Modeling the effects of consanguinity on autosomal and X-chromosomal runs of homozygosity and identity-by-descent sharing.

Runs of homozygosity (ROH) and identity-by-descent (IBD) sharing can be studied in diploid coalescent models by noting that ROH and IBD-sharing at a genomic site are predicted to be inversely related to coalescence times-which in turn can be mathematically obtained in terms of parameters describing consanguinity rates. Comparing autosomal and X-chromosomal coalescent models, we consider ROH and IBD-sharing in relation to consanguinity that proceeds via multiple forms of first-cousin mating. We predict that across populations with different levels of consanguinity, (1) in a manner that is qualitatively parallel to the increase of autosomal IBD-sharing with autosomal ROH, X-chromosomal IBD-sharing increases with X-chromosomal ROH, owing to the dependence of both quantities on consanguinity levels; (2) even in the absence of consanguinity, X-chromosomal ROH and IBD-sharing levels exceed corresponding values for the autosomes, owing to the smaller population size and lower coalescence time for the X chromosome than for autosomes; (3) with matrilateral consanguinity, the relative increase in ROH and IBD-sharing on the X chromosome compared to the autosomes is greater than in the absence of consanguinity. Examining genome-wide SNPs in human populations for which consanguinity levels have been estimated, we find that autosomal and X-chromosomal ROH and IBD-sharing levels generally accord with the predictions. We find that each 1% increase in autosomal ROH is associated with an increase of 2.1% in X-chromosomal ROH, and each 1% increase in autosomal IBD-sharing is associated with an increase of 1.6% in X-chromosomal IBD-sharing. For each calculation, particularly for ROH, the estimate is reasonably close to the increase of 2% predicted by the population-size difference between autosomes and X chromosomes. The results support the utility of coalescent models for understanding patterns of genomic sharing and their dependence on sex-biased processes.

Limiting distribution of X-chromosomal coalescence times under first-cousin consanguineous mating.

By providing additional opportunities for coalescence within families, the presence of consanguineous unions in a population reduces coalescence times relative to non-consanguineous populations. First-cousin consanguinity can take one of six forms differing in the configuration of sexes in the pedigree of the male and female cousins who join in a consanguineous union: patrilateral parallel, patrilateral cross, matrilateral parallel, matrilateral cross, bilateral parallel, and bilateral cross. Considering populations with each of the six types of first-cousin consanguinity individually and a population with a mixture of the four unilateral types, we examine coalescent models of consanguinity. We previously computed, for first-cousin consanguinity models, the mean coalescence time for X-chromosomal loci and the limiting distribution of coalescence times for autosomal loci. Here, we use the separation-of-time-scales approach to obtain the limiting distribution of coalescence times for X-chromosomal loci. This limiting distribution has an instantaneous coalescence probability that depends on the probability that a union is consanguineous; lineages that do not coalesce instantaneously coalesce according to an exponential distribution. We study the effects on the coalescence time distribution of the type of first-cousin consanguinity, showing that patrilateral-parallel and patrilateral-cross consanguinity have no effect on X-chromosomal coalescence time distributions and that matrilateral-parallel consanguinity decreases coalescence times to a greater extent than does matrilateral-cross consanguinity.

Ancient and modern genomics of the Ohlone Indigenous population of California.

SignificanceCalifornia supports a high cultural and linguistic diversity of Indigenous peoples. In a partnership of researchers with the Muwekma Ohlone tribe, we studied genomes of eight present-day tribal members and 12 ancient individuals from two archaeological sites in the San Francisco Bay Area, spanning ∼2,000 y. We find that compared to genomes of Indigenous individuals from throughout the Americas, the 12 ancient individuals are most genetically similar to ancient individuals from Southern California, and that despite spanning a large time period, they share distinctive ancestry. This ancestry is also shared with present-day tribal members, providing evidence of genetic continuity between past and present Indigenous individuals in the region, in contrast to some popular reconstructions based on archaeological and linguistic information.

LocalNgsRelate: a software tool for inferring IBD sharing along the genome between pairs of individuals from low-depth NGS data.

