Biology subjects

Conley, A. B.

Publications and source records attributed to Conley, A. B..

6 recordsLinked to original sources

bioRxiv2022

Rye: genetic ancestry inference at biobank scale

Biobank projects around the world are generating genomic data for many thousands and even millions of individuals. Computational methods are needed to handle these massive data sets, including tools for genetic ancestry (GA) inference. Current methods for GA inference are generally accurate, but they are slow and do not scale to biobank-size genomic datasets. Here we present Rye - a new algorithm for GA inference at biobank scale. We compare the accuracy and runtime performance of Rye to the widely used RFMix and ADMIXTURE programs, and we apply it to a dataset of 488,221 genome-wide variant samples from the UK Biobank. Rye infers GA based on principal component analysis (PCA) of genomic variant samples from ancestral reference populations and query individuals. The algorithms accuracy is powered by Metropolis-Hastings optimization and its speed is provided by non-negative least squares (NNLS) regression. Rye produces highly accurate GA estimates for three-way admixed populations - African, European, and Native American - compared to RFMix and ADMIXTURE (R2 = 0.998 - 1.00), and shows 50x runtime improvement compared to ADMIXTURE on the UK Biobank dataset. Rye analysis of UK Biobank samples demonstrates how it can be used to infer GA at different levels of relatedness. We discuss user consideration and options for the use of Rye; the program and its documentation are distributed on the GitHub repository: https://github.com/healthdisparities/rye.

bioinformatics↗

bioRxiv2020

Population structure and pharmacogenomic risk stratification in the United States

Pharmacogenomic (PGx) variants mediate how individuals respond to medication, and response differences among racial/ethnic groups have been attributed to patterns of PGx diversity. We hypothesized that genetic ancestry (GA) would provide higher resolution for stratifying PGx risk, since it serves as a more reliable surrogate for genetic diversity than self-identified race/ethnicity (SIRE), which includes a substantial social component. We analyzed a cohort of 8,628 individuals from the United States (US), for whom we had both SIRE information and whole genome genotypes, with a focus on the three largest SIRE groups in the US: White, Black, and Hispanic. Whole genome genotypes were used to characterize individuals continental ancestry fractions - European, African, and Native American - and individuals were grouped according to their GA profiles. SIRE and GA groups were found to be highly concordant. Continental ancestry predicts individuals SIRE with >96% accuracy, and accordingly GA provides only a marginal increase in resolution for PGx risk stratification. PGx variants are highly diverged compared to the genomic background; 82 variants show significant frequency differences among SIRE groups, and genome-wide patterns of PGx variation are almost entirely concordant with SIRE. Nevertheless, 97% of PGx variation is found within rather than between groups. Examples of highly differentiated PGx variants illustrate how SIRE partitions PGx variation based on group-specific ancestry patterns and contains valuable information for risk stratification. Finally, we show that individuals who identify as Black or Hispanic benefit more when SIRE is considered for treatment decisions than individuals from the majority White population.

genomics↗

bioRxiv2019

Admixture-enabled selection for rapid adaptive evolution in the Americas

BackgroundAdmixture occurs when previously isolated populations come together and exchange genetic material. We hypothesized that admixture can enable rapid adaptive evolution in human populations by introducing novel genetic variants (haplotypes) at intermediate frequencies, and we tested this hypothesis via the analysis of whole genome sequences sampled from admixed Latin American populations in Colombia, Mexico, Peru, and Puerto Rico.\n\nResultsOur screen for admixture-enabled selection relies on the identification of loci that contain more or less ancestry from a given source population than would be expected given the genome-wide ancestry frequencies. We employed a combined evidence approach to evaluate levels of ancestry enrichment at (1) single loci across multiple populations and (2) multiple loci that function together to encode polygenic traits. We found cross-population signals of African ancestry enrichment at the major histocompatibility locus on chromosome 6, consistent with admixture-enabled selection for enhanced adaptive immune response. Several of the human leukocyte antigen genes at this locus (HLA-A, HLA-DRB51 and HLA-DRB5) showed independent evidence of positive selection prior to admixture, based on extended haplotype homozygosity in African populations. A number of traits related to inflammation, blood metabolites, and both the innate and adaptive immune system showed evidence of admixture-enabled polygenic selection in Latin American populations.\n\nConclusionsThe results reported here, considered together with the ubiquity of admixture in human evolution, suggest that admixture serves as a fundamental mechanism that drives rapid adaptive evolution in human populations.

