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Haplotype-based inference of the distribution of fitness effects

View ORCID ProfileDiego Ortega-Del Vecchyo, Kirk E. Lohmueller, John Novembre
doi: https://doi.org/10.1101/770966
Diego Ortega-Del Vecchyo
1International Laboratory for Human Genome Research, National Autonomous University of Mexico, Santiago de Querétaro, Querétaro, 76230, México
2Interdepartmental Program in Bioinformatics, University of California, Los Angeles, CA 90095, United States of America
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  • For correspondence: gochambas@gmail.com
Kirk E. Lohmueller
2Interdepartmental Program in Bioinformatics, University of California, Los Angeles, CA 90095, United States of America
3Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, United States of America
4Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, United States of America
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John Novembre
5Department of Human Genetics, University of Chicago, Chicago, Illinois, 60637, United States of America
6Department of Ecology and Evolution, University of Chicago, Chicago, Illinois, 60637, United States of America
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Abstract

Recent genome sequencing studies with large sample sizes in humans have discovered a vast quantity of low-frequency variants, providing an important source of information to analyze how selection is acting on human genetic variation. In order to estimate the strength of natural selection acting on low-frequency variants, we have developed a likelihood-based method that uses the lengths of pairwise identity-by-state between haplotypes carrying low-frequency variants. We show that in some non-equilibrium populations (such as those that have had recent population expansions) it is possible to distinguish between positive or negative selection acting on a set of variants. With our new framework, one can infer a fixed selection intensity acting on a set of variants at a particular frequency, or a distribution of selection coefficients for standing variants and new mutations. We apply our method to the UK10K phased haplotype dataset of 3,781 individuals and find a similar proportion of neutral, moderately deleterious, and deleterious variants compared to previous estimates made using the site frequency spectrum. We discuss several interpretations for this result, including that selective constraints have remained constant over time.

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Posted September 16, 2019.
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Haplotype-based inference of the distribution of fitness effects
Diego Ortega-Del Vecchyo, Kirk E. Lohmueller, John Novembre
bioRxiv 770966; doi: https://doi.org/10.1101/770966
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Haplotype-based inference of the distribution of fitness effects
Diego Ortega-Del Vecchyo, Kirk E. Lohmueller, John Novembre
bioRxiv 770966; doi: https://doi.org/10.1101/770966

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