizes as well to the OMM and mitochondrial matrix. Further elucidation of PTP1Bs roles in these different locations (including the identification of its targets) will likely be critical for understanding its complex regulation of general cellular responses, cell proliferation, and diseased states.

2013-11-22

p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition

10.1101/001602

Senthil K Radhakrishnan;Willem den Besten;Raymond J Deshaies;

Proteasome inhibition elicits an evolutionarily conserved response wherein proteasome subunit mRNAs are upregulated, resulting in recovery of proteasome activity. We previously demonstrated that the transcription factor Nrf1 mediates this homeostatic response in mammalian cells. We show here that Nrf1 is initially translocated into the lumen of the ER, but is rapidly and efficiently retrotranslocated to the cytosolic side of the membrane in a manner that depends on p97/VCP. Normally, retrotranslocated Nrf1 is degraded by the proteasome and active species do not accumulate. However, in cells with compromised proteasomes, retrotranslocated Nrf1 escapes degradation and is cleaved N-terminal to Leu-104 to yield a fragment that is no longer tethered to the ER-membrane. Importantly, this cleavage event is essential for Nrf1-dependent activation of proteasome gene expression upon proteasome inhibition. Our data uncover an unexpected role for p97 in activation of a transcription factor by relocalizing it from the ER lumen to the cytosol.

2013-12-29

p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition

10.1101/001602

Senthil K Radhakrishnan;Willem den Besten;Raymond J Deshaies;

Proteasome inhibition elicits an evolutionarily conserved response wherein proteasome subunit mRNAs are upregulated, resulting in recovery of proteasome activity. We previously demonstrated that the transcription factor Nrf1 mediates this homeostatic response in mammalian cells. We show here that Nrf1 is initially translocated into the lumen of the ER, but is rapidly and efficiently retrotranslocated to the cytosolic side of the membrane in a manner that depends on p97/VCP. Normally, retrotranslocated Nrf1 is degraded by the proteasome and active species do not accumulate. However, in cells with compromised proteasomes, retrotranslocated Nrf1 escapes degradation and is cleaved N-terminal to Leu-104 to yield a fragment that is no longer tethered to the ER-membrane. Importantly, this cleavage event is essential for Nrf1-dependent activation of proteasome gene expression upon proteasome inhibition. Our data uncover an unexpected role for p97 in activation of a transcription factor by relocalizing it from the ER lumen to the cytosol.

2013-12-30

p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition

10.1101/001602

Senthil K Radhakrishnan;Willem den Besten;Raymond J Deshaies;

Proteasome inhibition elicits an evolutionarily conserved response wherein proteasome subunit mRNAs are upregulated, resulting in recovery of proteasome activity. We previously demonstrated that the transcription factor Nrf1 mediates this homeostatic response in mammalian cells. We show here that Nrf1 is initially translocated into the lumen of the ER, but is rapidly and efficiently retrotranslocated to the cytosolic side of the membrane in a manner that depends on p97/VCP. Normally, retrotranslocated Nrf1 is degraded by the proteasome and active species do not accumulate. However, in cells with compromised proteasomes, retrotranslocated Nrf1 escapes degradation and is cleaved N-terminal to Leu-104 to yield a fragment that is no longer tethered to the ER-membrane. Importantly, this cleavage event is essential for Nrf1-dependent activation of proteasome gene expression upon proteasome inhibition. Our data uncover an unexpected role for p97 in activation of a transcription factor by relocalizing it from the ER lumen to the cytosol.

2014-01-23

Microenvironmental variables must influence intrinsic phenotypic parameters of cancer stem cells to affect tumourigenicity

10.1101/000141

Jacob Scott;Anita Hjelmeland;Prakash Chinnaiyan;Alexander R A Anderson;David Basanta;

