Natural selection affects multiple aspects of genetic variation at putatively peutral sites across the human genome

Kirk E Lohmueller; Anders Albrechtsen; Yingrui Li; Su Yeon Kim; Thorfinn Sand Korneliussen; Nicolas Vinckenbosch; Geng Tian; Emilia Huerta-Sanchez; Alison F Feder; Niels Grarup; Torben Jørgensen; Tao Jiang; Daniel R Witte; Annelli Sandbæk; Ines Hellmann; Torsten Lauritzen; Torben Hansen; Oluf Pedersen; Jun Wang; Rasmus Nielsen

doi:10.1371/journal.pgen.1002326

Natural selection affects multiple aspects of genetic variation at putatively peutral sites across the human genome

Kirk E Lohmueller, Anders Albrechtsen, Yingrui Li, Su Yeon Kim, Thorfinn Sand Korneliussen, Nicolas Vinckenbosch, Geng Tian, Emilia Huerta-Sanchez, Alison F Feder, Niels Grarup, Torben Jørgensen, Tao Jiang, Daniel R Witte, Annelli Sandbæk, Ines Hellmann, Torsten Lauritzen, Torben Hansen, Oluf Pedersen, Jun Wang, Rasmus Nielsen

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Abstract

A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations.

Original language	English
Journal	P L o S Genetics
Volume	7
Issue number	10
Number of pages	15
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1002326
Publication status	Published - Oct 2011

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Lohmueller, K. E., Albrechtsen, A., Li, Y., Kim, S. Y., Korneliussen, T. S., Vinckenbosch, N., Tian, G., Huerta-Sanchez, E., Feder, A. F., Grarup, N., Jørgensen, T., Jiang, T., Witte, D. R., Sandbæk, A., Hellmann, I., Lauritzen, T., Hansen, T., Pedersen, O., Wang, J., & Nielsen, R. (2011). Natural selection affects multiple aspects of genetic variation at putatively peutral sites across the human genome. P L o S Genetics, 7(10). https://doi.org/10.1371/journal.pgen.1002326

Lohmueller, KE, Albrechtsen, A, Li, Y, Kim, SY, Korneliussen, TS, Vinckenbosch, N, Tian, G, Huerta-Sanchez, E, Feder, AF, Grarup, N, Jørgensen, T, Jiang, T, Witte, DR, Sandbæk, A, Hellmann, I, Lauritzen, T, Hansen, T , Pedersen, O, Wang, J & Nielsen, R 2011, 'Natural selection affects multiple aspects of genetic variation at putatively peutral sites across the human genome', P L o S Genetics, vol. 7, no. 10. https://doi.org/10.1371/journal.pgen.1002326

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abstract = "A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations.",

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AU - Albrechtsen, Anders

AU - Li, Yingrui

AU - Kim, Su Yeon

AU - Korneliussen, Thorfinn Sand

AU - Vinckenbosch, Nicolas

AU - Tian, Geng

AU - Huerta-Sanchez, Emilia

AU - Feder, Alison F

AU - Grarup, Niels

AU - Jørgensen, Torben

AU - Jiang, Tao

AU - Witte, Daniel R

AU - Sandbæk, Annelli

AU - Hellmann, Ines

AU - Lauritzen, Torsten

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Wang, Jun

AU - Nielsen, Rasmus

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N2 - A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations.

AB - A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations.

U2 - 10.1371/journal.pgen.1002326

DO - 10.1371/journal.pgen.1002326

M3 - Journal article

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SN - 1553-7390

VL - 7

JO - P L o S Genetics

JF - P L o S Genetics

IS - 10

ER -

Natural selection affects multiple aspects of genetic variation at putatively peutral sites across the human genome

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