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

在哺乳动物中，由于精子传递X或Y染色体的可能性相同，雄性通常有50：50的机会成为雄性或雌性后代的父亲。 然而，在某些情况下，50：50的性别比例被扭曲，倾向于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和Y染色体上的一些基因在“进化军备竞赛”中相互竞争，导致含X和Y的精子使卵子受精的能力存在差异。 该项目旨在了解这种竞争的分子细节，使用小鼠作为研究生物体。 通过解释哺乳动物正常和扭曲的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发展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。结合本项目的研究方向，教育和推广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研讨会系列为高中教师提供继续教育，并通过参加全州范围的密歇根州DNA日与高中学生进行互动。 公众将通过密歇根大学自然历史博物馆的一个展览来了解这项研究。进化论认为，高度分化的性染色体为基因相互竞争提供了一个理想的战场。 事实上，在动物中，有一些X和Y连锁基因的遗传冲突扭曲了性别比例。 然而，X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X连锁的，新获得的和大规模扩增的基因家族，只存在于小鼠谱系，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、共扩增的Y连锁基因家族Sly相冲突。Slxl1与Sly的遗传冲突似乎是剂量依赖性的，这是由于自从小鼠从大鼠分化以来，在过去的2000万年里，X和Y染色体上的基因剂量发生了巨大变化。利用先进的小鼠分子遗传学技术和计算分析相结合，该项目将解决三个重要问题，以了解Slxl1与Sly遗传冲突如何导致性别比例扭曲。 1)Slxl1基因表达水平对介导性别比例畸变重要吗？2)携带X和Y染色体的单倍体精子细胞之间的通讯是Slxl1和Sly竞争所必需的吗？3)其他大规模复制的性连锁基因如何影响Slxl1依赖性性别比例扭曲？ 该研究结果有望为剂量依赖性遗传冲突的新模型提供新的见解，并可能揭示X和Y连锁基因家族扭曲性别比的共同机制。该奖项反映了NSF的法定使命，并通过使用基金会的智力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.