Infertility, other health problems could be tied to Y chromosome

Scientists have finally decoded mysteries of the Y chromosome. Here's why it matters

Humans typically have a pair of sex chromosomes in each cell. (nathan devery/Alamy Stock Photo)

Scientists have fully sequenced the Y chromosome for the first time, uncovering information that could have implications for the study of male infertility and other health problems.

The first attempt to determine the building blocks of our genetic code took place 20 years ago, but there were still significant gaps left in the sequences of all 23 pairs of human chromosomes. Those blanks were largely filled in last year by an international group of 100 scientists called the Telomere-to-Telomere (T2T) Consortium.

However, over half of the sequences within the Y chromosome, the smallest and most complicated of the 46 human chromosomes, remained unknown. Now, the same group of researchers has filled in the missing information, publishing a complete Y chromosome sequence Wednesday .

"Just a few years ago, half of the human Y chromosome was missing (from the reference)," said Monika Cechova, co-lead author on the paper and postdoctoral scholar in biomolecular engineering at the University of California, Santa Cruz, in a statement.

"Back then we didn't even know if it could be sequenced, it was so puzzling," Cechova added. "This is really a huge shift in what's possible."

WHAT Y COULD REVEAL

Humans typically have a pair of sex chromosomes in each cell. People who are assigned male at birth have an X and a Y chromosome, while those assigned female at birth have two X chromosomes.

The more detailed information provided by the new Y reference sequence will make it easier to study conditions and disorders linked to the chromosome, such as lack of sperm production that leads to infertility.

Recent research suggests the Y chromosome is also important for health and longevity, said Kenneth Walsh, a professor of biochemistry and molecular genetics at the University of Virginia School of Medicine, who was not involved in the new research.

"Genes have been identified on the Y chromosome that have been shown to be required for the prevention of cancer and cardiovascular disease," Walsh said via email.

"The Y chromosome has represented the 'dark matter' of the genome," he added. "This new analysis will allow us to better understand the regions of the Y chromosome that have regulatory functions and may encode mRNA and proteins."

Many people , particularly those cells that undergo rapid turnover, such as blood cells.

Scientists have never fully understood why this happens and the effect it may have on a person's health, though the phenomenon has been linked in two recent scientific papers with an increased severity of bladder cancer and a Having a complete Y chromosome genetic reference may help scientists and doctors further explore this potential link.

"These papers likely represent the tip of the iceberg in terms of understanding the role of the Y chromosome in age-associated diseases," Walsh said, adding that the loss of the Y chromosome could partially account for men's shorter life spans. (Men live about six years less than women in Western, industrialized nations, Walsh said.)

"However, it has been questioned whether loss of the Y chromosome is a biomarker of biological aging or whether loss of the Y chromosome has a direct effect on the health of men," he said. "Recent research provides strong evidence to show that the effect is direct."

Y CHROMOSOME IS UNUSUALLY REPETITIVE

The Y chromosome was a particularly hard nut to crack because it is unusually repetitive.

The four letters or building blocks of DNA — adenine (A), cytosine (C), guanine (G) and thymine (T) — form specific pairs that bind together in a double helix shape. Chromosomes are threadlike structures made up of DNA.

While all human chromosomes contain repeats, more than 30 million letters of the Y chromosome — out of 62.5 million — are repetitive sequences, sometimes called satellite DNA or junk DNA. The Y chromosome also contains palindromes — sequences of letters that are the same backward and forward, like radar.

"Not only is (the Y chromosome) the smallest, but it's also the most complex so it has the highest amount of repetitive DNA, which are just like stretches of DNA that are repeated multiple, many, many times, sometimes in tandem and sometimes they can be interleaved with unique sequences," Cechova said.

Repetitive DNA complicates things because assembling data from genetic sequencing is a little like trying to read a long book cut into strips, according to the National Human Genome Research Institute.

"If all the lines in the book are unique, it's easier to determine the order the lines go in. However, if the same sentence is repeated thousands or millions of times, the original order of the strips is far less clear," the institute, which funds the T2T Consortium, noted in a news release.

In the case of the Y chromosome, it's as if the same few sentences were repeated for half the length of the book.

The researchers were able to achieve a complete reading of the Y chromosome, thanks to new "long-read" sequencing technology and computational methods that could handle repetitive sequences and transform raw data into a usable resource.

The completed Y chromosome adds more than 30 million base pairs — the repetitive sequences — to the human reference genome.

Earlier this year, researchers compiled a "pangenome" that incorporates the DNA of dozens of people from nearly every continent — essentially updating the human genome to make it more equitable and inclusive.

In accompanying research published in the same journal on Wednesday, a collaborating team of scientists assembled Y chromosomes from 43 male individuals from 21 world populations to capture genetic variation in the Y chromosome.

"Research is emerging that shows proper Y chromosome gene function is incredibly important for the overall health of men," said Charles Lee, a senior author on the accompanying research paper and professor and research director at the Jackson Laboratory for Genomic Medicine, in a statement.

"Our study enables the inclusion of the full Y chromosome in all future studies when sequencing male genomes to understand health and disease."

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