Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility.
Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility.
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DOI：
10.1038/nature19075
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发表时间：
2016-08-11
期刊：
影响因子：
64.8
通讯作者：
Eichler EE
中科院分区：
文献类型：
--
作者：
Nuttle X;Giannuzzi G;Duyzend MH;Schraiber JG;Narvaiza I;Sudmant PH;Penn O;Chiatante G;Malig M;Huddleston J;Benner C;Camponeschi F;Ciofi-Baffoni S;Stessman HA;Marchetto MC;Denman L;Harshman L;Baker C;Raja A;Penewit K;Janke N;Tang WJ;Ventura M;Banci L;Antonacci F;Akey JM;Amemiya CT;Gage FH;Reymond A;Eichler EE
人类进化的独特方面的遗传差异通常通过人类和密切相关的灵长类动物的基因组之间的比较分析来确定，包括最近的古人类基因组。然而，并不是基因组的所有区域都同样适合这样的研究。染色体16p11.2处的复发性拷贝数变异（CNV）约占自闭症病例的1%，并且由一组复杂的片段重复介导，其中许多是最近在人类进化过程中出现的。我们重建了该基因座的进化历史，并将BOLA 2（bolA家族成员2）鉴定为仅在智人中复制的基因。我们估计，含有BOLA 2的95 kbp片段在约28.2万年前（kya）的关键区域复制，这是一系列基因组变化中的最新变化之一，这些变化在原始人类进化过程中显着重组了基因座。所有被检测的人类都携带一个或多个复制体，这种复制体在人类谱系的早期几乎是固定的，在没有选择的情况下，这种模式不太可能如此迅速地出现（p < 0.0097）。我们发现，BOLA 2的重复导致了一种新的，人类特异性的框内融合转录本，BOLA 2拷贝数与RNA表达（r = 0.36）和蛋白质水平（r = 0.65）相关，在实验来源的干细胞中，人类和黑猩猩之间的表达差异最大。对152名携带染色体16p11.2重排的患者的分析表明，>96%的断裂点发生在人类特异性重复内。总之，在智人谱系~282 kya根部的BOLA 2重复转座同时增加了与铁稳态相关的基因的拷贝数，并使我们的物种易于发生与疾病相关的复发性重排。
Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for ~1% of autism cases and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. We reconstructed the evolutionary history of the locus and identified BOLA2 (bolA family member 2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95 kbp segment containing BOLA2 duplicated across the critical region ~282 thousand years ago (kya), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carry one or more copies of the duplication, which nearly fixed early in the human lineage—a pattern unlikely to have arisen so rapidly in the absence of selection (p < 0.0097). We show that the duplication of BOLA2 led to a novel, human-specific in-frame fusion transcript and that BOLA2 copy number correlates with both RNA expression (r = 0.36) and protein level (r = 0.65), with the greatest expression difference between human and chimpanzee in experimentally derived stem cells. Analyses of 152 patients carrying a chromosome 16p11.2 rearrangement showed that >96% of breakpoints occur within the Homo sapiens-specific duplication. In summary, the duplicative transposition of BOLA2 at the root of the Homo sapiens lineage ~282 kya simultaneously increased copy number of a gene associated with iron homeostasis and predisposed our species to recurrent rearrangements associated with disease.