After years of research, the Y chromosome has finally been unraveled. In 2022, the ‘complete’ human genome was presented with much fanfare, but one symbolic piece was still missing. Mapping the Y-chromosome, which determines the male sex, is the final piece of the puzzle.
The researchers used the DNA of one man. When placing the building blocks in sequence, the researchers discovered 41 extra genes, they write today in the scientific journal Nature. They also revealed new genes that play an important role in fertility and sperm production.
The Telomere-to-Telomere (T2T) consortium had already completely deciphered the X chromosome in 2020. Last year, the team of 100 scientists came up with the map of the entire human genome (T2T-CHM13), with the caveat that only the Y chromosome was still missing. Now we have succeeded in adding 30 million building blocks to what was previously known of the Y chromosome. This has cracked the entire code of 62 million pieces of the Y chromosome. The outcome is called T2T-Y and, together with T2T-CHM13, forms the complete genome of half of the world’s population.
Those born as boys have the Y chromosome, but it can also be found in intersex people, people born with both male and female sex characteristics. The human Y chromosome has a complex structure, with many more repeats than the other 23 chromosomes, and was therefore difficult to unravel.
The researchers compare it to a book that has been torn into strips. When all sentences are unique, it is easier to determine the order than when certain sentences are repeated thousands of times – or, in the case of the Y chromosome, as many as 30 million times. More than half of the Y chromosome was therefore not yet visible.
Puzzled together
DNA is made up of long chains of four chemical bases. The complete human genome is over three billion bases long. With the old techniques, a piece of DNA that had to be sequenced could not be longer than a thousand bases. Longer strands were cut into separate pieces and puzzled back together. But with many large pieces and much repetition of individual parts, an accurate reconstruction was impossible.
Modern techniques – long read and ultralong sequencing – can read much longer pieces, combine them with the short pieces, and put them in order. This explains why genome researchers are now coming up with one breakthrough after another, such as last May with the ‘pan-genome’, the complete human DNA based on the complete genetic codes of 47 people from all over the world. In line with this, 43 other human Y chromosomes have now also been examined, in addition to the complete Y chromosome map.
The Y chromosome researchers used an advanced technique – high fidelity and nanopore sequencing called. By sequencing the same pieces tens to hundreds of times (arranging them in order), the researchers were able to check the reliability of their findings. They could also draw on the knowledge gained from sequencing other chromosomes.
How the vole can live without a Y chromosome
The biggest surprise was how organized the replays were
Adam Phillippy researcher
The researchers now present all 62,460,029 base pairs of the Y chromosome, also correcting mistakes made in previous attempts to put the individual pieces together. This new composition could be a more reliable successor to the existing reference genome, with which researchers compare their own analyses.
“The biggest surprise was how organized the reruns were,” says Adam Phillippy, the magazine’s lead researcher Time elected one of the most influential people of 2022 for mapping the human genome. “Nearly half of the chromosome consists of alternating blocks of two specific repeating sequences. This creates a beautiful, quilt-like pattern.”
Risk of cancer
T2T-Y also shows more about medically relevant areas. This enabled the researchers to visualize a series of palindromes (long sequences that are the same in both directions) that influence fertility. The Y chromosome is not only important for the development of sex characteristics; it also contributes to, for example, the risk of cancer. “When you find new variations, you always hope that they help to better understand human health,” Phillippy said in a press release from the US National Human Genome Research Institute. “Medically relevant DNA variations can help make better diagnoses in the future.”
Manfred Kayser, professor of forensic molecular biology at Erasmus MC in Rotterdam and not involved in the research, is a bit more reserved. “Whether the genes they identified are clinically relevant, for example when it comes to genetic causes of male infertility, is not yet known.”
As far as he is concerned, the strength of this study is mainly that there is now a complete picture, so that everyone who does Y-chromosome research has a reference for their own results. “The biggest gains are in the regions with repeats. This makes it possible to investigate what this means and why there has been such an accumulation of repeats in evolution.”