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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 in GoNL data, for synonymous alleles and non-synonymous alleles stratified by PolyPhen-2 functional predictions.For better presentation, the graphs have been cropped at minor allele count 10.
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pgen-1003301-g004: Allele frequency spectra in GoNL data, for synonymous alleles and non-synonymous alleles stratified by PolyPhen-2 functional predictions.For better presentation, the graphs have been cropped at minor allele count 10.

Mentions: We subdivided all coding variants into synonymous and non-synonymous (missense and nonsense). We further annotated the missense variants using PolyPhen-2 predictions as benign, possibly damaging, and probably damaging [15]. In the GoNL dataset, consisting of 94 unrelated parents, there are 25997 common coding SNPs with a minor allele count 20. Of those common SNPs, 13956 (53.7%) are synonymous and 12041 (46.3%) are non-synonymous (including 1466, or 5.6%, of probably damaging missense SNPs). The fraction of non-synonymous and, especially probably damaging SNPs, increases for SNPs with low frequencies (Figure 4). At minor allele count 2 there are 7437 coding SNPs, of which 3102 (41.7%) are synonymous, and 4335 (58.2%) are non-synonymous (including 1176, or 15.7%, of probably damaging missense SNPs).


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 in GoNL data, for synonymous alleles and non-synonymous alleles stratified by PolyPhen-2 functional predictions.For better presentation, the graphs have been cropped at minor allele count 10.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1003301-g004: Allele frequency spectra in GoNL data, for synonymous alleles and non-synonymous alleles stratified by PolyPhen-2 functional predictions.For better presentation, the graphs have been cropped at minor allele count 10.
Mentions: We subdivided all coding variants into synonymous and non-synonymous (missense and nonsense). We further annotated the missense variants using PolyPhen-2 predictions as benign, possibly damaging, and probably damaging [15]. In the GoNL dataset, consisting of 94 unrelated parents, there are 25997 common coding SNPs with a minor allele count 20. Of those common SNPs, 13956 (53.7%) are synonymous and 12041 (46.3%) are non-synonymous (including 1466, or 5.6%, of probably damaging missense SNPs). The fraction of non-synonymous and, especially probably damaging SNPs, increases for SNPs with low frequencies (Figure 4). At minor allele count 2 there are 7437 coding SNPs, of which 3102 (41.7%) are synonymous, and 4335 (58.2%) are non-synonymous (including 1176, or 15.7%, of probably damaging missense SNPs).

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
Related in: MedlinePlus