Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity

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.

Keywords: ROH; admixture; deleterious alleles; haplotype; homozygosity; identity by descent; population bottleneck; runs of homozygosity.

Figure 1

A Ternary Plot of Global Ancestry Proportions Each point represents a single individual, with their global ancestry proportions shown on each of the three axes (European, EUR; African, AFR; and Native American, NAM). Individuals are colored based on their reported ethnicity, with African Americans (AA) colored gray, Puerto Ricans (PR) colored purple, and Mexican Americans (MX) colored green.

Figure 2

The Distribution of Summed ROH Lengths across Size Classes Shown are (A) all ROH, (B) short ROH, (C) medium ROH, and (D) long ROH. AA, African American; PR, Puerto Rican; MX, Mexican American.

Figure 3

The Distribution of Deleterious Alleles across Populations The number of (A) deleterious heterozygotes, (B) deleterious homozygotes, and (C) total deleterious alleles per individual using PolyPhen2 classifications. AA, African American; PR, Puerto Rican; MX, Mexican American.

Figure 4

Deleterious and Benign Homozygotes in ROH Classes The proportion of damaging (red) and benign (blue) homozygotes falling in ROH of different size classes: (A) all ROH, (B) short ROH, (C) medium ROH, and (D) long ROH. Data shown is across all populations. Gray line plots Y = X.

Figure 5

Deleterious and Benign Homozygotes in ROH Classes Separated by Ancestry The proportion of damaging (red) and benign (blue) homozygotes falling in ROH comprised of different ancestral haplotypes and size classes: (A) all NAM ROH, (B) all EUR ROH, (C) all AFR ROH, (D) long NAM ROH, (E) long EUR ROH, and (F) long AFR ROH. EUR, European; AFR, African, and NAM, Native American. Gray line plots Y = X.

Figure 6

Deleterious Homozygotes in ROH Classes Compared across Ancestry A direct comparison of the proportion of damaging homozygotes falling in ROH comprised of different ancestral haplotypes for (A) all ROH and (B) long ROH. EUR, European, colored blue; AFR, African, colored orange; and NAM, Native American, colored red. Gray line plots Y = X.

Figure 7

Enrichment of Low-Frequency Variants across ROH Sizes The difference in rate of gain of low-frequency minor allele homozygotes (MAF < 0.05) compared to common minor allele homozygotes (MAF ≥ 0.05; ${\beta }_3$ from regression analysis). ROH size classes: A, short; B, medium; C, long; R, all sizes. EUR, European, colored blue; AFR, African, colored orange; and NAM, Native American, colored red. Error bars represent standard error of the regression coefficient.