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Natural Selection Has Differentiated the Progesterone Receptor among Human Populations.

ABSTRACT: 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.

SUBMITTER: Li J

PROVIDER: S-EPMC6035283 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Natural Selection Has Differentiated the Progesterone Receptor among Human Populations.

Li Jingjing J Hong Xiumei X Mesiano Sam S Muglia Louis J LJ Wang Xiaobin X Snyder Michael M Stevenson David K DK Shaw Gary M GM

American journal of human genetics 20180621 1

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 selecti ...[more]

PMID: 29937092

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Project description:BackgroundSperm selection is essential for the health of offspring conceived via assistive reproductive technology (ART). Various methods of sperm preparation for in vitro fertilization and intracytoplasmic sperm injection have been developed to acquire sperm with better quality and to avoid potential genetic disorders. However, current sperm processing and selection techniques bypass the natural selection that occurs during fertilization in vivo. The aim of this study was to present a novel distance-progesterone-combined selection approach with an original device based on the human female reproductive tract, and to report on its effectiveness based on sperm progressive motility, as well as chemotaxis.MethodsA novel device with long distance channels which mimicked the female human reproductive system was designed and fabricated. This ready-to-be-used device was developed using a progesterone gradient and human tube fluid media. Sperm swam for 150 min in the device under conditions of 37 °C air temperature with 5% CO2 after separation from seminal plasma via discontinuous Percoll gradient treatment. The selected sperm were assessed for normal morphology using Diff-Quik staining. A chromatin diffusion assay assessed sperm for DNA fragments and apoptosis was assessed using annexin V-fluorescein isothiocyanate/propidium iodide fluorescent staining.ResultsOur distance-progesterone-combined sperm selection method was successfully established. After sperm were selected, the percentage of sperm with normal morphology increased (before vs. after selection, 11.2 ± 1.3% vs. 40.3 ± 6.6%, P = 0.000), the percentage of sperm with DNA fragmentation decreased (before vs. after selection, 15.4 ± 4.0% vs. 6.8 ± 3.3%, P = 0.001), and the percentage of sperm with apoptosis did not change significantly.ConclusionsOur newly-developed method is capable of successfully selecting sperm of high quality. The method will be benefit clinical ART practice as it can reduce sperm-related genetic risks.

Project description:Large-scale sequencing efforts have documented extensive genetic variation within the human genome. However, our understanding of the origins, global distribution, and functional consequences of this variation is far from complete. While regulatory variation influencing gene expression has been studied within a handful of populations, the breadth of transcriptome differences across diverse human populations has not been systematically analyzed. To better understand the spectrum of gene expression variation, alternative splicing, and the population genetics of regulatory variation in humans, we have sequenced the genomes, exomes, and transcriptomes of EBV transformed lymphoblastoid cell lines derived from 45 individuals in the Human Genome Diversity Panel (HGDP). The populations sampled span the geographic breadth of human migration history and include Namibian San, Mbuti Pygmies of the Democratic Republic of Congo, Algerian Mozabites, Pathan of Pakistan, Cambodians of East Asia, Yakut of Siberia, and Mayans of Mexico. We discover that approximately 25.0% of the variation in gene expression found amongst individuals can be attributed to population differences. However, we find few genes that are systematically differentially expressed among populations. Of this population-specific variation, 75.5% is due to expression rather than splicing variability, and we find few genes with strong evidence for differential splicing across populations. Allelic expression analyses indicate that previously mapped common regulatory variants identified in eight populations from the International Haplotype Map Phase 3 project have similar effects in our seven sampled HGDP populations, suggesting that the cellular effects of common variants are shared across diverse populations. Together, these results provide a resource for studies analyzing functional differences across populations by estimating the degree of shared gene expression, alternative splicing, and regulatory genetics across populations from the broadest points of human migration history yet sampled.

Dataset Information

Natural Selection Has Differentiated the Progesterone Receptor among Human Populations.

Publications

Natural Selection Has Differentiated the Progesterone Receptor among Human Populations.

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