Investigation into sexual dimorphisms in autosomal gene expression due to sex chromosome complement effects rather than phenotypic sex

两性之间的大部分差异都归因于荷尔蒙的差异。我们最近的研究表明，情况并不总是如此，男性和女性之间的基因活性差异可以独立于性别本身，而是由于性染色体的差异。正常情况下，女性有两条X染色体，男性有一条X和一条Y染色体。通过研究“性逆转”，即男性有两个X染色体，女性有一条X和一条Y染色体，我们发现男性和女性之间的许多差异不是由性别本身造成的，而是由性染色体造成的。这项提案将探讨在调节性别差异方面的这一额外层面是如何发挥作用的。我们将探索X染色体上存在特定基因的可能性，这些基因通过充当开关来打开或关闭许多不在X和Y染色体上的其他基因，从而导致这些差异。另一种可能性是，在雌性体内每个细胞中都关闭的X染色体之一(为了与只有一条X染色体的雄性保持平衡)隔离了重要的调节因子，从而减少了它们在雌性体内的可获得性。这种隔离机制可能会导致许多基因在女性身上受到不同的调控。我们可以通过引入正常情况下将X染色体关闭到另一条染色体的机制来测试这一想法，并寻找我们以前只在女性身上发现的男性性别差异。了解性别差异产生的机制对于了解许多疾病中如何产生强烈的性别偏见非常重要，并将进一步深入了解其潜在机制，从而开辟未来治疗的新途径。

Most differences between the sexes have been attributed to hormonal differences. We have recently shown that this is not always the case and that gene activity differences between males and females can be independent of sex itself and instead come about because of differences in the sex chromosomes. Normally females have two X chromosomes and males an X and a Y chromosome. By studying 'sex reversal' where males have two X chromsomes and females an X and a Y chromosome we found many differences between males and females that are not caused by sex itself but rather by the sex chromosomes. This proposal will explore how this additional layer in the regulation of differences between the sexes works. We will explore the possibility that there are specific genes on the X chromosome which cause these differences by acting as switches to turn on or off many other genes that are not on the X and Y chromosome. Another possibility is that one of the X-chromosomes, the one that is shut-down in every cell in females (to balance with males who have only one X chromosome) sequesters important regulatory factors thereby reducing their availabilty in females. Such a sequestration mechanism could lead to many genes being regulated differently in females. We can test this idea by introducing the mechanism that normally shuts down the X chromosome to another chromosomes and looking for the sex differences in males that we previously found only in females. Understanding the mechanism whereby sex differences come about is important for understanding how strong sex bias arises in many diseases, and will give further insight into the underlying mechanisms and hence open up new therapeutic avenues in the future.