Battle of the sex chromosomes in sperm may be key to understanding declining global fertility

Tech Science 21. dec 2022 3 min Senior Scientist Kristian Almstrup Written by Morten Busch

The only reason why the world population is still growing is because we are living longer than before. In many parts of the world, the fertility rate is in free fall. One reason for this is declining sperm quality. This may result from harmful substances in the environment and a change in culture but new research shows that the way sperm cells are created and the resulting selection process for genes, including sex genes, may also be part of the explanation for declining sperm quality.

Pesticides and steroids, obesity, smoking and alcohol, medication and the educational level are just some of the myriad reasons that explain why the population is declining in many places even though life expectancy is increasing. A 50% decrease in sperm counts since the 1970s is probably a significant part of the explanation, and this is of great concern globally. Researchers from Rigshospitalet in Copenhagen, Aarhus University and Copenhagen Zoo have now found an important reason that could contribute to the decreasing sperm production.

“Our new study suggests that part of the reason could be an internal genetic battle between the X and Y chromosomes, even before the sperm reach the egg, in fact during the formation of the sperm cells. We compared the sperm production of men and male primates and found that the primates are three times more successful in creating sperm cells. A possible explanation could be that the battle between the X and Y chromosomes has gone too far among humans, which means that things often go wrong,” explains Kristian Almstrup, Senior Scientist, Department of Growth and Reproduction, Julie Marie Centre, Rigshospitalet, Copenhagen.

Battle between X and Y

Following recent technological advances, the researchers in the new study were able to use single-nucleus RNA sequencing to successfully examine single cells taken from the testes of 11 species from the three major mammalian lineages (eutherians including humans, marsupials and egg-laying monotremes), birds and seven key primates.

“In addition to finding differences among the 11 species, we also aimed to map which genes are expressed in sperm cells with an X and a Y chromosome. We can thus create an image of which genes might be involved in the genetic battle between the X and Y chromosomes. In the long term, we hope that this knowledge can help to reveal why men are less efficient at creating sperm, and far worse than, for example, great apes,” says Kristian Almstrup.

According to this theory, the genetic battle occurs during meiosis – the process by which cells divide and become germ cells (for humans, egg cells and sperm cells) – with half the amount of DNA in each. Which genes end up in which germ cells is not random but is controlled by meiotic drift – a battle in each individual’s genome.

“We hypothesised that this battle is much stronger among humans than in great apes, for example, which means that apes are far more efficient at producing functioning sperm cells. Previous studies have shown that the battle between the genes in our X and Y sex chromosomes is likely involved in the meiotic drive, and in this study, we succeeded in identifying genes that are expressed in an X and Y sperm cell. This is the first step to characterise whether the meiotic battle can affect how men produce sperm cells compared to great apes,” explains Kristian Almstrup.

Increasing evolutionary chaos

Evolutionary forces such as meiotic drive have only recently been identified in primitive animals, but they have never yet been shown in higher animals, and although the new study does not definitively prove the evolutionary battle is taking place in germ cells of men, it suggests that they exist and are a likely factor in the deterioration of spermatogenesis and therefore also possibly the negative trends in declining human sperm counts.

“The testes are key to male reproduction because this is where sperm is produced through spermatogenesis. Evolutionary processes normally take place over multiple generations but, because of evolutionary pressure on males to successfully reproduce, the genes used during spermatogenesis and also the genes located on the X and Y chromosomes have evolved very quickly in mammals,” says Kristian Almstrup.

Since new genes that appear during evolution also tend to be predominantly expressed in the testes, they probably accelerate phenotypic evolution even more. According to Kristian Almstrup, the increasing evolutionary chaos and meiotic battle may only partly explain why the quality of men’s sperm is declining.

“Why the decline is extremely rapid at the moment cannot be immediately explained, but previous research indicates that environmental factors can also influence the processes that create meiotic drive. We will initially develop tools to investigate this, and then we plan to attempt to analyse the sex chromosomes from great apes and men – both with and without fertility problems,” explains Kristian Almstrup.

Why, how and when?

By comparing the differences in fertility with the gene expression, the researchers hope to be able to deduce exactly how the sex chromosomes affect the production of sperm cells. The researchers can access human tissue through a partnership in the Öresund region between ReproUnion Biobank and the Infertility Cohort. However, accessing testicular tissue from great apes is much more challenging. Therefore, the research involves close interdisciplinary collaboration with the Bioinformatics Research Center at Aarhus University and Copenhagen Zoo.

“For regulatory reasons, obtaining tissue from the testes of primates is actually far more difficult than obtaining tissue from humans. The limited access to tissue has meant that we have had to carry out the analysis in individual cell nuclei from the testicular tissue, and this analysis has only become possible now as a result of technological development,” says Kristian Almstrup.

To solve the technological challenges and to collect enough testicular tissue, leading researchers in evolutionary genetics, such as this year’s Nobel Laureate in Physiology or Medicine, Svante Pääbo, worked together with researchers within male reproduction. This interdisciplinary collaboration has been key to achieving these unique results.

“Since we now know which genes are conserved during spermatogenesis, genetic changes in these genes will probably also be critical for men’s ability to produce sperm. The new knowledge will therefore enable us to give better explanations to men about why they have difficulty having children,” concludes Kristian Almstrup.

The molecular evolution of spermatogenesis across mammals” has been published in Nature. In 2015, the Novo Nordisk Foundation awarded co-author Kristian Almstrup an Interdisciplinary Research Programme grant of DKK 15 million for investigating how the genetic struggle between X and Y chromosomes influences spermatogenesis and reproduction among primates. In 2020, the Foundation also awarded a Data Science Initiative grant to co-author Mikkel Heide Schierup and others, including Kristian Almstrup, for the project Mutational Processes in Spermatogenesis and their Consequences for Human Health.

The Almstrup group, which is part of the Dept. of Growth and Reproduction, at Rigshospitalet, has a particular focus on studies connecting genetic and...

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