Sequencing of human Y chromosomes sheds light on genomic function

Two publications about Y chromosome sequencing have contributed to the completion of the reference genome available to researchers, in a way that could improve understanding of male health and fertility.

The first paper, published in Nature and led by the Telomere-to-Telomere (T2T) consortium, has assembled the first complete sequence of a human Y chromosome, revealing important features and insights into function. The second, also published in Nature and led by Professor Charles Lee from the Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, has sequenced Y chromosomes from 43 unrelated males from all five continents, with half from men of African ancestry. The study revealed unexpected variation in the size and structure of the Y chromosome between individuals.

'Having fully resolved Y chromosome sequences from multiple individuals is essential in order for us to begin to understand how this variation can affect function,' said Dr Pille Hallast, first author of the Jackson lab paper.

'The degree of structural variation between individuals came as a big surprise to me, even though the nucleotide sequences within the Y chromosome genes are comparatively conserved. The variable gene copy numbers in certain gene families and extremely high inversion rates are almost certain to hold significant biological and evolutionary roles,' she added.

The Y chromosome is one of the two sex chromosomes, with the X chromosome being the other. While the X chromosome has been extensively studied and was included in the first gapless human genome sequence (see BioNews 1140), the Y chromosome has been more difficult to study due to its complex structure which includes many repetitive sequences of DNA. Until now, over half of the Y chromosome's sequence was unknown.

The Y chromosome carries important genes for sperm production; however, its contributions to male health are poorly understood. The Jackson lab team hopes that understanding variation will allow future work into associating sequences on the Y chromosome with human traits, health, and disease.

In addition, the research from the T2T consortium has provided new insights into the structure of regions of the Y chromosome known to be involved in sperm production, known as spermatogenesis. This includes the so-called 'azoospermia factor region' which contains a set of inverted repeats called palindromes. The presence of palindromic sequences can cause loops of DNA to form, which can be cut off resulting in deletions, which can create variants that lead to the inability to create sperm. The T2T team believes the completed Y chromosome sequence will help with understanding how deletions in this region affect spermatogenesis.

The T2T group also discovered 41 protein-coding genes on the Y chromosome and uncovered the structures of gene families involved in sperm development regulation and the functioning of the male reproductive system. They hope that improved understanding of the Y chromosome's genes and variants will be applied in fertility-related research.