Publications by authors named "Arun Durvasula"

All published methods for learning about demographic history make the simplifying assumption that the genome evolves neutrally, and do not seek to account for the effects of natural selection on patterns of variation. This is a major concern, as ample work has demonstrated the pervasive effects of natural selection and in particular background selection (BGS) on patterns of genetic variation in diverse species. Simulations and theoretical work have shown that methods to infer changes in effective population size over time (()) become increasingly inaccurate as the strength of linked selection increases.

View Article and Find Full Text PDF
Article Synopsis
  • The study introduces a new method called LDSPEC to estimate the relationship between causal disease effect sizes of nearby SNPs, challenging the assumption that they are independent.
  • It analyzes data from 70 diseases in the UK Biobank, discovering significant correlations in effect sizes among proximal SNP pairs, which vary based on different factors such as distance and allele frequency.
  • The research finds that SNP pairs with related functions show stronger correlations extending over longer genomic distances, and it reveals that SNP-heritability estimates are lower than previously thought, indicating a discrepancy between expected and real genetic contributions to diseases.
View Article and Find Full Text PDF
Article Synopsis
  • The study investigates the relationships between causal disease effect sizes of proximal SNPs (single nucleotide polymorphisms) using a new method called LDSPEC, suggesting that these SNPs are not independent as previously thought.
  • By applying LDSPEC to data from 70 diseases in the UK Biobank, researchers found that the correlations in effect sizes between nearby SNPs varied based on distance, allele frequency, and linkage disequilibrium (LD), indicating complex interactions.
  • The results reveal that SNP pairs with shared functions show stronger correlations over longer distances, leading to a significant discrepancy between SNP-heritability estimates and the total variance of causal effect sizes, challenging prior assumptions in genetic research.
View Article and Find Full Text PDF
Article Synopsis
  • - The study proposes a new method called age-dependent topic modeling (ATM) for analyzing longitudinal electronic health records (EHRs), aimed at improving disease diagnoses and personalized medicine by identifying disease subtypes based on patient comorbidities.
  • - Analysis of large datasets from the UK Biobank and All of Us found 52 diseases with varying comorbidity profiles, leading to the classification of disease subtypes and the examination of genetic risks associated with these subtypes through polygenic risk scores.
  • - The findings reveal 18 distinct disease subtypes showing significant differences in genetic risk, pointing to specific genetic variants that influence disease risk differently across these subtypes.
View Article and Find Full Text PDF
Article Synopsis
  • The paper investigates the interaction between genes and environmental factors (GxE) in relation to diseases and complex traits, using three statistical methods to analyze different types of GxE interactions.
  • The researchers applied these methods to data from 33 traits in the UK Biobank, revealing significant GxE interactions in numerous instances, including notable differences based on lifestyle factors like smoking and physical activity.
  • Findings included 19 trait-E pairs where GxE interaction was significant, 28 pairs with varying genetic influences across environmental conditions, and 15 pairs with uniform genetic influences regardless of the environment, highlighting the complexity of how genes and environments contribute to traits and diseases.
View Article and Find Full Text PDF

The genetic variants introduced into the ancestors of modern humans from interbreeding with Neanderthals have been suggested to contribute an unexpected extent to complex human traits. However, testing this hypothesis has been challenging due to the idiosyncratic population genetic properties of introgressed variants. We developed rigorous methods to assess the contribution of introgressed Neanderthal variants to heritable trait variation and applied these methods to analyze 235,592 introgressed Neanderthal variants and 96 distinct phenotypes measured in about 300,000 unrelated white British individuals in the UK Biobank.

View Article and Find Full Text PDF

Adaptive introgression (AI) facilitates local adaptation in a wide range of species. Many state-of-the-art methods detect AI with ad-hoc approaches that identify summary statistic outliers or intersect scans for positive selection with scans for introgressed genomic regions. Although widely used, approaches intersecting outliers are vulnerable to a high false-negative rate as the power of different methods varies, especially for complex introgression events.

View Article and Find Full Text PDF

Motivation: Admixture, the interbreeding between previously distinct populations, is a pervasive force in evolution. The evolutionary history of populations in the presence of admixture can be modeled by augmenting phylogenetic trees with additional nodes that represent admixture events. While enabling a more faithful representation of evolutionary history, admixture graphs present formidable inferential challenges, and there is an increasing need for methods that are accurate, fully automated and computationally efficient.