Since the discovery of tumour initiating cells (TICs) in solid tumours, studies focussing on their role in cancer initiation and progression have abounded. The biological interrogation of these cells continues to yield volumes of information on their pro-tumourigenic behaviour, but actionable generalised conclusions have been scarce. Further, new information suggesting a dependence of tumour composition and growth on the microenvironment has yet to be studied theoretically. To address this point, we created a hybrid, discrete/continuous computational cellular automaton model of a generalised stem-cell driven tissue with a simple microenvironment. Using the model we explored the phenotypic traits inherent to the tumour initiating cells and the effect of the microenvironment on tissue growth. We identify the regions in phenotype parameter space where TICs are able to cause a disruption in homeostasis, leading to tissue overgrowth and tumour maintenance. As our parameters and model are non-specific, they could apply to any tissue TIC and do not assume specific genetic mutations. Targeting these phenotypic traits could represent a generalizable therapeutic strategy across cancer types. Further, we find that the microenvironmental variable does not strongly effect the outcomes, suggesting a need for direct feedback from the microenvironment onto stem-cell behaviour in future modelling endeavours.\n\nAuthor SummaryIn this paper, we present a mathematical/computational model of a tumour growing according to the canonical cancer stem-cell hypothesis with a simplified microenvironment. We explore the parameters of this model and find good agreement between our model and other theoretical models in terms of the intrinsic cellular parameters, which are difficult to study biologically. We find, however, disagreement between novel biological data and our model in terms of the microenvironmental changes. We conclude that future theoretical models of stem-cell driven tumours must include specific feedback from the microenvironment onto the individual cellular behavior. Further, we identify several cell intrinsic parameters which govern loss of homeostasis into a state of uncontrolled growth.

2013-11-07

A filter-flow perspective of hematogenous metastasis offers a non-genetic paradigm for personalized cancer therapy

10.1101/000125

Jacob G Scott;Alexander G Fletcher;Philip K Maini;Alexander R A Anderson;Philip Gerlee;

Translational RelevanceSince the discovery of circulating tumor cells (CTC), we have struggled for ways to use them to inform treatment. The only currently accepted method for this is a more is worse paradigm by which clinicians measure CTC burden before and after treatment to assess efficacy. Research efforts are currently focused almost entirely on genetic classification of these cells, which has yet to bear any fruit translationally. We suggest that we should shift the focus of our investigation to one driven by a physical sciences perspective. Specifically, by understanding the vascular system as a network of interconnected organs and capillary beds as filters that capture CTCs. By ascertaining the distribution of CTCs in this network for individual patients, information about the existence of subclinical metastatic disease, and therefore metastatic propensity, will come to light, and allow for better staging, prognostication and rational use of organ-directed therapy in the setting of oligometastatic disease.\n\nAbstractO_ST_ABSPurposeC_ST_ABSResearch into mechanisms of hematogenous metastasis has largely become genetic in focus, attempting to understand the molecular basis of seed-soil relationships. However, preceding this biological mechanism is the physical process of dissemination of circulating tumour cells (CTCs) in the circulatory network. We utilize a novel, network perspective of hematogenous metastasis and a large dataset on metastatic patterns to shed new light on this process.\n\nExperimental DesignThe metastatic efficiency index (MEI), previously suggested by Weiss, quantifies the process of hematogenous metastasis by taking the ratio of metastatic incidence for a given primary-target organ pair and the relative blood flow between the two sites. In this paper we extend the methodology by taking into account the reduction in CTC number that occurs in capillary beds and a novel network model of CTC flow.\n\nResultsBy applying this model to a dataset of metastatic incidence, we show that the MEI depends strongly on the assumptions of micrometastatic lesions in the lung and liver. Utilizing this framework we can represent different configurations of metastatic disease and offer a rational method for identifying patients with oligometastatic disease for inclusion in future trials.\n\nConclusionsWe show that our understanding of the dynamics of CTC flow is significantly lacking, and that this specifically precludes our ability to predict metastatic patterns in individual patients. Our formalism suggests an opportunity to go a step further in metastatic disease characterization by including the distribution of CTCs at staging, offering a rational method of trial design for oligometastatic disease.

2013-11-07

Mutated SF3B1 is associated with transcript isoform changes of the genes UQCC and RPL31 both in CLLs and uveal melanomas

10.1101/000992

Alejandro Reyes;Carolin Blume;Vicent Pelechano;Petra Jakob;Lars M Steinmetz;Thorsten Zenz;Wolfgang Huber;

