Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity

Zachary A Szpiech,Angel C.Y Mak,Marquitta J White,Donglei Hu,Celeste Eng,Esteban G Burchard,Ryan D Hernandez

doi:10.1016/j.ajhg.2019.08.011

Abstract

Runs of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations.

Highlights

Runs of homozygosity (ROH) are long stretches of identical-by-descent (IBD) haplotypes that manifest in individual genomes as the result of recent parental relatedness
With high deleterious heterozygosity, we propose that African ancestral haplotypes may be most susceptible to large increases in deleterious homozygotes when subjected to harsh bottlenecks or inbreeding, as these low-frequency deleterious alleles will be paired into homozygotes as a result of increased genomic ROH
Admixture Using the subset of sites from our whole-genome sequencing data that intersected with our African, European, and Native American reference panels, we called 3-way local ancestry tracts in all 1,441 samples

Summary

Introduction

Runs of homozygosity (ROH) are long stretches of identical-by-descent (IBD) haplotypes that manifest in individual genomes as the result of recent parental relatedness. Several studies of the distribution of ROH in ostensibly outbred human populations have shown that ROH are common and range in size from tens of kilobases to several megabases in length.[2,3,4,5] total length and prevalence of ROH are correlated with distance from Africa,[3,4,5] with more and longer ROH manifesting in individuals from populations a longer distance away These patterns likely reflect increased IBD among haplotypes as a result of the serial bottlenecking process that humans experienced as they migrated out of Africa. With high deleterious heterozygosity, we propose that African ancestral haplotypes may be most susceptible to large increases in deleterious homozygotes when subjected to harsh bottlenecks or inbreeding, as these low-frequency deleterious alleles will be paired into homozygotes as a result of increased genomic ROH

Material and Methods

Results

Declaration of Interests