Long runs of homozygosity are enriched for deleterious variation

Abstract

Exome sequencing offers the potential to study the population-genomic variables that underlie patterns of deleterious variation. Runs of homozygosity (ROH) are long stretches of consecutive homozygous genotypes probably reflecting segments shared identically by descent as the result of processes such as consanguinity, population size reduction, and natural selection. The relationship between ROH and patterns of predicted deleterious variation can provide insight into the way in which these processes contribute to the maintenance of deleterious variants. Here, we use exome sequencing to examine ROH in relation to the distribution of deleterious variation in 27 individuals of varying levels of apparent inbreeding from 6 human populations. A significantly greater fraction of all genome-wide predicted damaging homozygotes fall in ROH than would be expected from the corresponding fraction of nondamaging homozygotes in ROH (p < 0.001). This pattern is strongest for long ROH (p < 0.05). ROH, and especially long ROH, harbor disproportionately more deleterious homozygotes than would be expected on the basis of the total ROH coverage of the genome and the genomic distribution of nondamaging homozygotes. The results accord with a hypothesis that recent inbreeding, which generates long ROH, enables rare deleterious variants to exist in homozygous form. Thus, just as inbreeding can elevate the occurrence of rare recessive diseases that represent homozygotes for strongly deleterious mutations, inbreeding magnifies the occurrence of mildly deleterious variants as well.

Figure 1

ROH Coverage across Individual Genomes The y axis gives the percentage of individual genomes covered by short (class A), medium (class B), and long (class C) ROH. Numbers on the x axis represent identification numbers in the HGDP-CEPH diversity panel.

Figure 2

PolyPhen2 Classification of the Final Set of 54,359 Variants after All Filtering

Figure 3

The Number of Damaging Nonreference Homozygotes versus the Fraction of the Genome Covered by ROH for Each Individual Red points represent the number of damaging homozygotes falling within ROH regions, and black points represent the number of damaging homozygotes falling outside ROH regions.

Figure 4

The Fraction of All Genome-wide Nonreference Homozygotes Falling in ROH Regions versus the Fraction of the Genome Covered by ROH, for Each Individual (A) Any ROH region. (B) Short (class A) ROH regions. (C) Medium (class B) ROH regions. (D) Long (class C) ROH regions. Red points represent damaging homozygotes, and blue points represent nondamaging homozygotes.

Figure 5

The Fraction of All Genome-wide Nonreference Homozygotes Falling in Different Sized ROH versus the Fraction of the Genome Covered by ROH, for Each Individual Orange points represent damaging homozygotes in long (class C) ROH regions, and green points represent damaging homozygotes in short (class A) ROH regions.

Figure 6

The Fraction of All Private Nonreference Variants that Are Synonymous or Missense Variants Private variants are defined as variants for which the nonreference allele appears only in a single population in our sample. Missense variants are further split by PolyPhen2 into predicted benign, predicted possibly damaging, and predicted probably damaging classes.

Figure 7

The Fraction of All Genome-wide Nonreference Homozygotes Falling in ROH Regions for Nondamaging Variants, Nonsense Variants, and LoF Nonsense Variants versus the Fraction of the Genome Covered by ROH, for Individuals Grouped into “Low-ROH” and “High-ROH” Groups (A) Any ROH region. (B) Short (class A) ROH regions. (C) Medium (class B) ROH regions. (D) Long (class C) ROH regions. Means that exceed the mean for benign sites for the same ROH coverage class at the p < 0.05 significance level are indicated by asterisks.