Human Molecular Genetics Advance Access originally published online on September 20, 2005
Human Molecular Genetics 2005 14(21):3191-3201; doi:10.1093/hmg/ddi350
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Distribution of the strength of selection against amino acid replacements in human proteins
1Department of Biological Sciences, East Tennessee State University, Johnson City, TN 37614-1710, USA, 2Section of Ecology, Behavior and Evolution, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0346, USA and 3National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD 20894, USA
* To whom correspondence should be addressed. Tel: +1 3014358944; Fax: +1 3014809241; Email: kondrashov{at}ncbi.nlm.nih.gov
Received May 3, 2005; Revised July 27, 2005; Accepted September 12, 2005
The impact of an amino acid replacement on the organism's fitness can vary from lethal to selectively neutral and even, in rare cases, beneficial. Substantial data are available on either pathogenic or acceptable replacements. However, the whole distribution of coefficients of selection against individual replacements is not known for any organism. To ascertain this distribution for human proteins, we combined data on pathogenic missense mutations, on human non-synonymous SNPs and on human–chimpanzee divergence of orthologous proteins. Fractions of amino acid replacements which reduce fitness by >10–2, 10–2–10–4, 10–4–10–5 and <10–5 are 25, 49, 14 and 12%, respectively. On average, the strength of selection against a replacement is substantially higher when chemically dissimilar amino acids are involved, and the Grantham's index of a replacement explains 35% of variance in the average logarithm of selection coefficients associated with different replacements. Still, the impact of a replacement depends on its context within the protein more than on its own nature. Reciprocal replacements are often associated with rather different selection coefficients, in particular, replacements of non-polar amino acids with polar ones are typically much more deleterious than replacements in the opposite direction. However, differences between evolutionary fluxes of reciprocal replacements are only weakly correlated with the differences between the corresponding selection coefficients.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Bachtrog The Temporal Dynamics of Processes Underlying Y Chromosome Degeneration Genetics, July 1, 2008; 179(3): 1513 - 1525. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Charlesworth and A. Eyre-Walker The McDonald-Kreitman Test and Slightly Deleterious Mutations Mol. Biol. Evol., June 1, 2008; 25(6): 1007 - 1015. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. T. Saunders and P. Green Insights from Modeling Protein Evolution with Context-Dependent Mutation and Asymmetric Amino Acid Selection Mol. Biol. Evol., December 1, 2007; 24(12): 2632 - 2647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Thorne, S. C. Choi, J. Yu, P. G. Higgs, and H. Kishino Population Genetics Without Intraspecific Data Mol. Biol. Evol., August 1, 2007; 24(8): 1667 - 1677. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Nackley, S. A. Shabalina, I. E. Tchivileva, K. Satterfield, O. Korchynskyi, S. S. Makarov, W. Maixner, and L. Diatchenko Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure Science, December 22, 2006; 314(5807): 1930 - 1933. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Subramanian and S. Kumar Higher Intensity of Purifying Selection on >90% of the Human Genes Revealed by the Intrinsic Replacement Mutation Rates Mol. Biol. Evol., December 1, 2006; 23(12): 2283 - 2287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Teshima, G. Coop, and M. Przeworski How reliable are empirical genomic scans for selective sweeps? Genome Res., June 1, 2006; 16(6): 702 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Eyre-Walker, M. Woolfit, and T. Phelps The Distribution of Fitness Effects of New Deleterious Amino Acid Mutations in Humans Genetics, June 1, 2006; 173(2): 891 - 900. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. P. Gorlov, M. Kimmel, and C. I. Amos Strength of the purifying selection against different categories of the point mutations in the coding regions of the human genome Hum. Mol. Genet., April 1, 2006; 15(7): 1143 - 1150. [Abstract] [Full Text] [PDF]
|
|