【PNAS】破解多年谜团:X染色体失活,试管婴儿男孩多于女孩
2016/03/10
3月7日中国科学家在《PNAS》杂志上揭露了体外受精小鼠后代性别失调的机制,此外还表明通过改变胚胎植入前IVF胚胎的生长环境可逆转这种性别失调。


通过体外受精生育的后代中男孩往往比女孩多,这有科学依据吗?日前,中国农业大学田见晖教授引领的研究发现该现象与X染色体失活有关,体外受精过程雌性胚胎中的一个X染色体沉默是导致体外受精小鼠性别比例失调的原因,此外该团队还揭示了通过改变胚胎植入前IVF胚胎的生长环境可逆转这种性别失调,相关研究成果于3月7日发表于《PNAS》杂志上。

中国科学家破解试管婴儿性别比例失调之谜

在美国,大约有1.5%的新生儿受益于试管婴儿技术,在其他地方,通过试管婴儿生育的概率高达4%。辅助生殖技术也广泛应用于牛、猪以及其他家畜的育种过程中。从90年代开始研究人员就开始记录体外受精后代偏雄性的现象。在过去的十年中,研究人员在人类体外受精胚胎中也出发现了类似的现象,但缺乏一致的证据。

在该研究中,研究人员通过比较体外受精与正常受孕小鼠胚胎X染色体印迹,结果发现X染色体失活似乎受Xist基因的表达以及Rnf12蛋白(ring finger protein)的影响。Xist是雌性哺乳动物一个X染色体的转录沉默所需的一个长非编码RNA,Rnf12是Xist基因的上游调控因子,在磁性胚胎中Xist基因和Rnf12的表达均受受损,但在雄性胚胎中则正常表达。研究人员通过实验室方法上调Rnf12的表达来拯救Xist基因。研究人员通过在胚胎植入前的培养环境中添加视黄酸有效扭转了体外受精小鼠的性别比例。

研究人员说,“我们的研究不仅揭示了体外受精过程中雌性妊娠丢失及后代性别失调的机制,同时还揭示了通过改变体外受精的培养环境来扭转后代性别失调的问题,为探索体外受精相关的并发症提供一个新的路线。”

关于X染色体失活


雌性哺乳动物携带两个版本的X-染色体,而雄性则携带一个X-染色和一个Y-染色体,为了抵消双剂量同一基因可能产生的毒性,X-染色体上的大多数基因都被沉默,该过程为X染色体失活。X染色体失活或里昂化(lyonization)是指雌性哺乳类细胞中两条X染色体的其中之一失去活性的现象,过程中X染色体会被包装成异染色质,进而因功能受抑制而沉默化。

国际专家对该研究的态度

加利福尼亚大学生殖内分泌专家Paulo Rinaudo表示,“先前研究者们就开始怀疑X染色体失活对体外受精后代性别产生重要的影响,该研究在探索该机制中作了很大的贡献。”

纽约大学兰贡医学中心David Keefe说,“如果辅助生殖技术如体外受精真的改变了基本生育过程,那么表观遗传学修饰是否会受体外受精的影响?性别失调只是冰山的一角。”

南加州大学的Kristin Bendikson 说,“这就是我们在体外受精实验室中需谨慎行事的原因”,她对中国研究团队改变胚胎植入前IVF胚胎生长环境留下了深刻的印象,“这提醒了每个人,我们在实验室里的每个行为都将影响胚胎遗传学,这是个非常重要的一课。”然而,该研究是否能用于人类还有待研究,Bendikson指出,“所有物种体内的机制都存在差异,将该研究结果转化为人类证据还需谨慎。”

延伸:辅助生殖IVF对表观遗传学的影响

动物和人类体外受精(IVF)的出现意味着新有机体的不同寻常时代已来临。日前,发表于《Biological Research》杂志上的论文综述了IVF等辅助生殖技术对表观遗传学的内在影响,并揭示了与辅助生殖相关的表观遗传学将有可能跨代遗传。哺乳动物受精发生在母体输卵管,母体输卵管是保证配子相遇和胚胎第一阶段发展的地方。在胚胎第一次发育时,表观遗传重编程对正常胚胎的命运至关重要,然而这种表观遗传重编程非常容易受到环境变化的影响,如体外受精中涉及到的体外培养、营养、光、温度、氧分压、胚胎产妇信号等可影响该过程的稳定性。

备注:本文根据The Scientist官网编译

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