Runs of homozygosity: windows into population history and trait architecture

Key Points

  • The inheritance of identical haplotypes from a common ancestor creates long tracts of homozygous genotypes known as runs of homozygosity (ROH).

  • ROH are ubiquitous across human populations, and they correlate with pedigree inbreeding. Larger populations have fewer, shorter ROH, whereas isolated or bottlenecked populations have more, somewhat longer ROH. Admixed groups have the fewest ROH, whereas consanguineous communities carry very long ROH. Native American populations have the highest burdens of ROH in the world.

  • ROH can be detected in microarray or whole-genome sequencing (WGS) data, using either observational approaches, for example, that implemented in PLINK, or model-based approaches. Simulations show that PLINK outperforms many other methods.

  • ROH are non-randomly distributed across the genome, being more prevalent in areas of low recombination, but are also concentrated in small regions called ROH islands.

  • Quantitative traits related to stature and cognition have been robustly associated with ROH burden, implying recessive variants contribute to their genetic architecture. Case–control analyses of ROH, on the other hand, appear more easily confounded by socioeconomic or cultural factors.

  • Both megacohorts and special populations are now being used to investigate diverse aspects of the scope and mechanism of inbreeding depression in humans.

Abstract

Long runs of homozygosity (ROH) arise when identical haplotypes are inherited from each parent and thus a long tract of genotypes is homozygous. Cousin marriage or inbreeding gives rise to such autozygosity; however, genome-wide data reveal that ROH are universally common in human genomes even among outbred individuals. The number and length of ROH reflect individual demographic history, while the homozygosity burden can be used to investigate the genetic architecture of complex disease. We discuss how to identify ROH in genome-wide microarray and sequence data, their distribution in human populations and their application to the understanding of inbreeding depression and disease risk.

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Figure 1: Demographic origins of ROH.
Figure 2: Global census of ROH.
Figure 3: Genomic distributions reveal common ROH islands and random patterning of long ROH.
Figure 4: Effect of genome-wide homozygosity on 16 complex traits.

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Acknowledgements

This work was supported by the Medical Research Council Human Genetics Unit quinquennial programme grant 'QTL in Health and Disease.' F.C.C. is supported by the South African National Research Foundation (NRF), and M.R. holds a South African Research Chair in Genomics and Bioinformatics of African populations hosted by the University of the Witwatersrand, funded by the Department of Science and Technology and administered by the NRF. The authors thank T. Gonzalez for help with figures and G. Alvarez, R. Vilas, O. Polašek, T. Esko, A. Wright, H. Campbell and C. Haley for helpful discussions and comments on the manuscript.

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F.C.C. and J.F.W. researched data for the article. F.C.C., P.K.J., D.W.C. and J.F.W. wrote the manuscript. All authors contributed to reviewing and editing the manuscript before submission.

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Correspondence to James F. Wilson.

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Glossary

Consanguinity

Mating among relatives, for example, first or second cousins. Literally 'of the same blood'.

Endogamy

Marriage within the population or community.

Runs of homozygosity

(ROH). Contiguous regions of the genome where an individual is homozygous across all sites. This arises if the haplotypes transmitted from the mother and father are identical, having in turn been inherited from a common ancestor at some point in the past. It is important to note that this notion does not rely on a known pedigree and does not require an (arbitrary) baseline population (the first generation of ancestors or founders in a pedigree). However, ROH in practice are required to have an (arbitrary) minimum size, depending on the density of genotypes available, to distinguish identity-by-descent from chance.

Autozygous

Also known as homozygosity-by-descent; homozygosity arising at a locus owing to identity-by-descent.

Effective population size

(Ne). The size of an idealized population that would show the same amount of genetic drift or inbreeding, often thought of as the number of breeding individuals and usually lower than the census population size.

Demographic histories

The histories of the changes in population size; for example, populations may be large or small, of constant size, or expanding or contracting; may undergo bottlenecks (severe declines in population size) or founder events (establishment of populations by a limited number of ancestors); may be substructured geographically; or may admix with one another.

