title: The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit.
abstract: The genetic consequences of population bottlenecks on patterns of deleterious genetic variation in human populations are of tremendous interest. Based on exome sequencing of 18 Greenlandic Inuit we show that the Inuit have undergone a severe ∼20,000-year-long bottleneck. This has led to a markedly more extreme distribution of allele frequencies than seen for any other human population tested to date, making the Inuit the perfect population for investigating the effect of a bottleneck on patterns of deleterious variation. When comparing proxies for genetic load that assume an additive effect of deleterious alleles, the Inuit show, at most, a slight increase in load compared to European, East Asian, and African populations. Specifically, we observe <4% increase in the number of derived deleterious alleles in the Inuit. In contrast, proxies for genetic load under a recessive model suggest that the Inuit have a significantly higher load (20% increase or more) compared to other less bottlenecked human populations. Forward simulations under realistic models of demography support our empirical findings, showing up to a 6% increase in the genetic load for the Inuit population across all models of dominance. Further, the Inuit population carries fewer deleterious variants than other human populations, but those that are present tend to be at higher frequency than in other populations. Overall, our results show how recent demographic history has affected patterns of deleterious variants in human populations.
authors.affiliation: Department of Biology, Section for Computational and RNA Biology, University of Copenhagen, 2200 Copenhagen N, Denmark ida@binf.ku.dk albrecht@binf.ku.dk.
authors.forename: Casper-Emil T
authors.initials: CT
authors.lastname: Pedersen
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, California 90095.|Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095.
authors.forename: Kirk E
authors.initials: KE
authors.lastname: Lohmueller
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen Ø, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.affiliation: National Institute of Public Health, University of Southern Denmark, 1353 Copenhagen K, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Bjerregaard
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen Ø, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: Department of Biology, Section for Computational and RNA Biology, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Siegismund
authors.affiliation: Department of Biology, Section for Computational and RNA Biology, University of Copenhagen, 2200 Copenhagen N, Denmark ida@binf.ku.dk albrecht@binf.ku.dk.
authors.forename: Ida
authors.initials: I
authors.lastname: Moltke
authors.affiliation: Department of Biology, Section for Computational and RNA Biology, University of Copenhagen, 2200 Copenhagen N, Denmark ida@binf.ku.dk albrecht@binf.ku.dk.
authors.forename: Anders
authors.initials: A
authors.lastname: Albrechtsen
mesh_terms: D019143:Evolution, Molecular; D059472:Exome; D005787:Gene Frequency; D040741:Genetic Load; D006116:Greenland; D063426:Human Migration; D006801:Humans; D004930:Inuit / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
keywords: disease mapping; founder population; genetic load; isolated human populations; neutral theory