Ubiquitous selective constraints in the Drosophila genome revealed by a genome-wide interspecies comparison
Ubiquitous selective constraints in the Drosophila genome revealed by a genome-wide interspecies comparison
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DOI：
10.1101/gr.5022906
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发表时间：
2006-07-01
期刊：
影响因子：
7
通讯作者：
Keightley, Peter D.
中科院分区：
文献类型：
--
作者：
Halligan, Daniel L.;Keightley, Peter D.
非编码DNA占果蝇基因组常染色质部分的80%。已知非编码序列包含控制基因表达的功能重要元件，但被选择性限制的位点的比例在很大程度上仍然未知。我们比较了完整的D。黑腹果蝇和拟果蝇的基因组序列，通过标准化pupiramunconstrained序列中的取代率来估计编码和非编码DNA中的平均选择约束（通过选择消除的突变的分数）。我们发现，约束与内含子和基因间序列长度呈正相关，并且在非编码DNA中通常非常强，这意味着果蝇基因组中超过一半的点突变是有害的。如果非编码DNA中的许多取代被适应性地驱动固定，则该分数也可能被低估。我们还表明，在长内含子和基因间序列的取代成簇，这样有一个多余的取代< 8 bp的距离和赤字更远。这些结果表明，有块限制核苷酸，大概参与基因表达控制，集中在长的非编码序列。此外，我们推断果蝇基因组中功能性非编码DNA的数量是蛋白质编码DNA的三倍多。因此，大多数有害突变发生在非编码DNA中，这些突变可能对各种各样的进化过程做出重要贡献。
Non-coding DNA comprises similar to 80% of the euchromatic portion of the Drosophila melanogaster genome. Non-coding sequences are known to contain functionally important elements controlling gene expression, but the proportion of sites that are selectively constrained is still largely unknown. We have compared the complete D. melanogaster and Drosophila simulans genome sequences to estimate mean selective constraint ( the fraction of mutations that are eliminated by selection) in coding and non-coding DNA by standardizing to substitution rates in putatively unconstrained sequences. We show that constraint is positively correlated with intronic and intergenic sequence length and is generally remarkably strong in non-coding DNA, implying that more than half of all point mutations in the Drosophila genome are deleterious. This fraction is also likely to be an underestimate if many substitutions in non-coding DNA are adaptively driven to fixation. We also show that substitutions in long introns and intergenic sequences are clustered, such that there is an excess of substitutions < 8 bp apart and a deficit farther apart. These results suggest that there are blocks of constrained nucleotides, presumably involved in gene expression control, that are concentrated in long non-coding sequences. Furthermore, we infer that there is more than three times as much functional non-coding DNA as protein-coding DNA in the Drosophila genome. Most deleterious mutations therefore occur in non-coding DNA, and these may make an important contribution to a wide variety of evolutionary processes.