CAREER: Dose-dependent genetic mechanisms driving X versus Y chromosomal competition

在哺乳动物中，雄性通常有50:50的机会生育雄性或雌性后代，因为从精子中遗传X染色体或Y染色体的可能性相同。然而，也存在50:50的性别比例扭曲的情况，即更多的男性或更多的女性后代。这种扭曲的基础尚不清楚。有证据表明，X染色体和Y染色体上的一些基因在一场“进化军备竞赛”中相互竞争，导致含X染色体的精子与含Y染色体的精子使卵子受精的能力存在差异。本项目旨在了解这场竞争的分子细节，以小鼠为研究对象。通过解释哺乳动物正常和扭曲性别比例的遗传基础，成功将有助于性染色体生物学的一个令人兴奋的新领域。参与这项研究的研究生和本科生将培养小鼠分子遗传学的新实验技能和分析大型DNA测序数据集的计算技能。结合本计划的研究方向，教育和外展部分将促进遗传学和进化方面的学习经验。研究生和博士后研究人员将通过专门的系列研讨会为高中教师提供继续教育，并通过参与全州范围的密歇根DNA日与高中生进行互动。公众将通过密歇根大学自然历史博物馆的展览了解这项研究。进化理论认为，高度分化的性染色体为基因相互竞争提供了理想的战场。事实上，在动物中，有一些例子表明，X和y相关的基因在基因冲突中扭曲了性别比例。然而，控制X连锁与y连锁基因竞争如何驱动性别比例扭曲的潜在分子机制仍不清楚。最近的研究已经确定了仅存在于小鼠谱系中的x连锁、新获得和大量扩增的基因家族，这些基因家族有助于性别比例扭曲。这个x连锁基因家族，被称为Slxl1，被认为与一个相关的，共同扩增的，y连锁基因家族，被称为Sly，存在冲突。Slxl1与Sly的基因冲突似乎是剂量依赖性的，因为在过去2000万年中，自从小鼠与大鼠分化以来，X和Y染色体上的基因剂量发生了巨大变化。结合先进的小鼠分子遗传学技术和计算分析，该项目将解决三个重要问题，以了解Slxl1与Sly基因冲突如何导致性别比例扭曲。1) Slxl1基因表达水平在调节性别比例扭曲中是否重要？2) Slxl1和Sly竞争是否需要携带X染色体和y染色体的单倍体精子细胞之间的交流？3)其他大量复制的性别连锁基因如何影响依赖slxl1的性别比例扭曲？研究结果有望为剂量依赖性基因冲突的新模型提供见解，并可能揭示X和y连锁基因家族扭曲性别比例的共同机制。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

In mammals, males typically have a 50:50 chance of fathering male or female offspring due to the equal likelihood of passing an X or a Y chromosome from sperm. However, cases exist in which the 50:50 sex ratio is distorted towards more male or more female offspring. The basis for this distortion is not understood. Evidence suggests that some of the genes on the X and Y chromosomes compete against each other in an ‘evolutionary arms race’ that leads to differences in the ability of X- versus Y-containing sperm to fertilize an egg. This project aims to understand the molecular details of this competition, using mouse as the study organism. Success will contribute to an exciting new field of sex chromosome biology by explaining the genetic basis for normal and distorted sex ratios in mammals. Graduate and undergraduate students participating in this research will develop new experimental skills in mouse molecular genetics and computational skills in analyzing large DNA sequencing datasets. In combination with the research directions of this project, educational and outreach components will promote learning experiences in genetics and evolution. Graduate and post-doctoral researchers will provide continuing education to high school teachers, via a dedicated seminar series, and interactive engagement with high school students by participation in a state-wide Michigan DNA Day. The general public will gain exposure to the research via an exhibit at the University of Michigan Natural History Museum.Evolutionary theory posits that highly differentiated sex chromosomes provide an ideal battleground for genes to compete against each other. Indeed, across animals, there are a few examples of X- and Y-linked genes in genetic conflict that distort the sex ratio. However, the underlying molecular mechanisms governing how X- versus Y-linked gene competition drives sex ratio distortion remain unclear. Recent studies have identified X-linked, newly acquired and massively amplified gene families present only in the mouse lineage that contributes to sex ratio distortion. This X-linked gene family, called Slxl1, is considered to be in conflict with a related, co-amplified, Y-linked gene family, called Sly. Slxl1 versus Sly genetic conflict appears to be dose-dependent due to massive changes in gene dosage on the X and Y chromosome over the last 20 million years since mice diverged from rats. Using a combination of advanced mouse molecular genetics techniques and computational analyses, the project will address three important questions to learn how Slxl1 versus Sly genetic conflict contributes to sex ratio distortion. 1) Is Slxl1 gene expression level important for mediating sex ratio distortion? 2) Is communication between X- and Y-bearing haploid sperm cells necessary for Slxl1 and Sly to compete? 3) How might other massively duplicated, sex-linked genes influence Slxl1-dependent sex ratio distortion? The results are expected to provide insights into a new model of dose-dependent genetic conflict and may reveal a common mechanism by which X- and Y-linked gene families distort the sex ratio.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.