Battle of the sexes – how mouse X and Y chromosomes compete with each other

The molecular function of genes in mice has a major influence on the sex of their offspring, according to a new discovery that reveals more about the impact of genes on animal fertility.

Under normal circumstances, the laws of genetics ensure that sperm carrying an X or a Y chromosome have an equal chance to fertilise the egg, and so parents have an equal chance of having a daughter or a son.

However, male mice with partial deletions on their Y chromosome (Yqdel males) break this iron-clad law, producing a distorted sex ratio with many more female than male offspring. Until now, how this occurs has been a mystery.

Now, joint research, published in Current Biology, carried out by teams from Kent, Essex, Cambridge and Paris Descartes Universities, shows that the key lies in the shape of the sperm and how well they are able to swim.

First, the team showed that they could correct the sex ratio distortion by performing IVF fertilisation – proving that the Yqdel males produce equal numbers of X and Y-bearing sperm and that both types of sperm are equally capable of producing offspring once they actually reach the egg.

Next, the team used high-resolution microscopy and state-of-the-art computer image analysis to show that sperm from Yqdel males are shrunken and distorted. Crucially, the Y-bearing sperm cells were more severely affected than X-bearing sperm cells, suggesting that their function was impaired.

To show this, they used FISH labelling – a technique that stains the X or Y chromosomal DNA different colours. This allowed them to identify which cells carried which chromosome, and correlate this to the shape of each individual cell. Using another transgenic strain of mice that “switches off” Y-linked genes rather than deleting them, they proved that the shape difference between X and Y-bearing sperm was caused by gene expression differences, and not simply by the loss of DNA in the Yqdel males.

Finally, they carried out “sperm races” to isolate the very fastest-swimming sperm cells from Yqdel males, and confirmed via FISH that these tiny athletes were predominantly X-bearing sperm cells – thus explaining the predominance of daughters in Yqdel offspring.

Lead academic Dr Peter Ellis. from Kent’s School of Biosciences, said: “We have known for some time that the mouse X and Y chromosomes compete to produce female versus male offspring, with genes on the X favouring the production of daughters and genes on the Y favouring sons. Our research now reveals for the first time how this occurs. When the Y-borne genes are deleted, the X-borne genes sabotage sperm head development, making the Y-bearing sperm swim slower and securing a ‘selfish’ advantage for X-bearing sperm in the race towards the egg. We also found that the use of IVF can reverse this imbalance, which has clear implications for the use of these techniques to influence the sex of mammal offspring.”

Dr Ben Skinner, from our School of Life Sciences, added: “A lot of image analysis tools for measuring shapes require careful manual identification of landmarks - the features of interest. Our software has allowed us to automate that process, which enabled us to screen the thousands of sperm needed to convincingly show the difference between X and Y-bearing sperm.

“The analysis tools that we developed in this project should be more widely applicable to the study of nuclear shape; my research group is working to make them more powerful for discovering and quantifying subtle variations in shape across different cell types and species.

“The work here shows the importance of how the shape of a cell can relate to or influence its function, and this has relevance not just in fertility, but also in diseases such as cancers, where disruptions to nuclear shape are common.”