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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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Allele frequency spectra and population-private coding alleles.The graphs show the proportion of population-private synonymous alleles and non-synonymous alleles stratified by PolyPhen-2 functional predictions.
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pgen-1003301-g007: Allele frequency spectra and population-private coding alleles.The graphs show the proportion of population-private synonymous alleles and non-synonymous alleles stratified by PolyPhen-2 functional predictions.

Mentions: As another independent test whether deleterious variants are on average younger than neutral alleles of the same frequency, we analyzed the fraction of population-specific SNPs. Because this analysis required data from multiple human populations, we used an entirely different data set, pilot data from the 1000 Genomes project (see Methods). We observed that non-synonymous SNPs, especially those predicted to be damaging, are more often population-specific (Figure 7) than synonymous SNPs of the same frequency. This is consistent with non-synonymous SNPs being on average younger. As expected, the difference disappears at population frequencies greater than 10%. Previously, also using 1000 Genomes data, Marth et al.[16] showed an increase in population specificity of variants in coding regions compared to intergenic regions. Importantly, this analysis is independent of the NC statistic and of the GoNL data, and thus provides additional evidence of the younger age of deleterious alleles.


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)

Allele frequency spectra and population-private coding alleles.The graphs show the proportion of population-private synonymous alleles and non-synonymous alleles stratified by PolyPhen-2 functional predictions.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1003301-g007: Allele frequency spectra and population-private coding alleles.The graphs show the proportion of population-private synonymous alleles and non-synonymous alleles stratified by PolyPhen-2 functional predictions.
Mentions: As another independent test whether deleterious variants are on average younger than neutral alleles of the same frequency, we analyzed the fraction of population-specific SNPs. Because this analysis required data from multiple human populations, we used an entirely different data set, pilot data from the 1000 Genomes project (see Methods). We observed that non-synonymous SNPs, especially those predicted to be damaging, are more often population-specific (Figure 7) than synonymous SNPs of the same frequency. This is consistent with non-synonymous SNPs being on average younger. As expected, the difference disappears at population frequencies greater than 10%. Previously, also using 1000 Genomes data, Marth et al.[16] showed an increase in population specificity of variants in coding regions compared to intergenic regions. Importantly, this analysis is independent of the NC statistic and of the GoNL data, and thus provides additional evidence of the younger age of deleterious alleles.

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