Unique region of the sex chromosomes crucial in human development

Breaking new ground 16. feb 2023 3 min Professor Mikkel Heide Schierup Written by Kristian Sjøgren

A tiny and almost imperceptible region of the human sex chromosomes called the pseudoautosomal region 1 (PAR1) is essential for segregating DNA in sperm and eggs. New research shows that PAR1 is crucial in influencing the evolutionary pressure on humans and that mutations are extremely frequent in PAR1.

When a man’s testicles produce sperm, each sperm must contain exactly one copy of all of the man’s chromosomes: chromosomes 1 through 22 and the sex chromosomes.

However, the cells that are the starting-point for forming the sperm contain two of each chromosome, except for the sex chromosomes that have one X and one Y chromosome. A genetic task is therefore how to divide the chromosome pairs so that only one of each chromosome is passed on to the next generation.

The sperm that are endowed with an X have the potential to become girls, and the sperm that are endowed with a Y can eventually become boys.

New research shows that PAR1, a tiny region of the genome that ensures that the sex chromosomes are distributed correctly in the sperm, is under enormous evolutionary pressure, resulting in very frequent mutations.

The research also shows that, although Homo sapiens shares parts of the material in the sex chromosomes with our closest relatives, the Neanderthals and the Denisovans, PAR1 belongs to Homo sapiens alone.

“PAR1 develops very rapidly but not so rapidly that this it loses function. Our study thus provides insight into the evolutionary process that has helped to shape our species and separate us from our closest relatives,” explains co-author Mikkel Heide Schierup, Professor, Bioinformatics Research Centre, Aarhus University.

The research, which has been published in Genome Biology, was also carried out by Juraj Bergman, a Postdoctoral Fellow at the Bioinformatics Research Centre.

Sex chromosomes differ

Cell division to form sperm is complicated.

The starting-point is a diploid assembly with two of each chromosome, except for the sex chromosomes, of which there is only one of each. This diploid assembly must split in two, and each of the daughter cells must end up with one of each of the 22 chromosomes plus one sex chromosome.

If the chromosomes are not distributed correctly, the sperm and any potential fetus are not usually viable. If the distribution is not consistently carried out correctly, the man will be infertile.

Fortunately, our bodies are so ingeniously arranged that they have many mechanisms to ensure that the chromosomes are distributed correctly in each of the two sperm that emerge from one cell division.

These mechanisms are based on the fact that the chromosomes are identical, and the cellular mechanisms can thereby recognise and distribute the chromosomes one by one.

The problem, however, is that the two X and Y chromosomes are not the same and determine the sex of the offspring.

To still be able to recognise the two sex chromosomes as chromosome pairs that must be split up and distributed into two different cells, nature has cleverly arranged that PAR1 is the same between X and Y.

This region is no more than 2.5 million base pairs long, which is small in a genetic context.

“PAR1 is absolutely necessary for successful cell division,” says Mikkel Heide Schierup.

40 times as many crossovers in PAR1

Successful cell division and getting each pair of chromosomes to divide correctly also requires crossover of the genome, where it is cut and reassembled. This helps to ensure that the child is not just a copy of the mother or father but has genes from both parents.

This crossover can take place anywhere on the chromosomes, but it must happen in PAR1, which means that the density of crossovers in this region is 40 times higher than in all other regions of our genome. Since crossovers can also cause mutations, the mutation density in this region also becomes at least twice as great.

“In our study, we investigated the evolutionary consequences of the need for crossover in such a small region of the sex chromosomes,” explains Mikkel Heide Schierup.

Extremely rapid development in PAR1

The researchers studied genetic material from humans, Neanderthals and Denisovans.

The results are very descriptive but show that PAR1 develops extremely rapidly with a high incidence of new mutations compared with other regions of the genome.

Thus, PAR1 becomes shorter, and the region on the Y chromosome constantly evolves differently from the region on the X chromosome.

“There is a trade-off, because they must not be too different, since this would mean more errors in dividing the sex chromosomes during the formation of sperm and could affect the survival of the species. Insight into the mutations in human PAR1 and comparison with the corresponding part of the genome of chimpanzees can also show us all the changes that have taken place in this part of our genome since these species diverged more than 6 million years ago. This will improve our understanding of speciation and what drives this,” says Mikkel Heide Schierup.

Donated the Y chromosome to the Neanderthals

Another interesting finding is that PAR1 is unique to Homo sapiens.

The first modern humans migrated from Africa 250,000 years ago, and in Europe they encountered the Neanderthals and reproduced. Thus, these first migrants passed on their Y chromosome and mitochondrial genes to the Neanderthals but did not do this to our other closest relatives, the Denisovans.

However, the new results reveal that PAR1 was not passed on from the first Homo sapiens to either the Neanderthals or the Denisovans.

“Today, our Y chromosome is very similar to that of the Neanderthals, and this indicates that they received our entire Y chromosome and yet retained the pseudoautosomal region from their original genome. This provides unique insight into how humans and Neanderthals developed separately, but also together, throughout prehistory,” concludes Mikkel Heide Schierup.

Evolutionary dynamics of pseudoautosomal region 1 in humans and great apes” has been published in Genome Biology. In 2018, the Novo Nordisk Foundation awarded a grant to Mikkel Heide Schierup for the project The Extraordinary Evolution of Human Sex Chromosomes.

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