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

两性之间的大多数差异都归因于荷尔蒙的差异。我们最近的研究表明，情况并非总是如此，男性和女性之间的基因活性差异可能与性别本身无关，而是由性染色体的差异引起的。正常情况下，女性有两条X染色体，男性有X染色体和Y染色体。通过研究“性别反转”，即男性有两条X染色体，女性有一条X染色体和一条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引起的，而是由性染色体引起的。本提案将探讨这一额外的调节性别差异的层是如何工作的。我们将探索在X染色体上有特定基因的可能性，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，在女性的每个细胞中都关闭的X染色体中的一条（为了与只有一条X染色体的男性保持平衡）隔离了重要的调节因子，从而减少了它们在女性中的可用性。这种隔离机制可能导致许多基因在女性中被不同地调节。我们可以通过引入通常关闭X染色体的机制来测试这个想法，并在男性中寻找我们之前只在女性中发现的性别差异。了解性别差异产生的机制对于理解许多疾病中强烈的性别偏见是如何产生的非常重要，并将进一步深入了解潜在的机制，从而在未来开辟新的治疗途径。

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.