Inbreeding depression

The reduction in evolutionary fitness of a population or individual due to the presence of increased homozygosity arising from inbreeding. Values of traits related to fitness, such as fertility, are reduced.

Genetic architecture

The makeup of the genetic basis of a trait, in particular whether there are few or many causal loci, whether the causal variants are rare or common or have small or large effect sizes and the degree to which dominance plays a part.

Haplotype

A set of alleles on a chromosome or chromosomal segment inherited from one parent — often a series of alleles at neighbouring loci that are strongly statistically associated due to lack of recombination. Certain haplotypes may become common in the population owing to natural selection or drift until broken down over time by recombination.

Admixed

Genetic admixture occurs when mating begins between two previously separate populations and individuals within the new population have a mix of haplotypes from each parental population.

Inbreeding loops

Also known as pedigree loops; the connection in a pedigree between the maternal and paternal ancestors of an individual. The closed loops show how the same haplotypes could pass down both sides of families.

Population bottleneck

A severe decline in population size over a short time or a lesser reduction over a longer time, followed by a recovery.

Cosmopolitan populations

Populations that are not isolated; typical urban populations.

Overdominance

Also known as heterozygote advantage; overdominance occurs if the heterozygote trait value (phenotype) is outside the range of the trait values of the two homozygotes.

Balancing selection

When two or more alleles are favoured by natural selection rather than one, for example, when the heterozygote is fitter than either homozygote.

Dominance

Dominance is present at a genetic locus when the effect of one copy of an allele gives rise to a trait or phenotypic value that, rather than being halfway between the values for the two homozygotes, is nearer the trait value for a carrier of two copies of the allele. In this situation, the other allele is recessive.

Directional dominance

Directional dominance occurs when the dominance effect across all causal loci in the genome has a trend in one direction, that is, to raise or lower the trait, rather than the individual dominance effects at loci cancelling each other out.

Identity-by-descent

(IBD). The inheritance of an identical haplotype from both parents owing to it having been passed without recombination from a common ancestor in the baseline population.

Inbreeding coefficient

The probability, denoted F, of inheriting two alleles identical-by-descent at an autosomal locus in the presence of consanguinity. F is one-sixteenth for first-cousin offspring, one-sixty-fourth for second cousins and one-eighth for the progeny of avuncular or double first-cousin matings.

Genomic inbreeding coefficient

FROH; the proportion of the genome that is in ROH. F and FROH have been shown to be highly correlated.

Avuncular union

Marriage or mating between an uncle and niece or aunt and nephew.

Confounding

Literally, confusion. Statistical confounding arises when the association between a proposed explanatory variable and an outcome is distorted by the presence of a third variable associating with both. Unless all confounding can be excluded, causal inferences cannot be made from observational associations.

Darwinian fitness

The expected relative contribution of an individual or allele to the next generation of the population. It is the ability of an organism of a particular genotype to survive and leave viable offspring in its particular environment, captured in the phrase 'the survival of the fittest', although reproduction of the fittest might be more apt.

Panmixia

Random mating rather than mating structured by geography, ethnicity, socioeconomic status or other factors.

Gene conversion

A mechanism of recombination where one DNA sequence is replaced by a highly homologous one, leaving the sequences identical. In mammals, gene conversion tracts are usually short, between 200 bp and 1 kb.

Heterosis

Also called hybrid vigour; the propensity when inbred lines of, for example, maize or domesticated animals are crossed to result in hybrids that are fitter than either parent. The trait values that were reduced by inbreeding depression increase after outbreeding.

Outbreeding depression

When the offspring of distantly related mates are less fit than the parents; for example, if one homozygote has the highest fitness, outbreeding will usually increase the number of heterozygotes and thus reduce fitness.

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Ceballos, F., Joshi, P., Clark, D. et al. Runs of homozygosity: windows into population history and trait architecture. Nat Rev Genet 19, 220–234 (2018). https://doi.org/10.1038/nrg.2017.109

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