Balancing selection on a regulatory region exhibiting ancient variation that predates human-neandertal divergence.
Balancing selection on a regulatory region exhibiting ancient variation that predates human-neandertal divergence.
复制标题
DOI：
10.1371/journal.pgen.1003404
复制
发表时间：
2013-04
期刊：
影响因子：
4.5
通讯作者：
Lee C
中科院分区：
文献类型：
--
作者：
Gokcumen O;Zhu Q;Mulder LC;Iskow RC;Austermann C;Scharer CD;Raj T;Boss JM;Sunyaev S;Price A;Stranger B;Simon V;Lee C
古代人口结构塑造当代遗传变异最近已被赞赏，并对我们理解现代人类基因组的结构具有重要意义。我们在人类基因组中发现了一个约36 kb的DNA片段，它显示了一个古老的子结构。该位点的变异主要以两个高度分化的单倍型群存在。其中一个单倍群（NE 1单倍群）与尼安德特人单倍型一致，并含有一个4.6 kb的缺失多态性，与不同人群中的12个单核苷酸多态性（SNP）完全连锁不平衡。另一个单倍型群不包含4.6 kb的缺失，与黑猩猩单倍型一致，可能是祖先。在NE 1基因座上，非洲人与尼安德特人单倍型的总体成对差异高于欧亚人（p<10−15）。此外，欧亚人在该位点的核苷酸多样性高于非洲人。这些结果模拟了最近的尼安德特人混合物的签名，有助于这个位点。然而，对该地区多个人群中的变异进行的深入评估表明，非洲NE 1单倍型虽然罕见，但比欧洲人中发现的NE 1单倍型具有更多的序列变异，这表明该单倍型群起源于古代非洲，并反驳了最近的尼安德特人混合物。这些单倍群内的SNP的群体遗传分析，沿着与全基因组的比较揭示了显着的FST（p = 0.00003）和积极的田岛的D（p = 0.00285）统计，指向该位点的非中性进化。 NE 1基因座不含蛋白质编码基因，但含有转录序列以及基于生物信息学预测和体外实验的具有推定调控功能的序列。我们假设，在这个位点观察到的变化早于人类-尼安德特人的分歧，并在平衡选择下不断发展，特别是在欧洲人群中。自然选择以一种非随机的方式塑造基因组，因为对物种生殖适应性贡献更大的等位基因在种群中的频率增加。在平衡选择（一种特殊的自然选择）下，种群中不止一个等位基因的频率增加，这可能是由于携带两个等位基因的个体具有繁殖优势。只有少数基因座已被充分证明在平衡选择下进化，HBB基因（镰状细胞基因座）是研究得最好的。在这里，我们报告了一个非编码（但pupelium功能）基因座，自人类-尼安德特人分歧之前，在人类群体中保持了两个不同的等位基因，因此可能处于平衡选择之下。这些发现也为古非洲的地下结构提供了一个明确的例子。
Ancient population structure shaping contemporary genetic variation has been recently appreciated and has important implications regarding our understanding of the structure of modern human genomes. We identified a ∼36-kb DNA segment in the human genome that displays an ancient substructure. The variation at this locus exists primarily as two highly divergent haplogroups. One of these haplogroups (the NE1 haplogroup) aligns with the Neandertal haplotype and contains a 4.6-kb deletion polymorphism in perfect linkage disequilibrium with 12 single nucleotide polymorphisms (SNPs) across diverse populations. The other haplogroup, which does not contain the 4.6-kb deletion, aligns with the chimpanzee haplotype and is likely ancestral. Africans have higher overall pairwise differences with the Neandertal haplotype than Eurasians do for this NE1 locus (p<10−15). Moreover, the nucleotide diversity at this locus is higher in Eurasians than in Africans. These results mimic signatures of recent Neandertal admixture contributing to this locus. However, an in-depth assessment of the variation in this region across multiple populations reveals that African NE1 haplotypes, albeit rare, harbor more sequence variation than NE1 haplotypes found in Europeans, indicating an ancient African origin of this haplogroup and refuting recent Neandertal admixture. Population genetic analyses of the SNPs within each of these haplogroups, along with genome-wide comparisons revealed significant FST (p = 0.00003) and positive Tajima's D (p = 0.00285) statistics, pointing to non-neutral evolution of this locus. The NE1 locus harbors no protein-coding genes, but contains transcribed sequences as well as sequences with putative regulatory function based on bioinformatic predictions and in vitro experiments. We postulate that the variation observed at this locus predates Human–Neandertal divergence and is evolving under balancing selection, especially among European populations. Natural selection shapes the genome in a non-random way, as an allele that contributes more to the reproductive fitness of a species increases in frequency within the population. Under balancing selection, a particular kind of natural selection, more than one allele increases in frequency in the population, likely due to a reproductive advantage of individuals carrying both alleles. Only a handful of loci have been well documented to evolve under balancing selection, with the HBB gene (sickle cell locus) being the best studied. Here, we report a non-coding (but putatively functional) locus that has maintained two divergent alleles in the human population since before the Human–Neandertal divergence and is therefore likely to be under balancing selection. These findings also provide a clear example for ancient African substructure.
登录
查看更多内容
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1098/rstb.2003.1394
发表时间：
2004-02-29
影响因子：
6.3
作者：
Forster, P
通讯作者：
Forster, P
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1016/0035-9203(54)90101-7
发表时间：
1954-01-01
影响因子：
2.2
作者：
ALLISON, AC
通讯作者：
ALLISON, AC
影响因子：
1.5
作者：
Charlesworth, B;Nordborg, M;Charlesworth, D
通讯作者：
Charlesworth, D