Evolutionary constraints in conserved nongenic sequences of mammals
Evolutionary constraints in conserved nongenic sequences of mammals
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DOI：
10.1101/gr.3942005
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发表时间：
2005-10-01
期刊：
影响因子：
7
通讯作者：
Gaffney, DJ
中科院分区：
文献类型：
--
作者：
Keightley, PD;Kryukov, GV;Gaffney, DJ
哺乳动物基因组包含许多高度保守的非基因序列（CNG），其功能意义尚不清楚。以前通过从染色体或基因组中选择最保守的元件来鉴定 CNG 组，但在这些高度选择的样本中，保守性可能与纯化选择无关。此外，CNG 的保护可能是由突变率变化而不是选择性限制引起的。为了解释选择性采样的影响，我们检查了类群中 CNG 的保守性，这些类群的进化在很大程度上独立于最初识别 CNG 的类群，并且我们控制了基因组中的突变率变化。我们表明，原始人类中 CNG 及其侧翼的选择性限制大约是鼠科动物的一半，这意味着原始人类在功能重要的非基因区域中积累了许多稍微有害的突变。这可能是原始人类有效种群规模低导致选择有效性降低的结果。我们估计 CNG 中的保守核苷酸数量分别是已知的原始人和鼠类蛋白质编码基因的一倍和两倍。 CNG 中的多态性频率表明纯化选择在这些序列中进行。在原始人类进化过程中，我们估计每代每个二倍体基因组中总共有大约三个 CNG 和蛋白质编码基因中的有害突变被选择性消除，这意味着有害突变是非独立地从种群中消除的，并且性对于长期种群持续存在是必要的。
Mammalian genomes contain many highly conserved nongenic sequences (CNGs) whose functional significance is poorly understood. Sets of CNGs have previously been identified by selecting the most conserved elements from a chromosome or genome, but in these highly selected samples, conservation may be unrelated to purifying selection. Furthermore, conservation of CNGs may be Caused by Mutation rate variation rather than selective constraints. To account for the effect of selective sampling, we have examined conservation of CNGs in taxa whose evolution is largely independent of the taxa from which the CNGs were initially identified, and we have controlled for mutation rate variation in the genome. We show that selective constraints in CNGs and their flanks are about one-half as strong in hominids as in murids, implying that hominids have accumulated many slightly deleterious Mutations in functionally important nongenic regions. This is likely to be a Consequence of the low effective Population size of hominids leading to a reduced effectiveness of selection. We estimate that there are one and two times as many conserved nucleotides in CNGs as in known protein-coding genes of hominids and murids, respectively. Polymorphism frequencies in CNGs indicate that Purifying selection operates in these sequences. During hominid evolution, we estimate that a total of about three deleterious Mutations in CNGs and protein-coding genes have been selectively eliminated per diploid genome each generation, implying that deleterious Mutations are eliminated from Populations non-independently and that sex is necessary for long-term Population persistence.