The role of meiosis on the evolution of the sex chromosomes

从一对假定的祖先常染色体中了解形成性染色体的进化选择力量是生物学中的一个主要问题(在Khil和Camerini-Otero(2005)Crit中回顾。Biochem牧师。摩尔。比奥尔。40,313)。几年前，有报道称，对线虫和黑腹线虫的全基因组分析表明，男性特有的基因在X染色体上的表达不足，而大约20多个小鼠的精原基因则相反。这款鼠标真的不一样吗？我们对Spo11成年小鼠微阵列数据的分析为睾丸基因的表达提供了一个时间线。我们发现，那些在减数分裂后期细胞中表达的基因，包括大多数富含睾丸的基因，在X染色体上表达不足。然而，早期基因被过度表达。由于先前发表的小鼠数据仅与早期精原基因有关，这些结果与所有数据相一致。此外，我们增加了一块缺失的拼图，提出在大多数生物中，X染色体的去维管化(男性基因的移除)受到男性减数分裂期间性染色体失活的影响(Khil等人)。(2004)NAT。吉内。36,642和Reinke(2004)NAT中的评论。吉内。36,548人)。实现X染色体重塑的一种方式是通过从X染色体到常染色体的逆转座，而不是在常染色体之间(Shiao等人(2007)Mol Biol Evol)。最近，我们在这一总体领域内的三个不同领域开展了工作。首先，我们一直在研究一种我们称之为伪性体(PSB)的结构是如何形成的。在Spo11基因敲除小鼠中，PSB在没有双链断裂的情况下被观察到作为GammaH2AX的积累，类似于在正常性体中看到的在野生型小鼠X和Y染色体上的积累。正如我们以前所表明的，PSB不包括性染色体(X和Y：Bellani等人。(2005)J Cell Science 118,3233)我们一直在使用芯片序列来研究特定的染色体或基因组区域是否被PSB中的GammaH2 AX包裹或装饰。这仍然是一个正在进行的项目。第二，在与辛辛那提儿童医院的Satoshi Namekawa的合作中，我们已经证明了MDC1指导了男性生殖细胞中性染色体的染色体范围的沉默(Ichijama等人。(2011)《基因与发展》25,959)。最后，我们与伦敦米尔希尔国家医学研究所的詹姆斯·特纳合作，确定了RSX，这是一种覆盖在不活跃的雌性有袋类X染色体上的RNA(Grant等人。(2012)《自然》487,254)。这是一个长期存在的生物学谜团，因为人们已经知道，有袋类雌性动物只会使父系遗传的X染色体失活，而不是像小鼠和人类那样，父系或母系染色体被失活。为此，有人提出，有袋类动物的X染色体失活机制不涉及覆盖在非活动染色体上的RNA，而不是真兽类动物(如小鼠和人)中的Xist RNA。在这项工作中，尽管与Xist没有序列同源性，但仍发现了这样一种RNA。 今年没有重大进展可供报告，尽管关于RSX的合作仍在进行中。

Understanding the evolutionary selective forces that fashioned the sex chromosomes from a putative ancestral autosome pair is a major problem in biology (reviewed in Khil and Camerini-Otero (2005) Crit. Rev. Biochem. Mol. Biol. 40, 313). A few years ago it was reported that genome-wide analyses of C. elegans and D. melanogaster revealed that male-specific genes are underrepresented on the X-chromosome whereas the opposite was reported for about 2 dozen mouse spermatogonial genes. Is the mouse really different? Our analysis of the Spo11 adult mice microarray data provided a time line for the expression of testis genes. We found that those genes expressed in cells late in meiosis, including the majority of testis-enriched genes, are underrepresented on the X. However, early genes are overrepresented. Since the previously published mouse data pertained to early spermatogonial genes only, these results reconcile all the data. Furthermore, we added a missing piece of the puzzle by proposing that the demasculinization (removal of male genes) of the X chromosome in most organisms is influenced by inactivation of the sex chromosomes during male meiosis (Khil et al. (2004) Nat. Genet. 36, 642 and commentary in Reinke (2004) Nat. Genet. 36, 548). One manner by which this reshaping of the X chromosome is achieved is by retrotransposition from the X chromosome to autosomes much more frequently than between autosomes (Shiao et al.(2007) Mol Biol Evol). Recently we have worked on three separate areas within this general area. First, we have been investigating how a structure we have named the Pseudo Sex-Body (PSB) is formed. The PSB is observed in the absence of double-strand breaks in a Spo11 knockout mouse as an accumulation of gammaH2AX, akin to the accumulation seen on the X and Y chromosomes in the normal sex body seen in wild-type mice. As we have previously shown that the PSB does not include the sex chromosomes (X and Y: Bellani et al. (2005) J Cell Science 118, 3233) we have been investigating by using ChIP-Seq whether particular chromosomes or genomic regions are encased or decorated by gammaH2AX in the PSB. This is still an ongoing project. Second, in collaboration with Satoshi Namekawa at Cincinnati Children's Hospital we have shown that MDC1 directs chromosome-wide silencing of the sex chromosomes in male germ cells (Ichijama et al. (2011) Genes and Development 25, 959). Finally, in collaboration with James Turner at National Institute for Medical Research at Mill Hill, London we have identified Rsx, an RNA that coats the inactive female marsupial X chromosome (Grant et al. (2012) Nature 487, 254). This has been a long-standing biological mystery as it has been known that marsupial females inactivate only the paternally-inherited X chromosome, not as in mice and man where either the paternal or maternal chromosome is inactivated. For this reason, it has been proposed that the mechanism of X chromosome inactivation in marsupials does not involve an RNA that coats the inactive chromosome, as is the case for Xist RNA in eutherian mammals such as mice and man. In this work, such an RNA has been identified even though it bears no sequence homology to Xist. No significant progress to report this year, although the collaboration on Rsx is ongoing.