In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 8 ( 2013-02-19)
Abstract:
The cause of the tremendous among-protein variation in the rate of sequence evolution is a central subject of molecular evolution. Expression level has been identified as a leading determinant of this variation among genes encoded in the same genome, but the underlying mechanisms are not fully understood. We here propose and demonstrate that a requirement for stronger folding of more abundant mRNAs results in slower evolution of more highly expressed genes and proteins. Specifically, we show that: ( i ) the higher the expression level of a gene, the greater the selective pressure for its mRNA to fold; ( ii ) random mutations are more likely to decrease mRNA folding when occurring in highly expressed genes than in lowly expressed genes; and ( iii ) amino acid substitution rate is negatively correlated with mRNA folding strength, with or without the control of expression level. Furthermore, synonymous ( d S ) and nonsynonymous ( d N ) nucleotide substitution rates are both negatively correlated with mRNA folding strength. However, counterintuitively, d S and d N are differentially constrained by selection for mRNA folding, resulting in a significant correlation between mRNA folding strength and d N / d S , even when gene expression level is controlled. The direction and magnitude of this correlation is determined primarily by the G+C frequency at third codon positions. Together, these findings explain why highly expressed genes evolve slowly, demonstrate a major role of natural selection at the mRNA level in constraining protein evolution, and reveal a previously unrecognized and unexpected form of nonprotein-level selection that impacts d N / d S .
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1218066110
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2013
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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