The First Gapless Y Chromosome Completes the Human Genome - With PacBio’s Long Read Sequencing Our expertise

The complete Y chromosome sequence has revealed new areas of the genome that have medical significance. One of these regions is known as the azoospermia factor region, which houses genes related to sperm production. In this recent sequencing, scientists identified a unique structure within this region, characterized by inverted repeats, or "palindromes."

Dr. Arang Rhie, a staff scientist at NHGRI and the first author of the Nature publication, emphasized the significance of this structure, explaining, "These palindromes can occasionally lead to the formation of DNA loops. Sometimes, these loops are inadvertently severed, resulting in deletions within the genome."

Such deletions caused by palindromes in this region can disrupt sperm production and potentially contribute to infertility-related diseases. Researchers are now using these newly published techniques to study these regions in greater depth, aiming to gain a better understanding of the pathways involved in fertility-related diseases.

Furthermore, this study focused on TSPY, another gene on the Y chromosome associated with sperm production. TSPY copies are organized into the second-largest gene array in the human genome. While TSPY's existence has been known for a few decades and its overexpression is linked to gonadoblastoma, the exact number of repeating copies has remained unclear. As researchers delved into this area, they found that different individuals may possess anywhere from 10 to 40 copies of TSPY. This discovery suggests that the TSPY copy number could serve as a genomic biomarker for diagnostic purposes in the future.

While all chromosomes have repetitive sections, the Y chromosome is exceptional due to its extensive repetition, making its sequencing complex. About 30 million letters on the Y chromosome are made up of these repeated patterns. Conventional sequencing methods read a few hundred base pairs and then assemble the complete sequence using established algorithms.

The T2T Consortium used advanced DNA sequencing, like PacBio's HiFi long reads, to tackle repetitive sections in the human genome. HiFi sequencing provides lengthy and highly accurate reads, which fill gaps in the Y chromosome's similar areas. The team completed nearly 50% of the chromosome, adding 30 million new bases and identifying 41 protein-coding genes. This detailed Y chromosome sequence is a valuable tool for research in sexual development, fertility, genealogy, cancer, evolution, and more.

HGSVC scientists recently conducted an in-depth study using PacBio HiFi sequencing and advanced techniques. They analysed Y chromosomes from 43 individuals with diverse genetic backgrounds. Their findings revealed significant genetic differences in male-specific sequences, including size variations and mutation rates. Surprisingly, Y chromosome size can vary by nearly double, ranging from about 45.2 to 84.9 Mbp in different individuals. This dataset also uncovered 183,000 years of human evolution, highlighting hidden complexities in the Y chromosome's structure. Most Y chromosome variation appears to be structural rather than changes in its building blocks.

The complete sequencing of the human Y chromosome marks a groundbreaking achievement, unlocking mysteries that were once inaccessible. The Telomere-to-Telomere Consortium spearheaded this milestone with support from the National Human Genome Research Institute, revealing 30 million new bases, 41 protein-coding genes, and unique insights into genetic variations. PacBio's HiFi Long Read Sequencing enabled this comprehensive data, providing invaluable resources for research in sexual development, fertility, genealogy, cancer, and evolution. With these discoveries, we delve deeper into understanding human genetics, paving the way for advancements in medical diagnostics and personalised treatments.