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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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Simulation and theoretical results for allelic age and sojourn times.a. Example trajectories for a neutral and deleterious allele with current population frequencies 3% (indicated by the arrow). The shaded areas indicate sojourn times at frequencies above 5%. b. Mean ages for neutral and deleterious alleles at a given population frequency (lines show theoretical predictions, dots show simulation results with standard error bars). Simulation results are averages of alleles in a frequency range, while theoretical prediction are for alleles at a fixed frequency. The graph shows that deleterious alleles at a given frequency are younger than neutral alleles, and that the effect is greater for more strongly selected alleles. c. Mean sojourn times for neutral and deleterious alleles. Vertical line denotes the current population frequency of the variant (3%). Mean sojourn times have been computed in bins of 1%. Line connects theoretical predictions for each frequency bin. Dots show simulation results. The graph illustrates that deleterious alleles spend much less time than neutral alleles at higher population frequencies in the past even if they have the same current frequency.
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pgen-1003301-g001: Simulation and theoretical results for allelic age and sojourn times.a. Example trajectories for a neutral and deleterious allele with current population frequencies 3% (indicated by the arrow). The shaded areas indicate sojourn times at frequencies above 5%. b. Mean ages for neutral and deleterious alleles at a given population frequency (lines show theoretical predictions, dots show simulation results with standard error bars). Simulation results are averages of alleles in a frequency range, while theoretical prediction are for alleles at a fixed frequency. The graph shows that deleterious alleles at a given frequency are younger than neutral alleles, and that the effect is greater for more strongly selected alleles. c. Mean sojourn times for neutral and deleterious alleles. Vertical line denotes the current population frequency of the variant (3%). Mean sojourn times have been computed in bins of 1%. Line connects theoretical predictions for each frequency bin. Dots show simulation results. The graph illustrates that deleterious alleles spend much less time than neutral alleles at higher population frequencies in the past even if they have the same current frequency.

Mentions: First, we recapitulated Maruyama's theory with diffusion approximation and simulations (see Methods) and confirm that neutral alleles at a given frequency are older than selected ones (Figure 1a, 1b). A neutral allele observed at frequency spent, on average, an equal amount of time at each frequency below , whereas a deleterious allele spent progressively shorter time at higher frequencies (Figure 1c). The difference in the average age of neutral and selected alleles is primarily due to shorter sojourn times at higher frequencies for selected alleles. This suggests that a statistic capturing sojourn times at higher frequencies would better discriminate between neutral and selected alleles than a statistic based on an accurate estimation of the allelic age.


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)

Simulation and theoretical results for allelic age and sojourn times.a. Example trajectories for a neutral and deleterious allele with current population frequencies 3% (indicated by the arrow). The shaded areas indicate sojourn times at frequencies above 5%. b. Mean ages for neutral and deleterious alleles at a given population frequency (lines show theoretical predictions, dots show simulation results with standard error bars). Simulation results are averages of alleles in a frequency range, while theoretical prediction are for alleles at a fixed frequency. The graph shows that deleterious alleles at a given frequency are younger than neutral alleles, and that the effect is greater for more strongly selected alleles. c. Mean sojourn times for neutral and deleterious alleles. Vertical line denotes the current population frequency of the variant (3%). Mean sojourn times have been computed in bins of 1%. Line connects theoretical predictions for each frequency bin. Dots show simulation results. The graph illustrates that deleterious alleles spend much less time than neutral alleles at higher population frequencies in the past even if they have the same current frequency.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585140&req=5

pgen-1003301-g001: Simulation and theoretical results for allelic age and sojourn times.a. Example trajectories for a neutral and deleterious allele with current population frequencies 3% (indicated by the arrow). The shaded areas indicate sojourn times at frequencies above 5%. b. Mean ages for neutral and deleterious alleles at a given population frequency (lines show theoretical predictions, dots show simulation results with standard error bars). Simulation results are averages of alleles in a frequency range, while theoretical prediction are for alleles at a fixed frequency. The graph shows that deleterious alleles at a given frequency are younger than neutral alleles, and that the effect is greater for more strongly selected alleles. c. Mean sojourn times for neutral and deleterious alleles. Vertical line denotes the current population frequency of the variant (3%). Mean sojourn times have been computed in bins of 1%. Line connects theoretical predictions for each frequency bin. Dots show simulation results. The graph illustrates that deleterious alleles spend much less time than neutral alleles at higher population frequencies in the past even if they have the same current frequency.
Mentions: First, we recapitulated Maruyama's theory with diffusion approximation and simulations (see Methods) and confirm that neutral alleles at a given frequency are older than selected ones (Figure 1a, 1b). A neutral allele observed at frequency spent, on average, an equal amount of time at each frequency below , whereas a deleterious allele spent progressively shorter time at higher frequencies (Figure 1c). The difference in the average age of neutral and selected alleles is primarily due to shorter sojourn times at higher frequencies for selected alleles. This suggests that a statistic capturing sojourn times at higher frequencies would better discriminate between neutral and selected alleles than a statistic based on an accurate estimation of the allelic age.

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