Molecular mechanisms and evolutionary origins of teratozoospermia and sex ratio skewing in mice with Y chromosome deletions

Y染色体缺失小鼠畸形精子症和性别比例偏差的分子机制和进化起源

• 批准号: BB/F007434/1
• 负责人: Nabeel Affara
• 金额: $ 65.61万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF007434%2F1
• 关键词: Molecular; mechanisms; evolutionary; origins; teratozoospermia

When a sperm fertilizes an egg, the sex of the resulting offspring is determined by whether the sperm carries an X or a Y chromosome. Normally, this is a 50:50 chance, and thus half the offspring are male and half are female. However, there is the possibility that genes on the sex chromosomes can act 'selfishly' to increase their likelihood of being passed on: for example if X-bearing sperm secrete a toxin that kills Y-bearing sperm, or makes them less effective at fertilising the egg. This is known as genomic competition. X chromosomes with more copies of such a 'distorter' gene spread more rapidly, leading to an increase in the copy number of these genes on the X chromosome. If such a genomic competition arises between the X and Y chromosomes, then natural selection will favour the survival of Y chromosomes which carry a 'repressor' gene opposing the action of the X-linked distorter gene. This then leads to an arms race, amplifying the competing genes on both X and Y chromosomes. This seems to be the case in mouse. There are several different families of genes on the Y chromosome which are present in many dozens of copies each. When these genes are deleted, there is a sex ratio skew in the offspring of the males carrying the deletion. We have identified several of these Y chromosome gene families in our recent work, and have shown that specific X chromosome genes are switched on when the Y chromosomal repressor genes are deleted. This 'overexpression' of the X chromosome genes leads to sperm with malformed heads, which are less effective at fertilising eggs. Of the sperm that are able to fertilise eggs, more than 50% are X-bearing sperm, leading to the sex ratio skew in favour of females in the next generation. Our proposed project is aimed at understanding the molecular basis of how this genomic competition arose during the evolutionary history of the mouse, how the distorter genes spread thereafter, and how they have been contained by the evolution of the repressor genes. In order to discover this, we will make special stains using antibodies to show where the X-encoded proteins are located within the sperm, and use this to work out how they may affect sperm head shape. It will be especially interesting to see if there is a difference between X-bearing and Y-bearing sperm in terms of protein location. We will also make transgenic mice that specifically overexpress one or more of the candidate X genes, and check for sperm shape abnormalities and/or a sex ratio skew in the transgenic lines. We will look in closer detail at the Y-linked repressor genes to see how they counteract the distorter genes. One gene, called Fly, is very interesting as it is transcribed in both directions. Transcription is the process that makes 'working copies' (mRNA copies) of active genes. If a gene is transcribed in both directions, the resulting mRNAs can silence related genes in a process called RNA inhibition (RNAi). We will test whether RNAi is the mechanism that lets the Y chromosomal repressor genes counteract the X chromosomal distorter genes. Finally, we will see how many copies of each of the candidate genes are present on the X and Y chromosomes of a range of different mouse species. This will tell us when the genomic conflict started. By comparing the sequence and activity patterns of genes before and after the start of the conflict, we may be able to find specific mutations that caused the conflict. A better understanding of sex ratio distortion, and the evolutionary processes behind it, is important not only in pure science terms, but also potentially in economic terms. For example, it may allow us to discover conflicting genes in farm animal species such as cattle, allowing selective breeding for bulls that preferentially generate female calves. Also, a fuller biochemical understanding of the pathways affected by the distorter genes could let us directly target these pathways in order to affect offspring sex ratio.