genomics↗

bioRxiv2019

Rapid Detection of Genetic Engineering, Structural Variation, and Antimicrobial Resistance Markers in Bacterial Biothreat Pathogens by Nanopore Sequencing

Widespread release of Bacillus anthracis (anthrax) or Yersinia pestis (plague) would prompt a public health emergency. During an exposure event, high-quality whole genome sequencing (WGS) can identify genetic engineering, including the introduction of antimicrobial resistance (AMR) genes. Here, we developed rapid WGS laboratory and bioinformatics workflows using a long-read nanopore sequencer (MinION) for Y. pestis (6.5h) and B. anthracis (8.5h) and sequenced strains with different AMR profiles. Both salt-precipitation and silica-membrane extracted DNA were suitable for MinION WGS using both rapid and field library preparation methods. In replicate experiments, nanopore quality metrics were defined for genome assembly and mutation analysis. AMR markers were correctly detected and >99% coverage of chromosomes and plasmids was achieved using 100,000 raw sequencing reads. While chromosomes and large and small plasmids were accurately assembled, including novel multimeric forms of the Y. pestis virulence plasmid, pPCP1, MinION reads were error-prone, particularly in homopolymer regions. MinION sequencing holds promise as a practical, front-line strategy for on-site pathogen characterization to speed the public health response during a biothreat emergency.

microbiology↗

bioRxiv2018

Cryptic Native American ancestry recapitulates population-specific migration and settlement of the continental United States

European and African descendants settled the continental US during the 17th-19th centuries, coming into contact with established Native American populations. The resulting admixture among these groups yielded a significant reservoir of cryptic Native American ancestry in the modern US population. We analyzed the patterns of Native American admixture seen for the three largest genetic ancestry groups in the US population: African American, European American, and Hispanic/Latino. The three groups show distinct Native American ancestry profiles, which are indicative of their historical patterns of migration and settlement across the country. Native American ancestry in the modern African American population does not coincide with local geography, instead forming a monophyletic group with origins in the southeastern US, consistent with the Great Migration of the early 20th century. European Americans show Native American ancestry that tracks their geographic origins across the US, indicative of ongoing contact during westward expansion, and Native American ancestry can resolve Hispanic/Latino individuals into distinct local groups formed by more recent migration from Mexico and Puerto Rico. We found an anomalous pattern of Native American ancestry from the US southwest, which most likely corresponds to the Nuevomexicano descendants of early Spanish settlers to the region. We addressed a number of controversies surrounding this population, including the extent of Sephardic Jewish ancestry. Nuevomexicanos are less admixed than nearby Mexican-American individuals, with more European and less Native American and African ancestry, and while they do show demonstrable Sephardic Jewish ancestry, the fraction is no greater than seen for other Hispanic/Latino populations.

genetics↗

bioRxiv2017

Assortative mating on ancestry-variant traits in admixed Latin American populations

BackgroundAssortative mating is a universal feature of human societies, and individuals from ethnically diverse populations are known to mate assortatively based on similarities in genetic ancestry. However, little is currently known regarding the exact phenotypic cues, or their underlying genetic architecture, which inform ancestry-based assortative mating.\n\nResultsWe developed a novel approach, using genome-wide analysis of ancestry-specific haplotypes, to evaluate ancestry-based assortative mating on traits whose expression varies among the three continental population groups - African, European, and Native American - that admixed to form modern Latin American populations. Application of this method to genome sequences sampled from Colombia, Mexico, Peru, and Puerto Rico revealed widespread ancestry-based assortative mating. We discovered a number of anthropometric traits (body mass, height, facial development and waist-hip ratio) and neurological attributes (educational attainment and schizophrenia) that serve as phenotypic cues for ancestry-based assortative mating. Major histocompatibility complex (MHC) loci show population-specific patterns of both assortative and disassortative mating in Latin America. Ancestry-based assortative mating in the populations analyzed here appears to be driven primarily by African ancestry.\n\nConclusionsThis study serves as an example of how population genomic analyses can yield novel insights into human behavior.

genomics↗