A Y CHROMOSOME MODEL FOR THE SEX DETERMINING FUNCTION OF THE HUMAN ATRX GENE

人类的性别决定是由一种遗传途径控制的，这种遗传途径在人类胚胎中睾丸或卵巢的发育中达到顶峰。在这条通路的顶端是Y染色体上的主开关基因SRY，它控制着其他一系列对睾丸发育开关至关重要的基因。其他几个基因已经通过临床突变被确定，这些突变可以逆转XY胚胎的性别。一种性别反转基因是人类X染色体上的ATRX。ATRX的突变导致XY胚胎发育为雌性，并引起许多不相关的疾病，如α -地中海贫血。ATRX似乎是一种控制其他基因活性的转录因子，但很难理解它是如何起作用的，因为它在身体的所有部位都很活跃，而且突变对人类有许多不同的影响。然而，我们最近发现，在有袋类哺乳动物中，这个基因在Y染色体（ATRY）和X染色体（ATRX）上都有一个拷贝。值得注意的是，仅在性腺发育中起作用的ATRY和在其他任何地方都活跃的ATRX之间存在分工。这个睾丸特异性的ATRY基因可能揭示了ATRX如何与其他基因相互作用形成睾丸，而不像它在其他组织中那样产生并发症。因此，我们将克隆和表征ATRX-Y及其蛋白产物，以找出它在性别决定途径中的作用时间和位置。我们将使用非常大的有袋动物基因组克隆片段来发现控制睾丸特异性表达的元素，我们将确定ATRY与其他蛋白质的相互作用。睾丸确定途径是人体其他器官分化的良好模型。我们对ATRY的研究将向我们展示这类转录因子在发育过程中如何在不同组织中被激活，以及它如何控制其他基因。这将有助于更好地了解人类器官发生的遗传控制以及突变对人类发育的影响。

Human sex determination is controlled by a genetic pathway which culminates in the development of a testis or an ovary in the human embryo. At the head of this pathway is the master switch gene SRY on the Y chromosome, which controls a cascade of other genes critical for switching on testis development. Several other genes have been identified by clinical mutations which reverse sex of XY embryos. One sex reversing gene is ATRX on the human X chromosome. Mutation in ATRX causes XY embryos to develop as females, as well as causing many unrelated disorders such as alpha-thalassemia. ATRX seems to be a transcription factor that controls the activity of other genes, but it is difficult to understand how it functions because it is active in all parts of the body and mutation has many different effects in humans. However, we recently discovered that in marsupial mammals that this gene has a copy on the Y chromosome (ATRY) as well as the X (ATRX). Remarkably, there is a division of labour between ATRY, which acts only in developing gonads, and ATRX, which is active everywhere else. This testis-specific ATRY gene may reveal how ATRX interacts with other genes to make a testis, without the complications of its action in other tissues. We will therefore clone and characterize ATRX-Y and its protein product to find out when and where it acts in the sex determining pathway. We will use very large cloned pieces of the marsupial genome to discover elements controlling the testis-specific expression, and we will identify the interactions of ATRY with other proteins. The testis determination pathway is a good model for the differentiation of other human organs. Our work on ATRY will show us how this class of transcription factors is activated in different tissues during development, and how it controls other genes. This will lead to a better understanding of the genetic control of human organogenesis and the effects of mutation on human development.