An evolutionary genomic approach to identify genes involved in human birth timing.
An evolutionary genomic approach to identify genes involved in human birth timing.
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DOI：
10.1371/journal.pgen.1001365
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发表时间：
2011-04
期刊：
影响因子：
4.5
通讯作者：
Muglia L
中科院分区：
文献类型：
--
作者：
Plunkett J;Doniger S;Orabona G;Morgan T;Haataja R;Hallman M;Puttonen H;Menon R;Kuczynski E;Norwitz E;Snegovskikh V;Palotie A;Peltonen L;Fellman V;DeFranco EA;Chaudhari BP;McGregor TL;McElroy JJ;Oetjens MT;Teramo K;Borecki I;Fay J;Muglia L
胎儿成熟与出生时间的协调对于哺乳动物的生殖是必不可少的。在人类中，早产是一种具有深远全球健康意义的疾病。由于人类和典型研究的模式生物之间的生理机制存在分歧，人类分娩的信号仍然难以捉摸。由于相对较大的人类头部大小和狭窄的产道横截面积相比，其他灵长类动物，我们假设，参与分娩的基因将显示加速进化沿着人类和/或更高的灵长类动物的系统发育谱系，以减少妊娠期的长度，并促进交付一个较小的胎儿，更容易通过产道。此外，我们测试了这种加速基因的当前变异是否会导致早产风险。从异速生长的胎龄比例的证据表明，人类怀孕已缩短相对于其他灵长类动物。与我们的假设一致，许多参与生殖的基因在其编码区或邻近的非编码区显示出人类加速。我们在165名芬兰早产母亲和163名对照母亲的150个人类加速基因中筛选了> 8，400个SNP，以研究与早产的关联。在这个队列中，最显著的关联是FSHR，10个最显著的SNP中有8个在这个基因中。在非裔美国人中发现了FSHR、rs 11686474、rs 11680730、rs 12473870和rs 1247381中SNP连锁不平衡块相关的进一步证据。通过考虑人类的加速度，我们确定了一个新的基因，可能与早产，FSHR。我们预计其他人类加速基因将同样与早产风险相关，并阐明人类分娩的基本途径。人类生育时间的控制是生殖生物学中最大的未解决问题，早产是孕产妇和儿童健康中最重要的医学问题。为了开始解决这个关键问题，我们测试了一个假设，即与其他灵长类和哺乳动物相比，人类的基因进化速度加快，这与出生时间有关。我们首先表明，人类妊娠期长度已被改变相对于其他非人类灵长类动物和哺乳动物。使用异速生长标度，我们证明，人类妊娠期短于其他哺乳动物物种的妊娠期长度的基础上预测。接下来，我们将展示人类中具有加速率的基因（在编码或调控区域）是参与出生时间的合理候选者。最后，我们发现人类加速基因（FSHR）的多态性可能会改变人类早产的风险，而以前与出生时间无关。我们对人类出生时间的途径的理解是有限的，但它的阐明仍然是生物学和医学中最重要的问题之一。我们应用的进化遗传学方法应该适用于许多人类疾病，并帮助其他研究早产的研究人员。
Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition. The control of birth timing in humans is the greatest unresolved question in reproductive biology, and preterm birth is the most important medical issue in maternal and child health. To begin to address this critical problem, we test the hypothesis that genes accelerated in their rate of evolution in humans, as compared with other primates and mammals, are involved in birth timing. We first show that human gestational length has been altered relative to other non-human primates and mammals. Using allometric scaling, we demonstrate that human gestation is shorter than predicted based upon gestational length in other mammalian species. Next, we show that genes with rate acceleration in humans—in coding or regulatory regions—are plausible candidates to be involved in birth timing. Finally, we find that polymorphisms in the human accelerated gene (FSHR), not before implicated in the timing for birth, may alter risk for human preterm birth. Our understanding of pathways for birth timing in humans is limited, yet its elucidation remains one of the most important issues in biology and medicine. The evolutionary genetic approach that we apply should be applicable to many human disorders and assist other investigators studying preterm birth.
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影响因子：
4.3
作者：
Arbiza L;Dopazo J;Dopazo H
通讯作者：
Dopazo H
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
56.9
作者：
Bailey, JA;Gu, ZP;Eichler, EE
通讯作者：
Eichler, EE
影响因子：
4.1
作者：
Li, Y.;Ganta, S.;Freeman, L. C.
通讯作者：
Freeman, L. C.
影响因子：
64.8
作者：
Bustamante, CD;Fledel-Alon, A;Clark, AG
通讯作者：
Clark, AG