Genetic landscapes reveal how human genetic diversity aligns with geography, bioRxiv, 2017-12-14
Summarizing spatial patterns in human genetic diversity to understand population history has been a persistent goal for human geneticists. Here, we use a recently developed spatially explicit method to estimate effective migration surfaces to visualize how human genetic diversity is geographically structured (the EEMS method). The resulting surfaces are rugged, which indicates the relationship between genetic and geographic distance is heterogenous and distorted as a rule. Most prominently, topographic and marine features regularly align with increased genetic differentiation (e.g. the Sahara desert, Mediterranean Sea or Himalaya at large scales; the Adriatic, inter-island straits in near Oceania at smaller scales). We also see traces of historical migrations and boundaries of language families. These results provide visualizations of human genetic diversity that reveal local patterns of differentiation in detail and emphasize that while genetic similarity generally decays with geographic distance, there have regularly been factors that subtly distort the underlying relationship across space observed today. The fine-scale population structure depicted here is relevant to understanding complex processes of human population history and may provide insights for geographic patterning in rare variants and heritable disease risk.
biorxiv evolutionary-biology 100-200-users 2017Geometry of the sample frequency spectrum and the perils of demographic inference, bioRxiv, 2017-12-14
AbstractThe sample frequency spectrum (SFS), which describes the distribution of mutant alleles in a sample of DNA sequences, is a widely used summary statistic in population genetics. The expected SFS has a strong dependence on the historical population demography and this property is exploited by popular statistical methods to infer complex demographic histories from DNA sequence data. Most, if not all, of these inference methods exhibit pathological behavior, however. Specifically, they often display runaway behavior in optimization, where the inferred population sizes and epoch durations can degenerate to 0 or diverge to infinity, and show undesirable sensitivity of the inferred demography to perturbations in the data. The goal of this paper is to provide theoretical insights into why such problems arise. To this end, we characterize the geometry of the expected SFS for piecewise-constant demographic histories and use our results to show that the aforementioned pathological behavior of popular inference methods is intrinsic to the geometry of the expected SFS. We provide explicit descriptions and visualizations for a toy model with sample size 4, and generalize our intuition to arbitrary sample sizes n using tools from convex and algebraic geometry. We also develop a universal characterization result which shows that the expected SFS of a sample of size n under an arbitrary population history can be recapitulated by a piecewise-constant demography with only κn epochs, where κn is between n2 and 2n – 1. The set of expected SFS for piecewise-constant demographies with fewer than κn epochs is open and non-convex, which causes the above phenomena for inference from data.
biorxiv evolutionary-biology 0-100-users 2017MAGpy a reproducible pipeline for the downstream analysis of metagenome-assembled genomes (MAGs), bioRxiv, 2017-12-14
AbstractRecent advances in bioinformatics have enabled the rapid assembly of genomes from metagenomes (MAGs), and there is a need for reproducible pipelines that can annotate and characterise thousands of genomes simultaneously. Here we present MAGpy, a Snakemake pipeline that takes FASTA input and compares MAGs to several public databases, checks quality, assigns a taxonomy and draws a phylogenetic tree.
biorxiv bioinformatics 100-200-users 2017Phasic Activation of Ventral Tegmental, but not Substantia Nigra, Dopamine Neurons Promotes Model-Based Pavlovian Reward Learning, bioRxiv, 2017-12-14
ABSTRACTDopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra (SNc) encode reward prediction errors (RPEs) and are proposed to mediate error-driven learning. However the learning strategy engaged by DA-RPEs remains controversial. Model-free associations imbue cueactions with pure value, independently of representations of their associated outcome. In contrast, model-based associations support detailed representation of anticipated outcomes. Here we show that although both VTA and SNc DA neuron activation reinforces instrumental responding, only VTA DA neuron activation during consumption of expected sucrose reward restores error-driven learning and promotes formation of a new cue→sucrose association. Critically, expression of VTA DA-dependent Pavlovian associations is abolished following sucrose devaluation, a signature of model-based learning. These findings reveal that activation of VTA-or SNc-DA neurons engages largely dissociable learning processes with VTA-DA neurons capable of participating in model-based predictive learning, while the role of SNc-DA neurons appears limited to reinforcement of instrumental responses.