MOTIVATION: Inference of identity-by-descent (IBD) sharing along the genome between pairs of individuals has important uses. But all existing inference methods are based on genotypes, which is not ideal for low-depth Next Generation Sequencing (NGS) data from which genotypes can only be called with high uncertainty. RESULTS: We present a new probabilistic software tool, LocalNgsRelate, for inferring IBD sharing along the genome between pairs of individuals from low-depth NGS data. Its inference is based on genotype likelihoods instead of genotypes, and thereby it takes the uncertainty of the genotype calling into account. Using real data from the 1000 Genomes project, we show that LocalNgsRelate provides more accurate IBD inference for low-depth NGS data than two state-of-the-art genotype-based methods, Albrechtsen et al. (2009) and hap-IBD. We also show that the method works well for NGS data down to a depth of 2×. AVAILABILITY AND IMPLEMENTATION: LocalNgsRelate is freely available at https://github.com/idamoltke/LocalNgsRelate. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The effect of consanguinity on coalescence times on the X chromosome.

Consanguineous unions increase the frequency at which identical genomic segments are inherited along separate paths of descent, decreasing coalescence times for pairs of alleles drawn from an individual who is the offspring of a consanguineous pair. For an autosomal locus, it has recently been shown that the mean time to the most recent common ancestor (TMRCA) for two alleles in the same individual and the mean TMRCA for two alleles in two separate individuals both decrease with increasing consanguinity in a population. Here, we extend this analysis to the X chromosome, considering X-chromosomal coalescence times under a coalescent model with diploid, male-female mating pairs. We examine four possible first-cousin mating schemes that are equivalent in their effects on autosomes, but that have differing effects on the X chromosome: patrilateral-parallel, patrilateral-cross, matrilateral-parallel, and matrilateral-cross. In each mating model, we calculate mean TMRCA for X-chromosomal alleles sampled either within or between individuals. We describe a consanguinity effect on X-chromosomal TMRCA that differs from the autosomal pattern under matrilateral but not under patrilateral first-cousin mating. For matrilateral first cousins, the effect of consanguinity in reducing TMRCA is stronger on the X chromosome than on the autosomes, with an increased effect of parallel-cousin mating compared to cross-cousin mating. The theoretical computations support the utility of the model in understanding patterns of genomic sharing on the X chromosome.

Variance and limiting distribution of coalescence times in a diploid model of a consanguineous population.

Recent modeling studies interested in runs of homozygosity (ROH) and identity by descent (IBD) have sought to connect these properties of genomic sharing to pairwise coalescence times. Here, we examine a variety of features of pairwise coalescence times in models that consider consanguinity. In particular, we extend a recent diploid analysis of mean coalescence times for lineage pairs within and between individuals in a consanguineous population to derive the variance of coalescence times, studying its dependence on the frequency of consanguinity and the kinship coefficient of consanguineous relationships. We also introduce a separation-of-time-scales approach that treats consanguinity models analogously to mathematically similar phenomena such as partial selfing, using this approach to obtain coalescence-time distributions. This approach shows that the consanguinity model behaves similarly to a standard coalescent, scaling population size by a factor 1-3c, where c represents the kinship coefficient of a randomly chosen mating pair. It provides the explanation for an earlier result describing mean coalescence time in the consanguinity model in terms of c. The results extend the potential to make predictions about ROH and IBD in relation to demographic parameters of diploid populations.

The Effect of Consanguinity on Between-Individual Identity-by-Descent Sharing.

Consanguineous unions increase the rate at which identical genomic segments are paired within individuals to produce runs of homozygosity (ROH). The extent to which such unions affect identity-by-descent (IBD) genomic sharing between rather than within individuals in a population, however, is not immediately evident from within-individual ROH levels. Using the fact that the time to the most recent common ancestor [Formula: see text] for a pair of genomes at a specific locus is inversely related to the extent of IBD sharing between the genomes in the neighborhood of the locus, we study IBD sharing for a pair of genomes sampled either within the same individual or in different individuals. We develop a coalescent model for a set of mating pairs in a diploid population, treating the fraction of consanguineous unions as a parameter. Considering mating models that include unions between sibs, first cousins, and nth cousins, we determine the effect of the consanguinity rate on the mean [Formula: see text] for pairs of lineages sampled either within the same individual or in different individuals. The results indicate that consanguinity not only increases ROH sharing between the two genomes within an individual, it also increases IBD sharing between individuals in the population, the magnitude of the effect increasing with the kinship coefficient of the type of consanguineous union. Considering computations of ROH and between-individual IBD in Jewish populations whose consanguinity rates have been estimated from demographic data, we find that, in accord with the theoretical results, increases in consanguinity and ROH levels inflate levels of IBD sharing between individuals in a population. The results contribute more generally to the interpretation of runs of homozygosity, IBD sharing between individuals, and the relationship between ROH and IBD.