The full sequence of the Y chromosome is one of the few remaining pieces missing from the human genomic puzzle. This chromosome has proved to be highly difficult to sequence due to its complex and repeating structure. However, a new study published in Nature finally solves the mystery of the Y chromosome.
The missing piece
The human Y chromosome is known to hold genes essential for fertility, in particular spermatogenesis, alongside SRY, the mammalian sex-determining gene. When the Human Genome Project was completed 20 years ago, around 92% of the genome was discovered. However, the missing 8% was thought to hold genes for important developmental processes. Unfortunately, the Y chromosome made up a significant part of this missing 8%, with gaps in over half of its genetic information.
The difficulties in sequencing this chromosome arose from its unusual repetitive nature, making it more difficult to decipher than other chromosomes. Researchers at the Telomere-to-Telomere (T2T) Consortium, funded by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), found that this chromosome has an abundance of large, tandemly arrayed and inverted repeats known as palindromes, which made the study of its genetic rearrangements, inversions, duplications and deletions incredibly difficult – until now.
A beautiful pattern
Building on lessons learned from the original Human Genome Project and other Y chromosome sequencing attempts over the past two decades, by using new DNA sequencing technologies and sequence assembly methods, the T2T Consortium was able to reconstruct the complete Y chromosome sequence for the first time.
“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”, says Adam Phillippy, leader of the T2T Consortium and senior investigator at NHGRI.
By taking into account population variation, clinical variants and functional genomics data, the group have now been able to create a complete and comprehensive reference sequence for all human chromosomes, which will have a wide array of future research and clinical uses.
One such use relates to a section of the Y chromosome known as the azoospermia factor region, which contains several genes involved in sperm production. Deletions in this region could affect fertility, so using this new complete Y chromosome sequence, it is hoped that this could be a targetable area to treat male infertility.
Many other health conditions, including several cancer types and Alzheimer’s disease, are also thought to be related to alterations in the Y chromosome, so using this new information, this will continue to be an active area of study.