Characteristics of Neutral and Deleterious Protein-Coding Variation among Individuals and Populations

Fu, Wenqing; Gittelman, Rachel M.; Bamshad, Michael J.; Akey, Joshua M.

doi:10.1016/j.ajhg.2014.09.006

Cited by 93 publications

(154 citation statements)

References 55 publications

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“…Our present findings of a higher genetic load in dogs compared with wolves supports the view that recent demographic history can affect genetic load. The magnitude of the increase in additive genetic load in non-African human populations has been estimated to be slight, ∼1-3% (5,6,8,37,38), which is similar in magnitude to the increase we observed in dogs relative to wolves (Fig. 3).…”

Section: Significancesupporting

confidence: 72%

“…Some studies showed similar numbers of putatively deleterious alleles per individual across human populations (3,4). In contrast, other recent studies reported a significant increase in the number of deleterious alleles (5, 37) and a higher additive genetic load in non-African populations compared with African populations (5,6,8,37,38). Our present findings of a higher genetic load in dogs compared with wolves supports the view that recent demographic history can affect genetic load.…”

Section: Significancecontrasting

confidence: 53%

“…This similarity indicates that, although detectable, the effect of recent demography on additive genetic load is likely to be subtle, even for extreme bottlenecks. Although dramatic fitness consequences in dogs are often thought to be caused by recessive mutations of large effect, we find that as in humans, most of the additive genetic load is accounted for by numerous weakly deleterious mutations (5,6), which are particularly hard to remove from bottlenecked populations. Second, intense artificial selection for desirable traits results in a concomitant accumulation of deleterious variation in genes trapped in sweep regions.…”

Section: Discussionmentioning

confidence: 86%

“…Consequently, understanding the reasons why deleterious mutations persist in populations and the role of demographic history in this process is of considerable interest (1)(2)(3)(4)(5)(6)(7)(8)(9). The radiation of domestic dogs offers a unique opportunity to address these questions.…”

mentioning

confidence: 99%

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Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs

Marsden

Vecchyo

O’Brien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

274

338

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Population bottlenecks, inbreeding, and artificial selection can all, in principle, influence levels of deleterious genetic variation. However, the relative importance of each of these effects on genome-wide patterns of deleterious variation remains controversial. Domestic and wild canids offer a powerful system to address the role of these factors in influencing deleterious variation because their history is dominated by known bottlenecks and intense artificial selection. Here, we assess genome-wide patterns of deleterious variation in 90 whole-genome sequences from breed dogs, village dogs, and gray wolves. We find that the ratio of amino acid changing heterozygosity to silent heterozygosity is higher in dogs than in wolves and, on average, dogs have 2-3% higher genetic load than gray wolves. Multiple lines of evidence indicate this pattern is driven by less efficient natural selection due to bottlenecks associated with domestication and breed formation, rather than recent inbreeding. Further, we find regions of the genome implicated in selective sweeps are enriched for amino acid changing variants and Mendelian disease genes. To our knowledge, these results provide the first quantitative estimates of the increased burden of deleterious variants directly associated with domestication and have important implications for selective breeding programs and the conservation of rare and endangered species. Specifically, they highlight the costs associated with selective breeding and question the practice favoring the breeding of individuals that best fit breed standards. Our results also suggest that maintaining a large population size, rather than just avoiding inbreeding, is a critical factor for preventing the accumulation of deleterious variants.M any of the mutations that arise in genomes are weakly deleterious and reduce fitness but are not always eliminated from the population by purifying natural selection. Consequently, understanding the reasons why deleterious mutations persist in populations and the role of demographic history in this process is of considerable interest (1-9). The radiation of domestic dogs offers a unique opportunity to address these questions. Dogs were originally domesticated from ancestral gray wolf populations >15,000 y ago in a process involving one or more severe population bottlenecks (10-12). The more recent isolation of modern dog breeds, which occurred over the last 300 y, involved additional population bottlenecks, intense artificial selection, and inbreeding Fig. 1A). Although this history is predicted to have resulted in the accumulation of deleterious variants, its specific effect on genomewide patterns of deleterious variation remains unclear.Here, we use complete genome sequencing data from 46 dogs representing 34 breeds, 25 village dogs, and 19 wolves to directly examine patterns of deleterious genetic variation across the dog genome (Dataset S1). Because more than half of these data derive from our own sequencing efforts, this project represents the largest survey of dog...

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Section: Significancesupporting

confidence: 72%

Section: Significancecontrasting

confidence: 53%

Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

See 2 more Smart Citations

Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs

Marsden

Vecchyo

O’Brien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

274

338

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“…Indeed, numerous studies have compared the patterns of deleterious variation across human populations Fu et al 2014;Lohmueller 2014a;Simons et al 2014;Do et al 2015;Henn et al 2015Henn et al , 2016Simons and Sella 2016). Most of these studies have focused on genetic consequences of the bottlenecks, i.e., rapid large decreases in population sizes, that all non-African populations went through during the Out-Of-Africa (OOA) dispersal.…”

mentioning

confidence: 99%

The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit

et al. 2017

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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.

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Expansion Load

Peischl

Excoffier

2016

Invasion Genetics

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Expanding populations incur a mutation burden -the so-called expansion load. Previous studies of expansion load have focused on co-dominant mutations. An important consequence of this assumption is that expansion load stems exclusively from the accumulation of new mutations occurring in individuals living at the wave front. Using individual-based simulations we study here the dynamics of standing genetic variation at the front of expansions, and its consequences on mean fitness if mutations are recessive. We find that deleterious genetic diversity is quickly lost at the front of the expansion, but the loss of deleterious mutations at some loci is compensated by an increase of their frequencies at other loci. The frequency of deleterious homozygotes therefore increases along the expansion axis whereas the average number of deleterious mutations per individual remains nearly constant across the species range. This reveals two important differences to co-dominant models: (i) mean fitness at the front of the expansion drops much faster if mutations are recessive, and (ii) mutation load can increase during the expansion even if the total number of deleterious mutations per individual remains constant. We use our model to make predictions about the shape of the site frequency spectrum at the front of range expansion, and about correlations between heterozygosity and fitness in different parts of the species range. Importantly, these predictions provide opportunities to empirically validate our theoretical results. We discuss our findings in the light of recent results on the distribution of deleterious genetic variation across human populations, and link them to empirical results on the correlation of heterozygosity and fitness found in many natural range expansions.

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Characteristics of Neutral and Deleterious Protein-Coding Variation among Individuals and Populations

Cited by 93 publications

References 55 publications

Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs

Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs

The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit

Expansion Load

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