Models of archaic admixture and recent history from two-locus statistics, bioRxiv, 2018-12-08
AbstractWe learn about population history and underlying evolutionary biology through patterns of genetic polymorphism. Many approaches to reconstruct evolutionary histories focus on a limited number of informative statistics describing distributions of allele frequencies or patterns of linkage disequilibrium. We show that many commonly used statistics are part of a broad family of two-locus moments whose expectation can be computed jointly and rapidly under a wide range of scenarios, including complex multi-population demographies with continuous migration and admixture events. A full inspection of these statistics reveals that widely used models of human history fail to predict simple patterns of linkage disequilibrium. To jointly capture the information contained in classical and novel statistics, we implemented a tractable likelihood-based inference framework for demographic history. Using this approach, we show that human evolutionary models that include archaic admixture in Africa, Asia, and Europe provide a much better description of patterns of genetic diversity across the human genome. We estimate that an unidentified, deeply diverged population admixed with modern humans within Africa both before and after the split of African and Eurasian populations, contributing 4 - 8% genetic ancestry to individuals in world-wide populations.Author SummaryThroughout human history, populations have expanded and contracted, split and merged, and ex-changed migrants. Because these events affected genetic diversity, we can learn about human history by comparing predictions from evolutionary models to genetic data. Here, we show how to rapidly compute such predictions for a wide range of diversity measures within and across populations under complex demographic scenarios. While widely used models of human history accurately predict common measures of diversity, we show that they strongly underestimate the co-occurence of low frequency mutations within human populations in Asia, Europe, and Africa. Models allowing for archaic admixture, the relatively recent mixing of human populations with deeply diverged human lineages, resolve this discrepancy. We use such models to infer demographic models that include both recent and ancient features of human history. We recover the well-characterized admixture of Neanderthals in Eurasian populations, as well as admixture from an as-yet unknown diverged human population within Africa, further suggesting that admixture with deeply diverged lineages occurred multiple times in human history. By simultaneously testing model predictions for a broad range of diversity statistics, we can assess the robustness of common evolutionary models, identify missing historical events, and build more informed models of human demography.
biorxiv genetics 100-200-users 2018The consensus molecular classification of muscle-invasive bladder cancer, bioRxiv, 2018-12-08
AbstractMuscle-Invasive Bladder Cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, yielding diverse sets of subtypes, which hampers the clinical implications of such knowledge. Here, we report the results of a large international effort to reach a consensus on MIBC molecular subtypes. Using 1750 MIBC transcriptomes and a network-based analysis of six independent MIBC classification systems, we identified a consensus set of six molecular classes Luminal Papillary (24%), Luminal Non-Specified (8%), Luminal Unstable (15%), Stroma-rich (15%), BasalSquamous (35%), and Neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics. This consensus system offers a robust framework that will enable testing and validating predictive biomarkers in future clinical trials.
biorxiv cancer-biology 100-200-users 2018The genomic and proteomic landscape of the rumen microbiome revealed by comprehensive genome-resolved metagenomics, bioRxiv, 2018-12-08
AbstractRuminants provide essential nutrition for billions of people worldwide. The rumen is a specialised stomach adapted to the breakdown of plant-derived complex polysaccharides, and collectively the rumen microbiota encode the thousands of enzymes responsible. Here we present a comprehensive analysis of over 6.5 terabytes of Illumina and Nanopore sequence data, including assembly of 4941 metagenome-assembled genomes, and several single-contig, whole-chromosome assemblies of novel rumen bacteria. We also present the largest dataset of predicted proteins from the rumen, and provide rich annotation against public datasets. Together these data will form an essential part of future studies of rumen microbiome structure and function.
biorxiv microbiology 100-200-users 2018High-resolution structure determination of sub-100 kilodalton complexes using conventional cryo-EM, bioRxiv, 2018-12-07
Determining high-resolution structures of biological macromolecules with masses of less than 100 kilodaltons (kDa) has long been a goal of the cryo-electron microscopy (cryo-EM) community. While the Volta Phase Plate has enabled cryo-EM structure determination of biological specimens of this size range, use of this instrumentation is not yet fully automated and can present technical challenges. Here, we show that conventional defocus-based cryo-EM methodologies can be used to determine the high-resolution structures of specimens amassing less than 100 kDa using a transmission electron microscope operating at 200 keV coupled with a direct electron detector. Our ~2.9 Å structure of alcohol dehydrogenase (82 kDa) proves that bound ligands can be resolved with high fidelity, indicating that these methodologies can be used to investigate the molecular details of drug-target interactions. Our ~2.8 Å and ~3.2 Å resolution structures of methemoglobin demonstrate that distinct conformational states can be identified within a dataset for proteins as small as 64 kDa. Furthermore, we provide the first sub-nanometer cryo-EM structure of a protein smaller than 50 kDa.
biorxiv biophysics 100-200-users 2018A comparison of gene expression and DNA methylation patterns across tissues and species, bioRxiv, 2018-12-05
AbstractPreviously published comparative functional genomic data sets from primates using frozen tissue samples, including many data sets from our own group, were collected and analyzed using non-optimal study designs and analysis approaches. In addition, when samples from multiple tissues were studied in a comparative framework, individual and tissue were confounded. We designed a multi-tissue comparative study of gene expression and DNA methylation in primates that minimizes confounding effects by using a balanced design with respect to species, tissues, and individuals. We also developed a comparative analysis pipeline that minimizes biases due to sequence divergence. We thus present the most comprehensive catalog of similarities and differences in gene expression and methylation levels between livers, kidneys, hearts, and lungs, in humans, chimpanzees, and rhesus macaques. We estimate that overall, only between 7 to 11% (depending on the tissue) of inter-species differences in gene expression levels can be accounted for by corresponding differences in promoter DNA methylation. However, gene expression divergence in conserved tissue-specific genes can be explained by corresponding inter-species methylation changes more often. We end the paper by providing recommendations for effective study design and best practices for meta-data recording for comparative functional genomic studies in primates.
biorxiv genomics 0-100-users 2018Natural selection contributed to immunological differences between human hunter-gatherers and agriculturalists, bioRxiv, 2018-12-05
AbstractThe shift from a hunter-gatherer (HG) to an agricultural (AG) mode of subsistence is believed to have been associated with profound changes in the burden and diversity of pathogens across human populations. Yet, the extent to which the advent of agriculture may have impacted the evolution of the human immune system remains unknown. Here we present a comparative study of variation in the transcriptional responses of peripheral blood mononuclear cells to bacterial and viral stimuli between Batwa rainforest hunter-gatherers and Bakiga agriculturalists from Uganda. We observed increased divergence between hunter-gatherers and agriculturalists in the transcriptional response to viruses compared to that for bacterial stimuli. We demonstrate that a significant fraction of these transcriptional differences are under genetic control, and we show that positive natural selection has helped to shape population differences in immune regulation. Across the set of genetic variants underlying inter-population immune response differences, however, the signatures of positive selection were disproportionately observed in the rainforest hunter-gatherers. This result is counter to expectations based on the popularized notion that shifts in pathogen exposure due to the advent of agriculture imposed radically heightened selective pressures in agriculturalist populations.
biorxiv evolutionary-biology 0-100-users 2018