Evidence for purifying selection against synonymous mutations in mammalian exonic splicing enhancers

被引:186
作者
Parmley, JL [1 ]
Chamary, JV [1 ]
Hurst, LD [1 ]
机构
[1] Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England
基金
英国医学研究理事会;
关键词
codon usage bias; mutation rate; purifying selection; splicing; synonymous sites;
D O I
10.1093/molbev/msj035
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Silent sites in mammals have classically been assumed to be free front selective pressures. Consequently, the synonymous substitution rate (K-s) is often used as it proxy for the Mutation rate. Although accumulating evidence demonstrates that the assumption is not valid, the mechanism by which selection acts remain Unclear. Recent work has revealed that the presence of exonic splicing enhancers (ESEs) in coding sequence might influence synonyomous evolution. ESEs are predominantly located near intron-exon junctions, which may explain the reduced single-nucleotide polymorphism (SNP) density in these regions. Here we show that synonymous Sites in putative ESEs evolve more slowly than the remaining exonic sequence. Differential mutabilities of ESEs do not appear to explain this difference. We observe that Substitution frequency ill four-fold synonymous sites decreases its one approaches the ends of exons, consistent with the existing SNP data. This gradient is at least in part explained by ESEs being more abundant near junctions. Between-gene variation in K-s is hence partly explained by the proportion of the gene that acts as,in ESE. Given the relative abundance of ESEs and the reduced rates of synonymous divergence within them, we estimate that constraints on synonymous evolution within ESEs Causes the true mutation rate to be Underestimated by not more than similar to 8%. We also find that K-s Outside of ESEs is much lower in alternatively spliced exons than in constitutive exons, implying that other causes of selection on synonymous mutations exist. Additionally, selection on ESEs appears to affect nonsynonymous sites and may explain why amino acid usage near intron-exon junctions is nonrandom.
引用
收藏
页码:301 / 309
页数:9
相关论文
共 62 条
[1]   Translational selection and molecular evolution [J].
Akashi, H ;
Eyre-Walker, A .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 1998, 8 (06) :688-693
[2]   DNA METHYLATION AND THE FREQUENCY OF CPG IN ANIMAL DNA [J].
BIRD, AP .
NUCLEIC ACIDS RESEARCH, 1980, 8 (07) :1499-1504
[3]   Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases [J].
Blencowe, BJ .
TRENDS IN BIOCHEMICAL SCIENCES, 2000, 25 (03) :106-110
[4]   SYNONYMOUS NUCLEOTIDE SUBSTITUTION RATES IN MAMMALIAN GENES - IMPLICATIONS FOR THE MOLECULAR CLOCK AND THE RELATIONSHIP OF MAMMALIAN ORDERS [J].
BULMER, M ;
WOLFE, KH ;
SHARP, PM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (14) :5974-5978
[5]   A maximum likelihood method for analyzing pseudogene evolution: Implications for silent site evolution in humans and rodents [J].
Bustamante, CD ;
Nielsen, R ;
Hartl, DL .
MOLECULAR BIOLOGY AND EVOLUTION, 2002, 19 (01) :110-117
[6]   A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups [J].
Capon, F ;
Allen, MH ;
Ameen, M ;
Burden, AD ;
Tillman, D ;
Barker, JN ;
Trembath, RC .
HUMAN MOLECULAR GENETICS, 2004, 13 (20) :2361-2368
[7]  
CARLINI DB, 2005, IN PRESS J MOL EVOL
[8]   Evidence for selection on synonymous mutations affecting stability of mRNA secondary structure in mammals [J].
Chamary, JV ;
Hurst, LD .
GENOME BIOLOGY, 2005, 6 (09)
[9]   Biased codon usage near intron-exon junctions: selection on splicing enhancers, splice-site recognition or something else? [J].
Chamary, JV ;
Hurst, LD .
TRENDS IN GENETICS, 2005, 21 (05) :256-259
[10]   Similar rates but different modes of sequence evolution in introns and at exonic silent sites in rodents: Evidence for selectively driven codon usage [J].
Chamary, JV ;
Hurst, LD .
MOLECULAR BIOLOGY AND EVOLUTION, 2004, 21 (06) :1014-1023