TY - JOUR
T1 - Determining the factors driving selective effects of new nonsynonymous mutations
AU - Huber, Christian D.
AU - Kim, Bernard Y.
AU - Marsden, Clare D.
AU - Lohmueller, Kirk E.
N1 - Funding Information:
Gossmann for providing access to site frequency spectrum data from Mus musculus castaneus and Saccharomyces paradoxus; and Maria T. Huber for the drawings in Figs. 1 and 4. C.D.H., C.D.M., and K.E.L. were supported by a Searle Scholars Fellowship, an Alfred P. Sloan Research Fellowship in Computational and Molecular Biology, and NIH Grant R35GM119856 (to K.E.L.).
PY - 2017/4/25
Y1 - 2017/4/25
N2 - The distribution of fitness effects (DFE) of new mutations plays a fundamental role in evolutionary genetics. However, the extent to which the DFE differs across species has yet to be systematically investigated. Furthermore, the biological mechanisms determining the DFE in natural populations remain unclear. Here, we show that theoretical models emphasizing different biological factors at determining the DFE, such as protein stability, back-mutations, species complexity, and mutational robustness make distinct predictions about how the DFE will differ between species. Analyzing amino acid-changing variants from natural populations in a comparative population genomic framework, we find that humans have a higher proportion of strongly deleterious mutations than Drosophila melanogaster. Furthermore, when comparing the DFE across yeast, Drosophila, mice, and humans, the average selection coefficient becomes more deleterious with increasing species complexity. Last, pleiotropic genes have a DFE that is less variable than that of nonpleiotropic genes. Comparing four categories of theoretical models, only Fisher's geometrical model (FGM) is consistent with our findings. FGM assumes that multiple phenotypes are under stabilizing selection, with the number of phenotypes defining the complexity of the organism. Our results suggest that long-term population size and cost of complexity drive the evolution of the DFE, withmany implications for evolutionary and medical genomics.
AB - The distribution of fitness effects (DFE) of new mutations plays a fundamental role in evolutionary genetics. However, the extent to which the DFE differs across species has yet to be systematically investigated. Furthermore, the biological mechanisms determining the DFE in natural populations remain unclear. Here, we show that theoretical models emphasizing different biological factors at determining the DFE, such as protein stability, back-mutations, species complexity, and mutational robustness make distinct predictions about how the DFE will differ between species. Analyzing amino acid-changing variants from natural populations in a comparative population genomic framework, we find that humans have a higher proportion of strongly deleterious mutations than Drosophila melanogaster. Furthermore, when comparing the DFE across yeast, Drosophila, mice, and humans, the average selection coefficient becomes more deleterious with increasing species complexity. Last, pleiotropic genes have a DFE that is less variable than that of nonpleiotropic genes. Comparing four categories of theoretical models, only Fisher's geometrical model (FGM) is consistent with our findings. FGM assumes that multiple phenotypes are under stabilizing selection, with the number of phenotypes defining the complexity of the organism. Our results suggest that long-term population size and cost of complexity drive the evolution of the DFE, withmany implications for evolutionary and medical genomics.
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U2 - 10.1073/pnas.1619508114
DO - 10.1073/pnas.1619508114
M3 - Article
C2 - 28400513
AN - SCOPUS:85018834601
SN - 0027-8424
VL - 114
SP - 4465
EP - 4470
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 17
ER -