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Ancestry-dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity

View ORCID ProfileZachary A. Szpiech, Angel C.Y. Mak, Marquitta J. White, Donglei Hu, Celeste Eng, Esteban G. Burchard, Ryan D. Hernandez
doi: https://doi.org/10.1101/382721
Zachary A. Szpiech
1Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
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  • ORCID record for Zachary A. Szpiech
  • For correspondence: zachary.szpiech@ucsf.edu ryan.hernandez@me.com
Angel C.Y. Mak
2Department of Medicine, University of California San Francisco, San Francisco, California, USA
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Marquitta J. White
2Department of Medicine, University of California San Francisco, San Francisco, California, USA
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Donglei Hu
2Department of Medicine, University of California San Francisco, San Francisco, California, USA
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Celeste Eng
2Department of Medicine, University of California San Francisco, San Francisco, California, USA
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Esteban G. Burchard
2Department of Medicine, University of California San Francisco, San Francisco, California, USA
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Ryan D. Hernandez
1Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
3Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA
4Quantitative Biosciences Institute, University of California San Francisco, San Francisco, California, USA
5Department of Human Genetics, McGill University, Montreal, Quebec, Canada
6Genome Quebec Innovation Center, McGill University, Montreal, Quebec, Canada
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  • For correspondence: zachary.szpiech@ucsf.edu ryan.hernandez@me.com
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Abstract

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 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.

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Posted August 02, 2018.
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Ancestry-dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity
Zachary A. Szpiech, Angel C.Y. Mak, Marquitta J. White, Donglei Hu, Celeste Eng, Esteban G. Burchard, Ryan D. Hernandez
bioRxiv 382721; doi: https://doi.org/10.1101/382721
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Ancestry-dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity
Zachary A. Szpiech, Angel C.Y. Mak, Marquitta J. White, Donglei Hu, Celeste Eng, Esteban G. Burchard, Ryan D. Hernandez
bioRxiv 382721; doi: https://doi.org/10.1101/382721

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