Accurate estimation of SNP-heritability from biobank-scale data irrespective of genetic architecture, bioRxiv, 2019-01-24
AbstractThe proportion of phenotypic variance attributable to the additive effects of a given set of genotyped SNPs (i.e. SNP-heritability) is a fundamental quantity in the study of complex traits. Recent works have shown that existing methods to estimate genome-wide SNP-heritability often yield biases when their assumptions are violated. While various approaches have been proposed to account for frequency- and LD-dependent genetic architectures, it remains unclear which estimates of SNP-heritability reported in the literature are reliable. Here we show that genome-wide SNP-heritability can be accurately estimated from biobank-scale data irrespective of the underlying genetic architecture of the trait, without specifying a heritability model or partitioning SNPs by minor allele frequency andor LD. We use theoretical justifications coupled with extensive simulations starting from real genotypes from the UK Biobank (N = 337K) to show that, unlike existing methods, our closed-form estimator for SNP-heritability is highly accurate across a wide range of architectures. We provide estimates of SNP-heritability for 22 complex traits and diseases in the UK Biobank and show that, consistent with our results in simulations, existing biobank-scale methods yield estimates up to 30% different from our theoretically-justified approach.
biorxiv genomics 0-100-users 2019Behavior influences range limits and patterns of coexistence across an elevational gradient in tropical bird diversity, bioRxiv, 2019-01-24
Does competition influence patterns of coexistence between closely related taxa? Here we address this basic question in ecology by analyzing patterns of range overlap between related bird species (sister pairs) distributed along a Neotropical elevational gradient. We explicitly contrast the behavioral dimension of interspecific competition (interference competition) with similarity in resource acquisition traits (exploitative competition). We find that behavioral interactions are generally important in setting elevational range limits and preventing coexistence of closely related species. Specifically, close relatives that defend year-round territories tend to live in non-overlapping elevational distributions, while close relatives that do not defend territories tend to broadly overlap in distribution. In contrast, neither similarity in beak morphology nor evolutionary relatedness was associated with patterns of range limitation. Our main result is that interference competition can be an important driver of species ranges at the scale of entire diverse assemblages. Consequently, we suggest that behavioral dimensions of the niche should be more broadly incorporated in macroecological studies.
biorxiv ecology 0-100-users 2019Mobile genetic element insertions drive antibiotic resistance across pathogens, bioRxiv, 2019-01-24
Mobile genetic elements contribute to bacterial adaptation and evolution; however, detecting these elements in a high-throughput and unbiased manner remains challenging. Here, we demonstrate a de novo approach to identify mobile elements from short-read sequencing data. The method identifies the precise site of mobile element insertion and infers the identity of the inserted sequence. This is an improvement over previous methods that either rely on curated databases of known mobile elements or rely on 'split-read' alignments that assume the inserted element exists within the reference genome. We apply our approach to 12,419 sequenced isolates of nine prevalent bacterial pathogens, and we identify hundreds of known and novel mobile genetic elements, including many candidate insertion sequences. We find that the mobile element repertoire and insertion rate vary considerably across species, and that many of the identified mobile elements are biased toward certain target sequences, several of them being highly specific. Mobile element insertion hotspots often cluster near genes involved in mechanisms of antibiotic resistance, and such insertions are associated with antibiotic resistance in laboratory experiments and clinical isolates. Finally, we demonstrate that mutagenesis caused by these mobile elements contributes to antibiotic resistance in a genome-wide association study of mobile element insertions in pathogenic Escherichia coli. In summary, by applying a de novo approach to precisely identify mobile genetic elements and their insertion sites, we thoroughly characterize the mobile element repertoire and insertion spectrum of nine pathogenic bacterial species and find that mobile element insertions play a significant role in the evolution of clinically relevant phenotypes, such as antibiotic resistance.
biorxiv microbiology 0-100-users 2019New Asgard archaea capable of anaerobic hydrocarbon cycling, bioRxiv, 2019-01-24
Large reservoirs of natural gas in the oceanic subsurface sustain a complex biosphere of anaerobic microbes, including recently characterized archaeal lineages that extend the potential to mediate hydrocarbon oxidation (methane and butane) beyond the Methanomicrobia. Here we describe a new archaeal phylum, Helarchaeota, belonging to the Asgard superphylum with the potential for hydrocarbon oxidation. We reconstructed Helarchaeota genomes from hydrothermal deep-sea sediment metagenomes in hydrocarbon-rich Guaymas Basin, and show that these encode novel methyl-CoM reductase-like enzymes that are similar to those found in butane-oxidizing archaea. Based on these results as well as the presence of several alkyl-CoA oxidation and Wood-Ljungdahl pathway genes in the Helarchaeota genomes, we suggest that members of the Helarchaeota have the potential to activate and subsequently anaerobically oxidize short-chain hydrocarbons. These findings link a new phylum of Asgard archaea to the microbial utilization of hydrothermally generated hydrocarbons, and extend this genomic blueprint further through the archaeal domain.
biorxiv microbiology 0-100-users 2019DNA methylation directs polycomb-dependent 3D genome re- organisation in naive pluripotency Supplementary information, bioRxiv, 2019-01-23
The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in 2i conditions results in redistribution of polycomb (H3K27me3) away from its target loci. Here we demonstrate that 3D genome organisation is also altered in 2i. We found chromatin decompaction at polycomb target loci as well as loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground-state, we are able to restore the H3K27me3 distribution, and polycomb-mediated 3D genome organisation that is characteristic of primed ESCs grown in serum, to ESCs in 2i. However, these cells retain the functional characteristics of 2i ground state ESCs. Our findings demonstrate the central role of DNA methylation in shaping major aspects of 3D genome organisation but caution against assuming causal roles for the epigenome and 3D genome in gene regulation and function in ESCs.
biorxiv cell-biology 0-100-users 2019Phase separation provides a mechanism to reduce noise in cells Supplementary text, bioRxiv, 2019-01-23
A central problem in cellular control is how cells cope with the inherent noise in gene expression. Although transcriptional and posttranscriptional feedback mechanisms can suppress noise, they are often slow, and cannot explain how cells buffer acute fluctuations. Here, by using a physical model that links fluctuations in protein concentration to the theory of phase separation, we show that liquid droplets can act as fast and effective buffers for gene expression noise. We confirm our theory experimentally using an engineered phase separating protein that forms liquid-like compartments in mammalian cells. These data suggest a novel role of phase separation in biological information processing.
biorxiv biophysics 0-100-users 2019