View Article and Find Full Text PDF

Phenotype prediction is a key goal for medical genetics. Unfortunately, most genome-wide association studies are done in European populations, which reduces the accuracy of predictions via polygenic scores in non-European populations. Here, we use population genetic models to show that human demographic history and negative selection on complex traits can result in population-specific genetic architectures.

View Article and Find Full Text PDF

Metabolic pathways differ across species but are expected to be similar within a species. We discovered two functional, incompatible versions of the galactose pathway in We identified a three-locus genetic interaction for growth in galactose, and used precisely engineered alleles to show that it arises from variation in the galactose utilization genes , , and phosphoglucomutase (), and that the reference allele of is incompatible with the alternative alleles of the other genes. Multiloci balancing selection has maintained the two incompatible versions of the pathway for millions of years.

View Article and Find Full Text PDF

The explosion in population genomic data demands ever more complex modes of analysis, and increasingly, these analyses depend on sophisticated simulations. Recent advances in population genetic simulation have made it possible to simulate large and complex models, but specifying such models for a particular simulation engine remains a difficult and error-prone task. Computational genetics researchers currently re-implement simulation models independently, leading to inconsistency and duplication of effort.

View Article and Find Full Text PDF

While introgression from Neanderthals and Denisovans has been documented in modern humans outside Africa, the contribution of archaic hominins to the genetic variation of present-day Africans remains poorly understood. We provide complementary lines of evidence for archaic introgression into four West African populations. Our analyses of site frequency spectra indicate that these populations derive 2 to 19% of their genetic ancestry from an archaic population that diverged before the split of Neanderthals and modern humans.

View Article and Find Full Text PDF

Statistical analyses of genomic data from diverse human populations have demonstrated that archaic hominins, such as Neanderthals and Denisovans, interbred or admixed with the ancestors of present-day humans. Central to these analyses are methods for inferring archaic ancestry along the genomes of present-day individuals (archaic local ancestry). Methods for archaic local ancestry inference rely on the availability of reference genomes from the ancestral archaic populations for accurate inference.

View Article and Find Full Text PDF

Dominance is a fundamental concept in molecular genetics and has implications for understanding patterns of genetic variation, evolution, and complex traits. However, despite its importance, the degree of dominance in natural populations is poorly quantified. Here, we leverage multiple mating systems in natural populations of Arabidopsis to co-estimate the distribution of fitness effects and dominance coefficients of new amino acid changing mutations.

View Article and Find Full Text PDF

Pigmentation is often used to understand how natural selection affects genetic variation in wild populations since it can have a simple genetic basis, and can affect a variety of fitness-related traits (e.g., camouflage, thermoregulation, and sexual display).

View Article and Find Full Text PDF

To investigate the consequences of hybridization between species, we studied three replicate hybrid populations that formed naturally between two swordtail fish species, estimating their fine-scale genetic map and inferring ancestry along the genomes of 690 individuals. In all three populations, ancestry from the "minor" parental species is more common in regions of high recombination and where there is linkage to fewer putative targets of selection. The same patterns are apparent in a reanalysis of human and archaic admixture.

View Article and Find Full Text PDF

Over the past 20 y, many studies have examined the history of the plant ecological and molecular model, , in Europe and North America. Although these studies informed us about the recent history of the species, the early history has remained elusive. In a large-scale genomic analysis of African , we sequenced the genomes of 78 modern and herbarium samples from Africa and analyzed these together with over 1,000 previously sequenced Eurasian samples.

View Article and Find Full Text PDF

High-throughput sequencing has changed many aspects of population genetics, molecular ecology and related fields, affecting both experimental design and data analysis. The software package angsd allows users to perform a number of population genetic analyses on high-throughput sequencing data. angsd uses probabilistic approaches which can directly make use of genotype likelihoods; thus, SNP calling is not required for comparative analyses.

View Article and Find Full Text PDF

Genetic diversity is shaped by the interaction of drift and selection, but the details of this interaction are not well understood. The impact of genetic drift in a population is largely determined by its demographic history, typically summarized by its long-term effective population size (Ne). Rapidly changing population demographics complicate this relationship, however.

View Article and Find Full Text PDF