title: 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.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA. zachary.szpiech@ucsf.edu
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Szpiech
authors.forename: Jishu
authors.initials: J
authors.lastname: Xu
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pemberton
authors.forename: Weiping
authors.initials: W
authors.lastname: Peng
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zöllner
authors.forename: Noah A
authors.initials: NA
authors.lastname: Rosenberg
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Li
mesh_terms: D000483:Alleles; D019295:Computational Biology / Q000379:methods; D003241:Consanguinity; D059472:Exome; D005828:Genetics, Population / Q000379:methods*; D015894:Genome, Human; D056914:Genomic Structural Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests