Estimates of genetic load suggest frequent purging of deleterious alleles in small populations

Valk, Tom van der; Manuel, Marc de; Guschanski, Katerina

doi:10.1101/696831

Cited by 57 publications

(74 citation statements)

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“…In population genetics, there is tremendous interest in understanding how much of the genome is under selection and the types of mutations underlying much of the phenotypic variation and adaptation in different species. Further, studies have aimed to precisely quantify the amount of deleterious variation segregating in populations to assess the role of population history at influencing deleterious variation and for determining whether small population size could lead to an accumulation of deleterious variants, potentially causing a mutational meltdown and extinction [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…Marsden et al [4] used GERP to identify deleterious amino acid changing mutations in dogs and wolves and found an increase in deleterious mutations (GERP>4) in dogs and that dogs have a higher summed GERP score across all amino acid changing variants as compared to wolves. Lastly, Valk et al [6] found that, across a range of mammals, species with historically low population size and low genetic diversity have a lower average GERP score of the derived allele than species with large population sizes, suggesting that purging of deleterious alleles reduces genetic load in small populations in the long term.…”

Section: Introductionmentioning

confidence: 99%

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Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution

Kim

Lohmueller

2020

PLoS Genet

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Comparative genomic approaches have been used to identify sites where mutations are under purifying selection and of functional consequence by searching for sequences that are conserved across distantly related species. However, the performance of these approaches has not been rigorously evaluated under population genetic models. Further, short-lived functional elements may not leave a footprint of sequence conservation across many species. We use simulations to study how one measure of conservation, the Genomic Evolutionary Rate Profiling (GERP) score, relates to the strength of selection (N e s). We show that the GERP score is related to the strength of purifying selection. However, changes in selection coefficients or functional elements over time (i.e. functional turnover) can strongly affect the GERP distribution, leading to unexpected relationships between GERP and N e s. Further, we show that for functional elements that have a high turnover rate, adding more species to the analysis does not necessarily increase statistical power. Finally, we use the distribution of GERP scores across the human genome to compare models with and without turnover of sites where mutations are under purifying selection. We show that mutations in 4.51% of the noncoding human genome are under purifying selection and that most of this sequence has likely experienced changes in selection coefficients throughout mammalian evolution. Our work reveals limitations to using comparative genomic approaches to identify deleterious mutations. Commonly used GERP score thresholds miss over half of the noncoding sites in the human genome where mutations are under purifying selection.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution

Kim

Lohmueller

2020

PLoS Genet

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show abstract

Section: Introductionmentioning

confidence: 99%

“…Marsden et al (Marsden et al 2016) used GERP to identify deleterious amino acid changing mutations in dogs and wolves and found an increase in deleterious mutations (GERP>4) in dogs and that dogs have a higher summed GERP score across all amino acid changing variants as compared to wolves. Lastly, Valk et al find that, across a range of mammals, species with historically low population size and low genetic diversity have a lower average GERP score of the derived allele than species with large population sizes (Valk et al, 2019) , suggesting that purging of deleterious alleles reduces genetic load in small populations in the long term.…”

Section: Introductionmentioning

confidence: 99%

Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution

Kim

Lohmueller²

2019

Preprint

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Comparative genomic approaches have been used to identify sites where mutations are under purifying selection and of functional consequence by searching for sequences that are conserved across distantly related species. However, the performance of these approaches has not been rigorously evaluated under population genetic models. Further, short-lived functional elements may not leave a footprint of sequence conservation across many species. Here, we use simulations to study how one measure of conservation, the GERP score, relates to the strength of selection ( N e s ). We show that the GERP score is related to the strength of purifying selection. However, changes in selection coefficients or functional elements over time (i.e. functional turnover) can strongly affect the GERP distribution, leading to unexpected relationships between GERP and N e s . Further, we show that for functional elements that have a high turnover rate, the optimal tree size is not necessarily the largest possible tree, and more turnover reduces the optimal tree size. Finally, we use the distribution of GERP scores across the human genome to compare models with and without turnover of sites where mutations under purifying selection. We show that mutations in 4.51% of the noncoding human genome are under purifying selection and that most of this sequence has likely experienced changes in selection coefficients throughout mammalian evolution.

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“…Evolutionary genomic constraints have been proposed as better predictors for the fitness consequences of mutations [291]. The most used comparative genomic approach is the Genomic Evolutionary Rate Profiling (GERP) score.…”

Section: Evolutionary Genomic Constraints and Genomic Fitnessmentioning

confidence: 99%

Using whole-genome sequencing data for demographic and functional evaluations of small managed populations

Bortoluzzi¹

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Bortoluzzi, C. (2020). Using whole-genome sequencing data for demographic and functional evaluations of small managed populations. PhD thesis, Wageningen University & Research, the Netherlands. Genetic diversity is the foundation for selection to act upon a population: without diversity, evolution can not occur and species can not adapt to changing environments. In this thesis, I provide an in-depth analysis of the genome-wide patterns of diversity in local chicken breeds of small effective population size. Since their domestication in Southeast Asia around 9,500 years ago, domestic chickens have undergone human-driven selection resulting in the creation of hundreds of breeds, each described by a precise set of morphological features. Domesticated chicken breeds are therefore an excellent study system to investigate the effects of demography on genomic variation. Using a combination of the latest genomics tools, I show that, besides signs of recent inbreeding and declined diversity, changes in breeding preferences generated novel and identifiable variation. Interestingly, the genetic basis of some of this variation has evolved in other bird species through parallel evolution despite their divergence from chicken millions of years ago. However, as I emphasize, the outstanding diversity harboured by local chicken breeds can only be preserved in the near future if conservation programmes become genomics-informed. The rationale is the ability of genomic data to provide additional information on the functional relevance of such variation, which has important implications for conservation. Therefore, by means of genomic data, we can better control for deleterious alleles, while increasing genetic diversity. The identification of functionally important mutations have for a long time been limited to protein-coding genes. In this thesis, I demonstrate through the development of the ch(icken)CADD model that sub-regions within conserved non-coding elements also harbour variants with a negative fitness effect, as their association with known disease genes in other vertebrate species demonstrate. Overall, the findings of this thesis show that genetic diversity should be characterized from both a demographic and functional perspective to best manage populations and genetic resources.

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Estimates of genetic load suggest frequent purging of deleterious alleles in small populations

Cited by 57 publications

References 58 publications

Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution

Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution

Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution

Using whole-genome sequencing data for demographic and functional evaluations of small managed populations

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