Higher intensity of purifying selection on >90% of the human genes revealed by the intrinsic replacement mutation rates

Sankar Subramanian, Sudhir Kumar

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

For over 3 decades, the rate of replacement mutations has been assumed to be equal to, and estimated from, the rate of "strictly" neutral sequence divergence in noncoding regions and in silent-codon positions where mutations do not alter the amino acid encoded. This assumption is fundamental to estimating the fraction of harmful protein mutations and to identifying adaptive evolution at individual codons and proteins. We show that the assumption is not justifiable because a much larger fraction of codon positions is involved in hypermutable CpG dinucleotides as compared with the introns, leading to a higher expected replacement mutation rate per site in a vast majority of the genes. Consideration of this difference reveals a higher intensity of purifying natural selection than previously inferred in human genes. We also show that a much smaller number of genes are expected to be evolving with positive selection than that predicted using sequence divergence at intron and silent positions in the human genome. These patterns indicate the need for using new approaches for estimating rates of amino acid-altering mutations in order to find positively selected genes and codons in genomes that contain hypermutable CpG's.

Original languageEnglish (US)
Pages (from-to)2283-2287
Number of pages5
JournalMolecular Biology and Evolution
Volume23
Issue number12
DOIs
StatePublished - Dec 2006

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selection intensity
Mutation Rate
Codon
mutation
codons
replacement
Genes
gene
Introns
Mutation
genes
introns
Amino Acids
genome
amino acid
divergence
Genetic Selection
Human Genome
amino acids
protein

Keywords

  • Adaptive evolution
  • Comparative genomics
  • Mutation rate
  • Test of selection

ASJC Scopus subject areas

  • Genetics
  • Biochemistry
  • Genetics(clinical)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Ecology, Evolution, Behavior and Systematics
  • Agricultural and Biological Sciences (miscellaneous)
  • Molecular Biology

Cite this

Higher intensity of purifying selection on >90% of the human genes revealed by the intrinsic replacement mutation rates. / Subramanian, Sankar; Kumar, Sudhir.

In: Molecular Biology and Evolution, Vol. 23, No. 12, 12.2006, p. 2283-2287.

Research output: Contribution to journalArticle

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