Hunting for Beneficial Mutations: Conditioning on SIFT Scores When Estimating the Distribution of Fitness Effect of New Mutations

TY - JOUR

T1 - Hunting for Beneficial Mutations

T2 - Conditioning on SIFT Scores When Estimating the Distribution of Fitness Effect of New Mutations

AU - Chen, Jun

AU - Bataillon, Thomas

AU - Glémin, Sylvain

AU - Lascoux, Martin

N1 - Publisher Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

PY - 2022/1/4

Y1 - 2022/1/4

N2 - The distribution of fitness effects (DFE) of new mutations is a key parameter of molecular evolution. The DFE can in principle be estimated by comparing the site frequency spectra (SFS) of putatively neutral and functional polymorphisms. Unfortunately, the DFE is intrinsically hard to estimate, especially for beneficial mutations because these tend to be exceedingly rare. There is therefore a strong incentive to find out whether conditioning on properties of mutations that are independent of the SFS could provide additional information. In the present study, we developed a new measure based on SIFT scores. SIFT scores are assigned to nucleotide sites based on their level of conservation across a multispecies alignment: the more conserved a site, the more likely mutations occurring at this site are deleterious, and the lower the SIFT score. If one knows the ancestral state at a given site, one can assign a value to new mutations occurring at the site based on the change of SIFT score associated with the mutation. We called this new measure d. We show that properties of the DFE as well as the flux of beneficial mutations across classes covary with d and, hence, that SIFT scores are informative when estimating the fitness effect of new mutations. In particular, conditioning on SIFT scores can help to characterize beneficial mutations.

AB - The distribution of fitness effects (DFE) of new mutations is a key parameter of molecular evolution. The DFE can in principle be estimated by comparing the site frequency spectra (SFS) of putatively neutral and functional polymorphisms. Unfortunately, the DFE is intrinsically hard to estimate, especially for beneficial mutations because these tend to be exceedingly rare. There is therefore a strong incentive to find out whether conditioning on properties of mutations that are independent of the SFS could provide additional information. In the present study, we developed a new measure based on SIFT scores. SIFT scores are assigned to nucleotide sites based on their level of conservation across a multispecies alignment: the more conserved a site, the more likely mutations occurring at this site are deleterious, and the lower the SIFT score. If one knows the ancestral state at a given site, one can assign a value to new mutations occurring at the site based on the change of SIFT score associated with the mutation. We called this new measure d. We show that properties of the DFE as well as the flux of beneficial mutations across classes covary with d and, hence, that SIFT scores are informative when estimating the fitness effect of new mutations. In particular, conditioning on SIFT scores can help to characterize beneficial mutations.

KW - beneficial mutations

KW - DFE

KW - SIFT

UR - http://www.scopus.com/inward/record.url?scp=85119117158&partnerID=8YFLogxK

U2 - 10.1093/gbe/evab151

DO - 10.1093/gbe/evab151

M3 - Journal article

C2 - 34180988

AN - SCOPUS:85119117158

SN - 1759-6653

VL - 14

JO - Genome Biology and Evolution

JF - Genome Biology and Evolution

IS - 1

M1 - evab151

ER -