Journal article
Fixation of deleterious mutations at critical positions in human proteins
Molecular Biology and Evolution, Vol.28(9), pp.2687-2693
2011
Abstract
Deleterious mutations associated with human diseases are predominantly found in conserved positions and positions that are essential for the structure and/or function of proteins. However, these mutations are purged from the human population over time and prevented from being fixed. Contrary to this belief, here I show that high proportions of deleterious amino acid changing mutations are fixed at positions critical for the structure and/or function of proteins. Similarly, a high rate of fixation of deleterious mutations was observed in slow-evolving amino acid positions of human proteins. The fraction of deleterious substitutions was found to be two times higher in relatively conserved amino acid positions than in highly variable positions. This study also found fixation of a much higher proportion of radical amino acid changes in primates compared with rodents and artiodactyls in slow-evolving positions. Previous studies observed a higher proportion of nonsynonymous substitutions in humans compared with other mammals, which was taken as indirect evidence for the fixation of deleterious mutations in humans. However, the results of this investigation provide direct evidence for this prediction by suggesting that the excess nonsynonymous mutations fixed in humans are indeed deleterious in nature. Furthermore, these results suggest that studies on disease-associated mutations should consider that a significant fraction of such deleterious mutations has already been fixed in the human genome, and thus, the effects of new mutations at those amino acid positions may not necessarily be deleterious and might even result in reversion to benign phenotypes. © 2011 The Author.
Details
- Title
- Fixation of deleterious mutations at critical positions in human proteins
- Authors
- Sankar Subramanian (Author) - Griffith University
- Publication details
- Molecular Biology and Evolution, Vol.28(9), pp.2687-2693
- Publisher
- Oxford University Press
- DOI
- 10.1093/molbev/msr097
- ISSN
- 0737-4038
- Organisation Unit
- Centre for Bioinnovation; School of Science, Technology and Engineering; University of the Sunshine Coast, Queensland; School of Science and Engineering - Legacy
- Language
- English
- Record Identifier
- 99451147402621
- Output Type
- Journal article
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