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

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

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.