Natural Selection Has Differentiated the Progesterone Receptor among Human Populations
Natural Selection Has Differentiated the Progesterone Receptor among Human Populations
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DOI：
10.1016/j.ajhg.2018.05.009
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发表时间：
2018-07-05
影响因子：
9.8
通讯作者：
Shaw, Gary M.
中科院分区：
文献类型：
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作者：
Li, Jingjing;Hong, Xiumei;Shaw, Gary M.
孕激素受体（PGR）在维持妊娠中起着核心作用，并与美国12.6%的新生儿早产等医疗条件显著相关。自人类和黑猩猩的共同祖先以来，PGR一直在迅速进化，我们在此研究了PGR在近期人类迁徙和种群分化中的进化动态。我们的研究揭示了在自然选择的驱动下，PGR位点上存在大量的群体分化，其中最近东亚人的正选择通过几乎固定进化上新的等位基因，大大降低了其遗传多样性。相反，在欧洲种群中，PGR位点可能由于平衡选择而被提升到高度多态状态。结合多种组织类型的转录组数据和大规模的早产全基因组关联数据，我们的研究证明了东亚人的选择事件对PGR表达重塑的影响，特别是在卵巢中，并确定了早期自发性早产与进化选择变异的显著关联。为了重建其在人类谱系上的进化轨迹，我们观察到现代人和古人类在PGR位点上的显著差异，包括尼安德特人基因组中一个有害的错义等位基因的固定，该等位基因后来在现代人中渗入。综上所述，我们的研究揭示了PGR的重大进化创新，甚至在最近的人类进化中，它在不同人群中的不同形式可能导致对黄体酮相关疾病（包括早产）的不同易感性。
The progesterone receptor (PGR) plays a central role in maintaining pregnancy and is significantly associated with medical conditions such as preterm birth that affects 12.6% of all the births in U.S. PGR has been evolving rapidly since the common ancestor of human and chimpanzee, and we herein investigated evolutionary dynamics of PGR during recent human migration and population differentiation. Our study revealed substantial population differentiation at the PGR locus driven by natural selection, where very recent positive selection in East Asians has substantially decreased its genetic diversity by nearly fixing evolutionarily novel alleles. On the contrary, in European populations, the PGR locus has been promoted to a highly polymorphic state likely due to balancing selection. Integrating transcriptome data across multiple tissue types together with large-scale genome-wide association data for preterm birth, our study demonstrated the consequence of the selection event in East Asians on remodeling PGR expression specifically in the ovary and determined a significant association of early spontaneous preterm birth with the evolutionarily selected variants. To reconstruct its evolutionary trajectory on the human lineage, we observed substantial differentiation between modern and archaic humans at the PGR locus, including fixation of a deleterious missense allele in the Neanderthal genome that was later introgressed in modern human populations. Taken together, our study revealed substantial evolutionary innovation in PGR even during very recent human evolution, and its different forms among human populations likely result in differential susceptibility to progesterone-associated disease conditions including preterm birth.