A team of more than 100 researchers from around the world in the Telomere-to-Telomere (T2T) consortium has succeeded in fully sequencing the only remaining mysterious piece of the human genome, the male sex chromosome.
For decades, the genomics community has tried to unravel the genetic code of the Y chromosome, a task that has been especially difficult due to the complexity of its structure and which until now meant that the only reference complete human genome was that of two X chromosomes.
Now, according to work published today in Nature, sequencing of the male sex chromosome adds 30 million new DNA bases to the human genome reference, mostly from satellite DNA (highly repetitive sequences of DNA) that is hard to sequence. Researchers have discovered an additional 41 protein-coding genes on the Y chromosome and have deciphered gene structures thought to play important roles in the growth and function of the male reproductive system.
The structure of the Y chromosome has been a challenge for geneticists because some of the DNA is organized into palindromes (long sequences that are the same forward and backward) spanning up to more than a million base pairs, because two satellite DNAs are interconnected. , and it was hard to tell when those repeating patterns were reversed. But advances in sequencing technology and bioinformatics algorithms have now allowed the T2T team co-led by Karen Miga, a biomolecular engineer at the University of California, Santa Cruz, to solve these DNA sequences.
The methods used and reproduced in their paper will now allow scientists to complete further end-to-end reads of human Y chromosomes to better understand how this genetic material affects different human population groups.
In this sense, the specialists explain that the achievement of completing the genetic code of the Y chromosome reveals details that can help to understand the role it plays in specific male development, fertility or diseases with a genetic origin such as cancer, but also to better study the evolution of the human population.
This is because the Y chromosome, unlike the X, is passed from parent to child with very little recombination, so it is easier to trace genes from generation to generation and see how they have changed over time.
When scientists and doctors study a person’s genome, they do so by comparing their DNA to a standard reference to see where there is variation, and until now, that reference had large gaps in the portion relative to the Y chromosome.
“Previously we were blind to different parts of the genome and to different mutations, but now we can see the whole genome and hopefully we can add new insights into the genetics of many different diseases,” said Michael Schatz, professor of computer science, biology and oncology at Johns Hopkins University who is part of the T2T team.
The Y chromosome is best known for its role in sexual development and spermatogenesis (the production of sperm) and is usually associated with male births, although it is also found in intersex people. But, in addition, recent studies have shown that it also contributes to other aspects of human biology, such as the risk of cancer and its severity. Hence, the researchers ensure that their discovery will allow progress in other fields of research and make new discoveries.
In fact, during the sequencing work they already had an unexpected one: they saw that human DNA appeared as a contaminant in genomic samples of bacterial species because, because large parts of the Y chromosome were missing from the reference human genome, certain sequences had not been identified as human contamination (bacterial DNA is often extracted from human skin) and had been mistaken for part of the DNA of the species being studied.
In addition, in collaboration with the Human Pangenome Reference Consortium (which combines genomic information from people of diverse ancestral origins), the researchers plan to incorporate complete Y-chromosome sequences into the individual genomes that make up the pangenome to facilitate better understanding of the male sex chromosome throughout the diversity of the human population.
The new knowledge is also being integrated into studies of primates to delve into the evolution of the Y chromosome and analyze clinically relevant genes that could influence personalized medicine for pancreatic cancer and other diseases, according to members of the research team from the University Johns Hopkins.
“Our goal is to make this data widely accessible; by creating and sharing these important catalogs of genetic differences on the Y chromosome we can expand genetic studies of human diseases and provide new insights into basic biology,” said researcher Karen Miga. .