biorxiv neuroscience 100-200-users 2017Ultrafast glutamate sensors resolve high-frequency release at Schaffer collateral synapses, bioRxiv, 2017-12-14
ABSTRACTGlutamatergic synapses display a rich repertoire of plasticity mechanisms on many different time scales, involving dynamic changes in the efficacy of transmitter release as well as changes in the number and function of postsynaptic glutamate receptors. The genetically encoded glutamate sensor iGluSnFR enables visualization of glutamate release from presynaptic terminals at frequencies up to ∼10 Hz. However, to resolve glutamate dynamics during high frequency bursts, faster indicators are required. Here we report the development of fast (iGluf) and ultrafast (iGluu) variants with comparable brightness, but increased Kd for glutamate (137 μM and 600 μM, respectively). Compared to iGluSnFR, iGluu has a 6-fold faster dissociation rate in vitro and 5-fold faster kinetics in synapses. Fitting a three-state model to kinetic data, we identify the large conformational change after glutamate binding as the rate-limiting step. In rat hippocampal slice culture stimulated at 100 Hz, we find that iGluu is sufficiently fast to resolve individual glutamate release events, revealing that glutamate is rapidly cleared from the synaptic cleft. Depression of iGluu responses during 100 Hz trains correlates with depression of postsynaptic EPSPs, indicating that depression during high frequency stimulation is purely presynaptic in origin. At individual boutons, the recovery from depression could be predicted from the amount of glutamate released on the second pulse (paired pulse facilitationdepression), demonstrating differential frequency-dependent filtering of spike trains at Schaffer collateral boutons.Significance StatementExcitatory synapses convert presynaptic action potentials into chemical signals that are sensed by postsynaptic glutamate receptors. To eavesdrop on synaptic transmission, genetically encoded fluorescent sensors for glutamate have been developed. However, even the best available sensors lag behind the very fast glutamate dynamics in the synaptic cleft. Here we report the development of an ultrafast genetically encoded glutamate sensor, iGluu, which allowed us to image glutamate clearance and synaptic depression during 100 Hz spike trains. We found that only boutons showing paired-pulse facilitation were able to rapidly recover from depression. Thus, presynaptic boutons act as frequency-specific filters to transmit select features of the spike train to specific postsynaptic cells.
biorxiv neuroscience 0-100-users 2017A revised understanding of Tribolium morphogenesis further reconciles short and long germ development, bioRxiv, 2017-12-13
AbstractIn Drosophila melanogaster, the germband forms directly on the egg surface and solely consists of embryonic tissue. In contrast, most insect embryos undergo a complicated set of tissue rearrangements to generate a condensed, multi-layered germband. The ventral side of the germband is embryonic, while the dorsal side is thought to be an extraembryonic tissue called the amnion. While this tissue organisation has been accepted for decades, and has been widely reported in insects, its accuracy has not been directly tested in any species. Using live cell tracking and differential cell labelling in the short germ beetle Tribolium castaneum, I show that most of the cells previously thought to be amnion actually give rise to large parts of the embryo. This process occurs via the dorsal-to-ventral flow of cells and contributes to germband extension. In addition, I show that true ‘amnion’ cells in Tribolium originate from a small region of the blastoderm. Together, my findings show that development in the short germ embryos of Tribolium and the long germ embryos of Drosophila is more similar than previously proposed. Dorsal-to-ventral cell flow also occurs in Drosophila during germband extension, and I argue that the flow is driven by a conserved set of underlying morphogenetic events in both species. Furthermore, the revised Tribolium fatemap that I present is far more similar to that of Drosophila than the classic Tribolium fatemap. Lastly, my findings show that there is no qualitative difference between the tissue structure of the cellularised blastoderm and the shortintermediate germ germband. As such, the same tissue patterning mechanisms could function continuously throughout the cellularised blastoderm and germband stages, and easily shift between them over evolutionary time.Author summaryIn many animals, certain groups of cells in the embryo do not directly contribute to adult structures. Instead, these cells generate so-called ‘extra-embryonic tissues’ that support and facilitate development, but degenerate prior to birthhatching. In most insect species, embryos are described as having two major extra-embryonic tissues; the serosa, which encapsulates the entire embryo and yolk, and the amnion, which covers one side of the embryo. This tissue structure has been widely reported for over a century, but detailed studies on the amnion are lacking. Working in the beetle Tribolium castaneum, I used long-term fluorescent live imaging, cell tracking and differential cell labelling to investigate amnion development. In contrast to our current understanding, I show that most cells previously thought to be amnion actually form large parts of the embryo. In addition, I show how these cells ‘flow’ as a whole tissue and contribute to elongation of the embryo, and how only a relatively small number of cells form the actual amnion. Lastly, I describe how my findings show that despite exhibiting substantial differences in overall structure, embryos of Tribolium and the fruit fly, Drosophila melanogaster, utilise a conserved set of morphogenetic processes.
biorxiv developmental-biology 0-100-users 2017