当一个精子使一个卵子受精时，所产生的后代的性别取决于精子是否携带X或Y染色体。通常情况下，这是一个50：50的机会，因此一半的后代是男性和女性的一半。然而，性染色体上的基因可能会“自私地”行事，以增加它们被传递的可能性：例如，如果X精子分泌一种毒素杀死Y精子，或者使它们在受精卵时效率降低。这被称为基因组竞争。具有更多这种“扭曲”基因拷贝的X染色体传播得更快，导致X染色体上这些基因的拷贝数增加。如果这种基因组竞争发生在X和Y染色体之间，那么自然选择将有利于携带“阻遏物”基因的Y染色体的生存，该基因与X连锁的扭曲基因的作用相反。这就导致了一场军备竞赛，扩增了X和Y染色体上的竞争基因。这似乎是老鼠的情况。Y染色体上有几个不同的基因家族，每个家族都有几十个拷贝。当这些基因被删除时，携带删除基因的雄性后代的性别比例就会出现偏差。在我们最近的工作中，我们已经确定了几个这样的Y染色体基因家族，并且已经表明当Y染色体阻遏基因被删除时，特定的X染色体基因被打开。这种X染色体基因的“过度表达”导致精子头部畸形，使卵子受精的效率降低。在能够使卵子受精的精子中，超过50%是带有X染色体的精子，导致下一代的性别比例偏向女性。我们提出的项目旨在了解这种基因组竞争如何在小鼠的进化历史中出现的分子基础，扭曲基因如何在此后传播，以及它们如何被抑制基因的进化所包含。为了发现这一点，我们将使用抗体进行特殊染色，以显示X编码蛋白质在精子中的位置，并利用这一点来研究它们如何影响精子头部形状。这将是特别有趣的，看看是否有一个X轴承和Y轴承精子之间的差异，在蛋白质的位置。我们还将制造特异性过表达一个或多个候选X基因的转基因小鼠，并检查转基因品系中的精子形状异常和/或性别比例偏斜。我们将更详细地研究Y连锁阻遏基因，看看它们如何抵消扭曲基因。有一个基因叫做Fly，非常有趣，因为它是双向转录的。转录是制造活性基因的“工作拷贝”（mRNA拷贝）的过程。如果一个基因在两个方向上转录，产生的mRNA可以在一个称为RNA抑制（RNAi）的过程中沉默相关基因。我们将测试RNAi是否是让Y染色体阻遏基因抵消X染色体扭曲基因的机制。最后，我们将看到在一系列不同小鼠物种的X和Y染色体上存在每个候选基因的多少拷贝。这将告诉我们基因组冲突何时开始。通过比较冲突开始前后基因的序列和活动模式，我们也许能够找到导致冲突的特定突变。更好地理解性别比例扭曲及其背后的进化过程不仅在纯科学方面很重要，而且在经济方面也很重要。例如，它可以让我们发现家畜物种（如牛）中的冲突基因，从而允许选择性繁殖公牛，优先产生雌性小牛。此外，对受扭曲基因影响的途径的更全面的生物化学理解可以让我们直接针对这些途径来影响后代的性别比例。

项目成果

A genetic basis for a postmeiotic X versus Y chromosome intragenomic conflict in the mouse.

• DOI: 10.1371/journal.pgen.1002900
• 发表时间: 2012-09
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Cocquet J;Ellis PJ;Mahadevaiah SK;Affara NA;Vaiman D;Burgoyne PS
• 通讯作者: Burgoyne PS

Association of Sly with sex-linked gene amplification during mouse evolution: a side effect of genomic conflict in spermatids?

• DOI: 10.1093/hmg/ddr204
• 发表时间: 2011-08-01
• 期刊: HUMAN MOLECULAR GENETICS
• 影响因子: 3.5
• 作者: Ellis, Peter J. I.;Bacon, Joanne;Affara, Nabeel A.
• 通讯作者: Affara, Nabeel A.

The multicopy gene Sly represses the sex chromosomes in the male mouse germline after meiosis.

• DOI: 10.1371/journal.pbio.1000244
• 发表时间: 2009-11
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Cocquet J;Ellis PJ;Yamauchi Y;Mahadevaiah SK;Affara NA;Ward MA;Burgoyne PS
• 通讯作者: Burgoyne PS

Deficiency in the multicopy Sycp3-like X-linked genes Slx and Slxl1 causes major defects in spermatid differentiation.

• DOI: 10.1091/mbc.e10-07-0601
• 发表时间: 2010-10-15
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Cocquet J;Ellis PJ;Yamauchi Y;Riel JM;Karacs TP;Rattigan A;Ojarikre OA;Affara NA;Ward MA;Burgoyne PS
• 通讯作者: Burgoyne PS