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An international research team has achieved the first complete sequencing of the human Y chromosome, which is closely linked to male development.
This is the last of the human chromosomes to be fully sequenced, an effort that may shed light on everything from fertility to disease.
The work was led by the Telomere-to-Telomere (T2T) Consortium, which is a team of researchers funded by the National Human Genome Research Institute (NHGRI) in Bethesda, Md., part of the U.S. National Institutes of Health.
The new sequence fills in gaps across more than 50% of the Y chromosome's length.
The research, published Aug. 23 in Nature, uncovered important genomic features, including factors in sperm production.
While both the X and Y chromosomes have a central role in sexual development, the factors involved are spread across the genome and very complex, according to the study.
Other recent work has shown that genes on the Y chromosome contribute to other aspects of human biology, including cancer risk.
Researchers completed the first human genome sequence 20 years ago, but there were gaps in the sequences of all 24 chromosomes. While some had just small gaps, more than half of the Y chromosome's sequence was unknown.
The Y chromosome is unusually repetitive, which made its sequence particularly difficult to complete.
Study authors explained the challenge with an example of reading a book. If the lines in a book are all unique, then putting together long strips of text to create the book is easier. If the lines are repeated thousands or millions of times, it's hard to determine what the order should be.
About 30 million letters of the Y chromosome are repetitive sequences.
The T2T Consortium applied new DNA sequencing technologies and sequence assembly methods, along with knowledge gained from generating the first gapless sequences for the other 23 human chromosomes, to solve this mystery.
"The biggest surprise was how organized the repeats are,” said Adam Phillippy, a senior investigator at NHGRI and leader of the consortium.
“We didn't know what exactly made up the missing sequence. It could have been very chaotic, but instead, nearly half of the chromosome is made of alternating blocks of two specific repeating sequences known as satellite DNA. It makes a beautiful, quilt-like pattern," he said in a NIH news release.
The research revealed information about the azoospermia factor region, which is a stretch of DNA containing several genes known to be involved in sperm production.
Researchers were able to study the structure of a set of inverted repeats or “palindromes” in this region.
"This structure is very important because occasionally these palindromes can create loops of DNA,” said study first author Arang Rhie, an NHGRI staff scientist. "Sometimes, these loops accidentally get cut off and create deletions in the genome."
Deletions in this region are known to disrupt sperm production, and this could influence fertility. With a complete Y chromosome sequence, now researchers can more precisely analyze these deletions and their effects on sperm production.
Other regions with potential medical relevance contain genes that repeat, according to the study. While most genes in the human genome have two copies, one inherited from each parent, some genes have many copies that repeat along a stretch of DNA, sometimes called a “gene array."
The researchers focused on the TSPY gene, thought to be involved in sperm production. Copies of TSPY are organized in the second largest gene array in the human genome, according to the study. Researchers found that different individuals contained between 10 and 40 copies of TSPY.
“When you find variation that you haven't seen before, the hope is always that those genomic variants will be important for understanding human health,” said Phillippy. “Medically relevant genomic variants can help us design better diagnostics in the future."
The Urology Care Foundation has more on male infertility.
SOURCE: NIH/National Human Genome Research Institute, news release, Aug. 23, 2023
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