Scientists have successfully sequenced the entire human Y chromosome, revealing critical genomic features. This groundbreaking research offers deep insights into human biology and potential medical advances. The new sequence reveals genomic factors in fertility, including sperm production.
An international research team has succeeded in producing the first complete sequence of a human Y chromosome, the last of the 24 human chromosomes to be fully sequenced. The new sequence, which fills gaps over more than 50% of the length of the Y chromosome, reveals important genomic features with implications for fertility, such as factors in sperm production. The study, led by the Telomere-Telomere Consortium (T2T), a team of researchers funded by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, was published this week (August 23) in the journal Nature.
The complex roles of the Y chromosome
The Y chromosome, along with the X chromosome, are often discussed for their role in the development of sex. While these chromosomes play a central role, the factors involved in the development of the human species are spread throughout the genome and are highly complex, creating a variety of human sex characteristics found among male, female, and intersex individuals. These categories are not equivalent to gender, which is a social category. In addition, recent work shows that genes on the Y chromosome contribute to other aspects of human biology, such as cancer risk and severity.
Challenges in Y chromosome sequencing
When researchers completed the first human genome sequence 20 years ago, gaps remained in the sequences of all 24 chromosomes. However, unlike the small gaps scattered throughout the rest of the genome sequence - more than half of the Y chromosome sequence remains a mystery. The T2T consortium filled in these gaps in the Y chromosome genome last year.
All chromosomes have certain repetitive regions, but the Y chromosome is unusually repetitive, making its sequence particularly difficult to complete. Assembling sequences is like trying to read a long book cut into strips. If all the lines in the book are unique, it is easier to determine the order in which the lines come in. However, if the same sentence is repeated thousands or millions of times, the original order of the strips is less clear. While all human chromosomes have repeats, about 30 million letters of the Y chromosome are repeated sequences. It is as if the same few sentences are repeated throughout half the length of the book.
Innovative techniques lead to success
To tackle the most repetitive parts of the human genome, the T2T consortium applied new DNA sequencing technologies and sequencing methods, as well as knowledge gained from creating the first consecutive sequences for the other 23 human chromosomes.
"The biggest surprise was how organized the returns are," said Adam Filippi, Ph.D., senior researcher at NHGRI and head of the consortium. "We didn't know exactly what constituted the missing sequence. It could have been very chaotic, but instead, almost half of the chromosome is made of alternating repeating blocks of two specific sequences known as satellite DNA (DNA non-coded made up of long segments containing short sequences of nucleotides, sequences that repeat themselves many times). It creates a beautiful pattern similar to a quilt of squares."
Medical relevance and future research
The complete sequence of the Y chromosome also reveals important features of medically relevant regions. Such a region of the Y chromosome is called the azoospermia factor region, a segment of DNA that contains several genes known to be involved in the production of sperm cells. With the complete sequence recently obtained, the researchers learned about the structure of inverted repeats or "palindromes" in the azoospermia factor region.
"This structure is very important because sometimes these palindromes can create loops of DNA," said Arang Rhee, Ph.D., NHGRI team scientist and first author of the Nature publication. "Sometimes, these loops are accidentally cut and create deletions in the genome."
It is known that deletions in the region causing azoospermia interfere with the production of sperm cells, so these palindromes can affect fertility. With a complete sequence of the Y chromosome, researchers can now analyze these deletions and their effects on sperm production more precisely.
Other regions with potential medical relevance contain repetitive genes. Most genes in the human genome have two copies, one inherited from each parent. However, some genes have many copies that repeat along a stretch of DNA, sometimes called a "gene array."
The researchers focused on TSPY, another gene thought to be involved in sperm production. Copies of TSPY are organized in the second largest gene set in the human genome. As with other repetitive regions, repetitive genes are a challenge to analyze, so while TSPY is known to exist as multiple repetitive copies, the specific DNA sequence and organization of this array were previously unknown. When the researchers analyzed this region, they found that different people have between 10 and 40 copies of TSPY.
"When you find variation that you haven't seen before, the hope is always that these genomic variants will be important to understanding human health," Dr. Filippi said. "Genomic variants with medical relevance can help us give better medical diagnosis in the future."
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