Conquered the Y chromosome, the last unexplored territory of human DNA

A person’s DNA is a recipe book for making the proteins essential for life, such as myosin in muscles and hemoglobin that carries oxygen in the blood. An international consortium of scientists has announced this Wednesday that it has finally managed to read the last blurred page of that recipe book: the hitherto illegible Y chromosome, involved in determining the male sex or in the production of spermatozoa; but also, when there are failures, in serious diseases such as cancer. The advance, which has required more than 30 years of work, is published this Wednesday in the journal Nature, a showcase for the best world science.

The challenge was monumental. Current technology doesn’t allow you to read a person’s entire DNA (their genome) in one go, so researchers have to unscramble millions of tiny jumbled fragments and then assemble them. It is like reconstructing a text of more than 3,000 million letters from misplaced sentences and paragraphs. The Y chromosome barely has 62 million letters (2% of the total), but the difficulty was devilish because its structure is very confusing, full of repeated sections. If the genome were the song Macarena, it would be easy to reorganize its chorus based on its misplaced fragments: “joy, Macarena”, “give your body”, “joy and a good thing”, “that your body is for him”. However, it would be more cumbersome to find out that this chorus appears 15 times in the song or to intuit the triple repetition in “Macarena, Macarena, Macarena, that you like Marbella summers”.

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A person’s DNA appears in each of their cells, grouped into 46 packages, the chromosomes, which are structures shaped like a skein of thread. Two of the chromosomes, X and Y, determine sex. Most women have two X chromosomes. In men, it is common to have one X and one Y. The Y chromosome contains the genetic information that causes the male genitalia to develop in the embryo, but it also has other essential roles. Men who lack a Y chromosome in some of their cells (due to causes such as tobacco addiction and aging) are at greater risk of cancer, Alzheimer’s, and heart disease.

The consortium, baptized T2T and led by the US National Institutes of Health, already published last year the first absolutely complete human genome, letter by letter, but the entire enigmatic male sex chromosome had yet to be read. It was “the last unexplored territory of human DNA”, according to biologist Tomàs Marquès Bonet, from the Institute of Evolutionary Biology, in Barcelona.

amazing variability

Another international team of scientists, the Consortium for the Structural Variation of the Human Genome, published this Wednesday the almost complete sequences of another 43 Y chromosomes from people from different parts of the world, showing an astonishing variability. There are men with 45 million letters on their Y chromosome, while others are close to 85 million. “This is especially important for biomedical research, since the structural variants of the Y are at the root of many characteristics and diseases,” says Marquès Bonet, who has not participated in this research.

The biologist Bernardo Rodríguez emphasizes that half of the Y chromosome has been resisting for decades. “The half was missing, which is highly repetitive. If it were the puzzle of a landscape, the pieces of the blue sky remained to be placed”, points out Rodríguez, from the European Laboratory of Molecular Biology, in Heidelberg (Germany). The T2T consortium estimates that the human genome has about 20,000 genes (short segments of DNA), each with its recipe for making proteins, but only 106 of them are on the Y chromosome. One is the SRY gene, called the “male determining gene.” ” because it causes the testicles to form in the embryo.

Geneticist Karen Miga, co-director of the T2T consortium and a researcher at the University of California, Santa Cruz.Nick Gonzales/UC Santa Cruz

Rodríguez points out that the existence of 41 of these Y chromosome genes was unknown. “Now we have to see what role they play. In addition, it is being observed that these missing regions are the most variable in the genome, because, being very repetitive, they change a lot from one individual to another”, points out the researcher, a member of the Consortium for the Structural Variation of the Human Genome. “Accessing the Y chromosome can lead to the discovery of new variants associated with diseases, including cancer,” he says. Geneticist Karen Miga, co-director of the T2T consortium and researcher at the University of California at Santa Cruz, has stated in a statement that her goal is to make the data available to the international scientific community.

Half of men will suffer a malignant tumor before the age of 85, compared to just a third of women, according to the Spanish Society of Medical Oncology. The greater male susceptibility to tumors is explained by the greater consumption of tobacco and alcohol, but also by biological intricacies, such as the loss of genetic material from the Y chromosome throughout life, as shown in 2020 by the team of bioinformatician Juan Ramón Gonzalez. “This study opens up new perspectives to understand how the loss of the Y chromosome is associated with a higher incidence of certain diseases and mortality in men,” says González, from the Barcelona Institute for Global Health.

Genomics steps on the accelerator

Technological advances have made the conquest of the Y chromosome possible. The machines of the British company Oxford Nanopore now allow millions of letters to be read in a row, with errors that are corrected with the American tool PacBio, which achieves an accurate reading of stretches of more than 20,000 letters. González applauds that there is finally a reference sequence for the Y chromosome. “The main advantage of this study lies in its applicability, since it enables the efficient analysis of millions of genomes belonging to different populations,” he celebrates.

The bioinformatician stresses that this work could also be crucial in forensic medicine and human evolution research, since a man inherits the Y chromosome from his father, who inherited it from his father, forming a direct line. Therefore, a man’s male sex chromosome will be virtually identical to his siblings and other paternal relatives. And that information is very useful both for identifying a serial killer from his DNA and for tracking migrations over the centuries.

The current reference genome, called GRCh38, is a mosaic of genetic information, 70% from a man who volunteered in 1997 for the Human Genome Project in the United States because he read an advertisement in The Buffalo News. The first draft was presented in 2001 to great fanfare, despite being very incomplete, and since then the scientific community has used that benchmark to search for genetic variants associated with diseases.

The T2T consortium has now completed its alternative: the truly complete sequence of a human genome, named CHM13, now incorporating the Y chromosome. But the ancestors of this genome are mostly European, so another international consortium is finalizing a pangenome that it will include 350 complete genomes from around the world, to reflect the genetic diversity of humans.

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