BackgroundGenome sequencing studies of chronic lympoid leukemia (CLL) have provided a comprehensive overview of recurrent somatic mutations in coding genes. One of the most intriguing discoveries has been the prevalence of mutations in the HEAT-repeat domain of the splicing factor SF3B1. A frequently observed variant is predicted to cause the substitution of a lysine with a glutamic acid at position 700 of the protein (K700E). However, the molecular consequences of the mutations are largely unknown.\n\nResultsTo start exploring this question, we sequenced the transcriptomes of six samples: four samples of CLL tumour cells, of which two contained the K700E mutation in SF3B1, and CD19 positive cells from two healthy donors. We identified 41 genes that showed differential usage of exons statistically associated with the mutated status of SF3B1 (false discovery rate of 10%). These genes were enriched in pathways related to interferon signaling and mRNA splicing.\n\nAmong these genes, we found UQCC and RPL31; notably, a similar effect on these genes was described in a previously published study of uveal melanoma. In addition, while this manuscript was under revision, another study independently reported the common splicing signature of the gene UQCC in different tumour types with mutations in SF3B1.\n\nConclusionsOur results suggest common effects of isoform deregulation in the genes UQCC and RPL31 upon mutations in SF3B1. Additionally, our data provide a candidate list of potential isoform consequences of the SF3B1 (K700E) mutation in CLL, some of which might contribute to the tumourigenesis.\n\nValidation studies on larger cohorts and model systems are required to extend these findings.

2013-12-02

Mutated SF3B1 is associated with transcript isoform changes of the genes UQCC and RPL31 both in CLLs and uveal melanomas

10.1101/000992

Alejandro Reyes;Carolin Blume;Vicent Pelechano;Petra Jakob;Lars M Steinmetz;Thorsten Zenz;Wolfgang Huber;

BackgroundGenome sequencing studies of chronic lympoid leukemia (CLL) have provided a comprehensive overview of recurrent somatic mutations in coding genes. One of the most intriguing discoveries has been the prevalence of mutations in the HEAT-repeat domain of the splicing factor SF3B1. A frequently observed variant is predicted to cause the substitution of a lysine with a glutamic acid at position 700 of the protein (K700E). However, the molecular consequences of the mutations are largely unknown.\n\nResultsTo start exploring this question, we sequenced the transcriptomes of six samples: four samples of CLL tumour cells, of which two contained the K700E mutation in SF3B1, and CD19 positive cells from two healthy donors. We identified 41 genes that showed differential usage of exons statistically associated with the mutated status of SF3B1 (false discovery rate of 10%). These genes were enriched in pathways related to interferon signaling and mRNA splicing.\n\nAmong these genes, we found UQCC and RPL31; notably, a similar effect on these genes was described in a previously published study of uveal melanoma. In addition, while this manuscript was under revision, another study independently reported the common splicing signature of the gene UQCC in different tumour types with mutations in SF3B1.\n\nConclusionsOur results suggest common effects of isoform deregulation in the genes UQCC and RPL31 upon mutations in SF3B1. Additionally, our data provide a candidate list of potential isoform consequences of the SF3B1 (K700E) mutation in CLL, some of which might contribute to the tumourigenesis.\n\nValidation studies on larger cohorts and model systems are required to extend these findings.

2014-06-12

Mutated SF3B1 is associated with transcript isoform changes of the genes UQCC and RPL31 both in CLLs and uveal melanomas

10.1101/000992

Alejandro Reyes;Carolin Blume;Vicent Pelechano;Petra Jakob;Lars M Steinmetz;Thorsten Zenz;Wolfgang Huber;

BackgroundGenome sequencing studies of chronic lympoid leukemia (CLL) have provided a comprehensive overview of recurrent somatic mutations in coding genes. One of the most intriguing discoveries has been the prevalence of mutations in the HEAT-repeat domain of the splicing factor SF3B1. A frequently observed variant is predicted to cause the substitution of a lysine with a glutamic acid at position 700 of the protein (K700E). However, the molecular consequences of the mutations are largely unknown.\n\nResultsTo start exploring this question, we sequenced the transcriptomes of six samples: four samples of CLL tumour cells, of which two contained the K700E mutation in SF3B1, and CD19 positive cells from two healthy donors. We identified 41 genes that showed differential usage of exons statistically associated with the mutated status of SF3B1 (false discovery rate of 10%). These genes were enriched in pathways related to interferon signaling and mRNA splicing.\n\nAmong these genes, we found UQCC and RPL31; notably, a similar effect on these genes was described in a previously published study of uveal melanoma. In addition, while this manuscript was under revision, another study independently reported the common splicing signature of the gene UQCC in different tumour types with mutations in SF3B1.\n\nConclusionsOur results suggest common effects of isoform deregulation in the genes UQCC and RPL31 upon mutations in SF3B1. Additionally, our data provide a candidate list of potential isoform consequences of the SF3B1 (K700E) mutation in CLL, some of which might contribute to the tumourigenesis.\n\nValidation studies on larger cohorts and model systems are required to extend these findings.

2014-07-13