Distribution and intensity of constraint in mammalian genomic sequence
Distribution and intensity of constraint in mammalian genomic sequence
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DOI：
10.1101/gr.3577405
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发表时间：
2005-07-01
期刊：
影响因子：
7
通讯作者：
Sidow, A
中科院分区：
文献类型：
--
作者：
Cooper, GM;Stone, EA;Sidow, A
同源基因组DNA序列的比较可用于表征已经进行纯化选择并富集功能元件的区域。我们在这里提出了这样的所有分析的结果，从29个哺乳动物物种的序列的所有比对。比对捕获每个位点约3.9个中性置换，并且跨度类似于人类基因组的1.9Mbp。我们确定了长度从3 bp到超过1 kbp的约束元件，覆盖了人类基因座的5.5%。我们估计这个基因座经历的非外显子约束的总量大约是外显子约束的两倍。受约束的元素往往集群，我们确定了大的约束区域，以及与已知的功能元素。虽然约束密度与移动的元件密度呈负相关，我们也表明存在明确的约束元件重叠哺乳动物的祖先重复。此外，我们描述了一些元素在这个地区，在整个哺乳动物进化过程中经历了激烈的净化选择，我们表明，这些重要的元素比以前认为的更多。这些结果是用基因组进化速率分析（GERP）获得的，GERP是一种用于约束元件识别的统计学上严格且生物学上透明的框架。CERP以高分辨率识别显示核苷酸取代缺陷的区域，并将这些缺陷测量为“拒绝取代”。“被拒绝的替代反映了过去净化选择的强度，并用于对受约束的元素进行排名和表征。我们预计，随着哺乳动物基因组序列数据变得更加丰富，GERP及其促进的分析类型将为人类基因组提供进一步的见解和改进的注释。
Comparisons of orthologous genomic DNA sequences call be used to characterize regions that have been subject to purifying selection and are enriched for functional elements. We here present the results of such ail analysis on ail alignment of sequences from 29 mammalian species. The alignment captures -3.9 neutral Substitutions per site and spans similar to 1.9 Mbp of the human genome. We identify constrained elements from 3 bp to over 1 kbp in length, covering similar to 5.5% of the human locus. Our estimate for the total amount of nonexonic constraint experienced by this locus is roughly twice that for exonic constraint. Constrained elements tend to Cluster, and we identify large constrained regions that correspond well with known functional elements. While constraint density inversely correlates with mobile element density, we also show the presence of unambiguously constrained elements overlapping mammalian ancestral repeats. In addition, we describe a number of elements in this region that have undergone intense purifying selection throughout mammalian evolution, and we show that these important elements are more numerous than previously thought. These results were obtained with Genomic Evolutionary Rate Profiling (GERP), a statistically rigorous and biologically transparent framework for constrained element identification. CERP identifies regions at high resolution that exhibit nucleotide substitution deficits, and measures these deficits as "rejected substitutions." Rejected substitutions reflect the intensity of past Purifying selection and are used to rank and characterize constrained elements. We anticipate that GERP and the types of analyses it facilitates will provide further insights and improved annotation for the human genome as mammalian genome sequence data become richer.