Patterns of evolutionary constraints in intronic and intergenic DNA of Drosophila
Patterns of evolutionary constraints in intronic and intergenic DNA of Drosophila
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DOI：
10.1101/gr.1329204
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发表时间：
2004-02-01
期刊：
影响因子：
7
通讯作者：
Keightley, PD
中科院分区：
文献类型：
--
作者：
Halligan, DL;Eyre-Walker, A;Keightley, PD
我们开发的方法来推断基因组中的进化限制水平，通过比较非编码DNA中的核苷酸取代率与从相邻基因或其他pupelinessneutrally进化位点的同义位点进化率预测的速率，同时考虑碱基组成的差异。我们应用该方法估计果蝇非编码DNA的约束水平。在内含子中，限制（被选择性消除的突变的估计分数）在S'和3'剪接点二核苷酸处是绝对的，并且在5 '端的碱基对3-6中平均为72%。在5'碱基对3-6的限制在导致黑腹果蝇的谱系中比在拟果蝇中显著更低，这一发现与果蝇基因组进化的其他特征一致，并表明选择对内含子功能的影响在黑腹果蝇谱系中较弱。在内含子序列的其他地方，核苷酸取代率显着高于同义位点。以剪接控制区以外的内含子位点作为假定的中性进化标准，蛋白质编码基因的基因间DNA上下游500 bp区域的限制平均相似于44%。虽然在基因间区域接近基因的估计水平的限制只有大约一半的氨基酸位点，选择对单核苷酸突变的基因间DNA的突变量在果蝇中作出了重大贡献。
We develop methods to infer levels of evolutionary constraints in the genome by comparing rates of nucleotide substitution in noncoding DNA with rates predicted from rates of synonymous site evolution in adjacent genes or other putatively neutrally evolving sites, while accounting for differences in base composition. We apply the methods to estimate levels of constraint in noncoding DNA of Drosophila. In introns, constraint (the estimated fraction of mutations that are selectively eliminated) is absolute at the S' and 3' splice junction dinucleotides, and averages 72% in base pairs 3-6 at the 5'-end. Constraint at the 5' base pairs 3-6 is significantly lower in the lineage leading to Drosophila melanogaster than in Drosophila simulans, a finding that agrees with other features of genome evolution in Drosophila and indicates that the effect of selection on intron function has been weaker in the melanogaster lineage. Elsewhere in intron sequences, the rate of nucleotide substitution is significantly higher than at synonymous sites. By using intronic sites outside splice control regions as a putative neutrally evolving standard, constraint in the 500 bp of intergenic DNA upstream and downstream regions of protein-coding genes averages similar to44%. Although the estimated level of constraint in intergenic regions close to genes is only about one-half of that of amino acid sites, selection against single-nucleotide mutations in intergenic DNA makes a substantial contribution to the mutation load in Drosophila.