Nov 7, 2014

Approximation to the distribution of fitness effects across functional categories in human segregating polymorphisms

PLoS Genetics
Fernando Racimo, Joshua G Schraiber

Abstract

Quantifying the proportion of polymorphic mutations that are deleterious or neutral is of fundamental importance to our understanding of evolution, disease genetics and the maintenance of variation genome-wide. Here, we develop an approximation to the distribution of fitness effects (DFE) of segregating single-nucleotide mutations in humans. Unlike previous methods, we do not assume that synonymous mutations are neutral or not strongly selected, and we do not rely on fitting the DFE of all new nonsynonymous mutations to a single probability distribution, which is poorly motivated on a biological level. We rely on a previously developed method that utilizes a variety of published annotations (including conservation scores, protein deleteriousness estimates and regulatory data) to score all mutations in the human genome based on how likely they are to be affected by negative selection, controlling for mutation rate. We map this and other conservation scores to a scale of fitness coefficients via maximum likelihood using diffusion theory and a Poisson random field model on SNP data. Our method serves to approximate the deleterious DFE of mutations that are segregating, regardless of their genomic consequence. We can then compare t...Continue Reading

  • References52
  • Citations18

Mentioned in this Paper

Vertebrates
Gene Polymorphism
Genome-Wide Association Study
Deoxyribonuclease I
Genome
Diffusion Weighted Imaging
Transcription Initiation Site
Transcription, Genetic
CCCTC-binding factor
Dicom Derivation

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