Consanguinity Rates Predict Long Runs of Homozygosity in Jewish Populations

Kang, Jonathan T. L.; Goldberg, Amy; Edge, Michael D.; Behar, Doron M.; Rosenberg, Noah A.

doi:10.1159/000478897

Cited by 31 publications

(56 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, multiple population-genetic studies have shown that relatively large ROH (>1Mb) are common even in outbred populations [24][25][26][27] ; we recapitulate this result in eight cohorts in the 23andMe dataset ( Supplementary Figure 2). Thus, an effective ROH-based method for UPD detection must be able to identify UPD chromosomes in the presence of large ROH on non-UPD chromosomes.…”

Section: New Roh-based Upd Detection Without Parental Genotypesmentioning

confidence: 54%

Characterization of prevalence and health consequences of uniparental disomy in four million individuals from the general population

Nakka

Smith

O’Donnell-Luria

et al. 2019

Preprint

View full text Add to dashboard Cite

Meiotic nondisjunction and resulting aneuploidy can lead to severe health consequences in humans. Aneuploidy rescue can restore euploidy but may result in uniparental disomy (UPD), the inheritance of both homologs of a chromosome from one parent with no representative copy from the other. Current understanding of UPD is limited to ~3,300 cases for which UPD was associated with clinical presentation due to imprinting disorders or recessive diseases. Thus, the prevalence of UPD and its phenotypic consequences in the general population are unknown. We searched for instances of UPD in over four million consented research participants from the personal genetics company 23andMe, Inc., and 431,094 UK Biobank participants. Using computationally detected DNA segments identical-by-descent (IBD) and runs of homozygosity (ROH), we identified 675 instances of UPD across both databases. Here we present the first characterization of UPD prevalence in the general population, a machinelearning framework to detect UPD using ROH, and a novel association between autism and UPD of chromosome 22. Putative UPD22Putative UPDX Class A ROH Class B ROH Class C ROH Key:the chromosomes represent Class A ROH, red rectangles represent Class B ROH, and green rectangles represent Class C ROH.

show abstract

Section: New Roh-based Upd Detection Without Parental Genotypesmentioning

confidence: 54%

Characterization of prevalence and health consequences of uniparental disomy in four million individuals from the general population

Nakka

Smith

O’Donnell-Luria

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…62 Because previous research has shown a strong correlation between recent inbreeding, quantified by both F SNP and F PED , and long runs of homozygosity, we were particularly interested in the mechanism behind the generation of long ROHs. [56][57][58][59][60][61][76][77][78] We used simulations to test which demographic scenarios could produce long ROHs ( Figure 5). These simulations and availability of extended pedigree data were crucial, because the F SNP metric can also be influenced by a recent bottleneck.…”

Section: Discussionmentioning

confidence: 99%

“…SNPs with missing data were removed from these analyses. There was a total of 16 SNPs out of the 57,597,196 SNPs that were removed due to missing data.…”

Section: Site Frequency Spectrum (Sfs)mentioning

confidence: 99%

“…Next, we examined patterns of long runs (>2 Mb, see Subjects and Methods) of homozygosity, since ROHs have been linked to recent consanguinity. [56][57][58][59][60] The YRI and CEU had the lowest amount of their genome contained within an ROH ( Figure 4A). The FIN had higher median (median ¼ 11 Mb and SD ¼ 6.3 Mb) amounts of their genome within an ROH in comparison to the CEU (median ¼ 2.4 Mb and SD ¼ 2.1 Mb).…”

Section: Exploring Recent Consanguinitymentioning

confidence: 99%

See 1 more Smart Citation

Understanding the Hidden Complexity of Latin American Population Isolates

Mooney

Huber

Marsden

et al. 2018

The American Journal of Human Genetics

View full text Add to dashboard Cite

Most population isolates examined to date were founded from a single ancestral population. Consequently, there is limited knowledge about the demographic history of admixed population isolates. Here we investigate genomic diversity of recently admixed population isolates from Costa Rica and Colombia and compare their diversity to a benchmark population isolate, the Finnish. These Latin American isolates originated during the 16 th century from admixture between a few hundred European males and Amerindian females, with a limited contribution from African founders. We examine whole-genome sequence data from 449 individuals, ascertained as families to build mutigenerational pedigrees, with a mean sequencing depth of coverage of approximately 363. We find that Latin American isolates have increased genetic diversity relative to the Finnish. However, there is an increase in the amount of identity by descent (IBD) segments in the Latin American isolates relative to the Finnish. The increase in IBD segments is likely a consequence of a very recent and severe population bottleneck during the founding of the admixed population isolates. Furthermore, the proportion of the genome that falls within a long run of homozygosity (ROH) in Costa Rican and Colombian individuals is significantly greater than that in the Finnish, suggesting more recent consanguinity in the Latin American isolates relative to that seen in the Finnish. Lastly, we find that recent consanguinity increased the number of deleterious variants found in the homozygous state, which is relevant if deleterious variants are recessive. Our study suggests that there is no single genetic signature of a population isolate.

show abstract

“…Originally conceived to improve the accuracy of homozygosity mapping of recessive Mendelian diseases, ROH have formed the foundation of studies investigating the contribution of recessive deleterious variants to the genetic risk for complex diseases and to the determination of complex traits. 1 Moreover, they have provided unique insights into the demographic and sociocultural processes 1 that have shaped genomic variation patterns in contemporary worldwide human populations, [2][3][4][5][6][7][8] ancient hominins, [9][10][11][12] non-human primates, 13,14 woolly mammoths, 15 livestock, [16][17][18][19][20][21] birds, 22,23 felines, 24 and canids. [25][26][27][28][29][30][31] Recent population bottlenecks, cultural preferences for endogamy or consanguineous marriage, and natural selection can create increased rates of ROH in individual genomes, substantially increasing overall homozygosity in such populations.…”

Section: Introductionmentioning

confidence: 99%

Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity

Szpiech

Mak

White

et al. 2019

The American Journal of Human Genetics

View full text Add to dashboard Cite

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.

show abstract

Consanguinity Rates Predict Long Runs of Homozygosity in Jewish Populations

Cited by 31 publications

References 33 publications

Characterization of prevalence and health consequences of uniparental disomy in four million individuals from the general population

Characterization of prevalence and health consequences of uniparental disomy in four million individuals from the general population

Understanding the Hidden Complexity of Latin American Population Isolates

Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity

Contact Info

Product

Resources

About