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Deleterious alleles in the human genome are on average younger than neutral alleles of the same frequency.

Kiezun A, Pulit SL, Francioli LC, van Dijk F, Swertz M, Boomsma DI, van Duijn CM, Slagboom PE, van Ommen GJ, Wijmenga C, Genome of the Netherlands Consortiumde Bakker PI, Sunyaev SR - PLoS Genet. (2013)

Bottom Line: A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness.When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function.The results confirm the abundance of slightly deleterious coding variation in humans.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669-673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans.

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Age distributions for neutral and deleterious alleles from simulations.(A) Constant-size, (B) recently rapidly expanding population, and (C) bottleneck followed by rapid expansion. For presentation, distributions are trimmed. Deleterious alleles in all cases are younger than neutral alleles at the same frequency, though the effect is weaker in rapidly expanding populations.
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pgen-1003301-g002: Age distributions for neutral and deleterious alleles from simulations.(A) Constant-size, (B) recently rapidly expanding population, and (C) bottleneck followed by rapid expansion. For presentation, distributions are trimmed. Deleterious alleles in all cases are younger than neutral alleles at the same frequency, though the effect is weaker in rapidly expanding populations.

Mentions: Both mean allelic age and mean sojourn times at each frequency are exactly symmetric with respect to the sign of selection coefficient. However, the symmetry is limited to the case of constant size population and no dominance. In a growing population the mean ages of deleterious and beneficial alleles of the same frequency differ (see Methods). The assumption of constant population size greatly simplifies the analysis of allelic ages under a standard diffusion approximation. However, the assumption of constant population size is clearly violated for the human population. To investigate the case of a growing population, we resorted to forward computer simulations (see Methods for exact details of demographic history). Computer simulations indicated that the difference between mean ages of deleterious and neutral alleles of the same frequency is present in a recently rapidly expanding population, though it is smaller than in the case of a constant-size population (Figure 2A, 2B). The difference in ages was present also in a demographic scenario that included a bottleneck followed by a rapid recent population expansion (Figure 2C).


Deleterious alleles in the human genome are on average younger than neutral alleles of the same frequency.

Kiezun A, Pulit SL, Francioli LC, van Dijk F, Swertz M, Boomsma DI, van Duijn CM, Slagboom PE, van Ommen GJ, Wijmenga C, Genome of the Netherlands Consortiumde Bakker PI, Sunyaev SR - PLoS Genet. (2013)

Age distributions for neutral and deleterious alleles from simulations.(A) Constant-size, (B) recently rapidly expanding population, and (C) bottleneck followed by rapid expansion. For presentation, distributions are trimmed. Deleterious alleles in all cases are younger than neutral alleles at the same frequency, though the effect is weaker in rapidly expanding populations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585140&req=5

pgen-1003301-g002: Age distributions for neutral and deleterious alleles from simulations.(A) Constant-size, (B) recently rapidly expanding population, and (C) bottleneck followed by rapid expansion. For presentation, distributions are trimmed. Deleterious alleles in all cases are younger than neutral alleles at the same frequency, though the effect is weaker in rapidly expanding populations.
Mentions: Both mean allelic age and mean sojourn times at each frequency are exactly symmetric with respect to the sign of selection coefficient. However, the symmetry is limited to the case of constant size population and no dominance. In a growing population the mean ages of deleterious and beneficial alleles of the same frequency differ (see Methods). The assumption of constant population size greatly simplifies the analysis of allelic ages under a standard diffusion approximation. However, the assumption of constant population size is clearly violated for the human population. To investigate the case of a growing population, we resorted to forward computer simulations (see Methods for exact details of demographic history). Computer simulations indicated that the difference between mean ages of deleterious and neutral alleles of the same frequency is present in a recently rapidly expanding population, though it is smaller than in the case of a constant-size population (Figure 2A, 2B). The difference in ages was present also in a demographic scenario that included a bottleneck followed by a rapid recent population expansion (Figure 2C).

Bottom Line: A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness.When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function.The results confirm the abundance of slightly deleterious coding variation in humans.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669-673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans.

Show MeSH