Diversity of human Y chromosome revealed

Researchers assemble the full Y chromosome across multiple individuals for the first time, revealing unexpected diversity, with clues for its role in health, disease and evolution

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Scientists have uncovered a full picture of the Y chromosome, one of the two sex chromosomes in humans, for the first time, revealing its highly variable nature across multiple individuals and over time. Their discovery of its striking variation in size and structure indicates its important function in humans.

With the complete genetic information of the human Y chromosome, future research can now begin to investigate the chromosome’s contributions to health and disease, which until now have remained largely unknown, as well as its evolutionary history.

Researchers from the Jackson Laboratory (JAX) and their collaborators at the Wellcome Sanger Institute, Clemson University, Heinrich Heine University and others sequenced and assembled 43 human Y chromosomes, spanning 183,000 years of human evolution, to shed light on its structure and function across individuals.

The findings, published today (23 August) in Nature, provide a unique opportunity to identify new associations of traits with specific Y-chromosomal variants and gain novel insights into the evolution and function of complex regions of the human genome.

Many scientists believe that the sex chromosomes in humans – X and Y chromosomes – started out as a pair of structurally similar chromosomes, but that over time, the ancestral Y chromosome underwent significant changes and lost a huge portion – 97 per cent – of its original genes over millions of years. Due to this unique evolutionary process, some believe that the Y chromosome might eventually disappear completely.

While the much larger and gene-rich other sex chromosome — the X chromosome — has been extensively studied, the Y chromosome has been often overlooked outside of male-based fertility studies. The current reference genome sequence – known as GRCh38 – assembles less than half of the Y chromosome.

The Y chromosome is exceptionally difficult to fully assemble, due to the challenges posed by it containing a large proportion of repetitive and heterochromatic sequences, where DNA molecules are tightly packed or folded within a cell’s nucleus, gene-poor and not transcribed to messenger RNA. But the limited molecular understanding of the Y chromosome means its impact on health isn’t fully understood. Some males lose parts of their Y chromosomes as they age and their cells divide. Also, a recent study** has indicated it lessens an effective adaptive immune response to bladder cancer.

In this new study, a team led by JAX set out to assemble complete sequences of multiple human Y chromosomes for the first time, to better understand its key characteristics and variation between individuals.

The team created de novo assemblies – newly constructed sequences – of 43 Y chromosomes*, spanning a time period of 183,000 years of human evolution. This came from 43 unrelated males around the world, representing diverse Y lineages. Nearly half came from African lineages. This enabled a broader understanding of the Y chromosome’s role in human evolution and biology.

The researchers identified an extensive, close to two-fold variation in the size of the Y chromosome, ranging from 45.2 million to 84.9 million base pairs in length. This is not seen in any other human chromosome.

They uncovered an unexpected degree of structural variation across the Y chromosomes. About half of the male-specific euchromatic region – the gene-rich region of the chromosomes – had sections where the genetic sequence is the same but flipped in the opposite direction – called ‘large recurrent inversions’ – at a rate over two times higher than anywhere else in the human genome***.

The team identified regions of the Y chromosome that showed less change in the individual ‘letters’” – nucleotides – that make up the DNA sequence, but the number of certain genes could vary a lot between individuals in these repeated sequences. Certain groups of genes however, such as those related to fertility and normal development, didn’t change much in their numbers between individuals, consistent with their crucial roles in these biological processes.

Overall, the sequencing work reveals the diversity of the Y chromosome across males and provides a basis for investigations harnessing these novel structural insights. For example, looking at the specific variants on the Y chromosome and traits, as well as gaining insights into the evolution and function of complex regions of the human genome.

“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. 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.”

Pille Hallast, first author and associate research scientist at the Jackson Laboratory (JAX) and former postdoctoral scientist and visitor at the Wellcome Sanger Institute

“Research is emerging that shows proper Y chromosome gene function is incredibly important for the overall health of men. Our study enables the inclusion of the full Y chromosome in all future studies when sequencing male genomes to understand health and disease.”

Professor Charles Lee, senior author on the paper at the Jackson Laboratory (JAX)

“Beyond its role in determining maleness, the Y chromosome influences male fertility and other less well-understood aspects of our health and well-being. These complete sequences are a vitally important step in opening doors to investigating some of the questions that have puzzled scientists for decades. For example, European men who carry a deletion of part of the Y chromosome known as the ‘gr/gr deletion’ are often infertile or sub-fertile. In contrast, Japanese men who appear to carry the same gr/gr deletion have normal fertility. Something somewhere else on the chromosome must make a key difference. Now that we have the fully resolved Y chromosome, future work should allow us to shed light on these intricacies.”

Dr Chris Tyler-Smith,author on the paper and former senior group leader at the Wellcome Sanger Institute

This web story was adapted from the Jackson Laboratory (JAX).

More information

* At the same time, the Telomere-to-Telomere (T2T) consortium has now published the first complete Y chromosome assembly (Rhie et al. Nature – In Press, DOI: 10.1038/s41586-023-06457-y) from a single individual of European descent.

** A recent study showed that tumours that had lost the Y chromosomes can more effectively evade T cell immunity and are infiltrated with higher numbers of dysfunctional CD8+ T cells. Plus they are more responsive to anti-PD1 treatments compared to similar tumours retaining the Y chromosome. Full study DOI: 10.1038/s41586-023-06234-x

***Additionally, they found inversions involved ampliconic sequences. The researchers found that mutation rates within ampliconic sequences, which are highly repetitive DNA segments associated with the inversions, are influenced by the surrounding DNA sequence context. Additionally, some ampliconic genes showed signs of concerted evolution, implying certain groups of genes have evolved together. This suggests functional interdependence, with implications for our understanding of gene functions and how they are regulated. It can also help researchers identify key genes involved in male reproduction and development.


P. Hallast, M.K. Konkel, C. Lee et al. (2023) ‘Assembly of 43 human Y chromosomes reveals extensive complexity and variation.’ Nature. DOI: 10.1038/s41586-023-06425-6.