Sequencing The ‘Notoriously Difficult’ Human Y Chromosome



Since the 1980s, scientists have been working on identifying every part of the human genome . The sequence of the Y chromosome  has remained a mystery, and in the words of biological anthropologist Agnar Helgeson, “the most troublesome chromosome in our genome.”


That is, until now. Thanks to the efforts of a group of researchers from the Telomere-to-Telomere (T2T) consortium, the sequence of the elusive Y chromosome has finally been solved.


We inherit physical characteristics or traits , from the color of our eyes to our blood type, from our parents. Every single one of these traits is carried inside molecules of deoxyribonucleic acid , or DNA – our very own genetic blueprint. Francis Crick, Rosalind Franklin, and James Watson discovered the double-helix shape of DNA in 1953.


Almost every cell of every living thing has DNA, which, along with proteins , forms chromosomes. We get 23 chromosomes from each parent. Out of these 46 chromosomes that make up our genome, two are sex chromosomes. Most females have two X chromosomes, while most males have one X and one Y chromosome. Intersex people may also have Y chromosomes.


The DNA molecule is made up of four chemical building blocks, which are called bases. These bases are adenine, thymine, cytosine, and guanine.  Each chemical base bonds with a partner, forming base pairs . In every case, cytosine pairs with guanine, and adenine pairs with thymine.

Diagram showing human chromosome
DNA and its bases, Credit: Freepik/brgfx

There are 3 billion base pairs in the human genome!


When scientists sequence DNA, they try to identify the order in which the four bases occur in the molecule.  But the Y chromosome was especially challenging because many stretches were repetitive, and other sections were inverted. There were numerous palindromes , meaning long sequences that read the same backward and forwards.


As one of the lead authors, Monika Cechova, described the process:


“Just a few years ago, half of the human Y chromosome was missing – the challenging, complex satellite areas. Back then we didn’t even know if it could be sequenced, it was so puzzling. This is really a huge shift in what’s possible.”


Once upon a time, the Y chromosome might have been identical to the X chromosome. However, the genes in the Y chromosome, over time, got smaller and smaller and smaller. Today, it is one-sixth the size of the X chromosome, and has only half as many genes! The remaining genes code for important functions such as the production of sperm.


The Y chromosome’s small size did not make the process any easier. Researchers made use of state-of-the-art sequencing technology and cutting-edge computational methods that could process the repetitive sequences accurately.


This allowed them to find the point of inversion  in the palindromic sequence – where the sequence begins to flip. They then used these techniques to find other inversions.


The team had to sequence each part of the DNA, and then put it all back together in the right order. In total, they analysed 62 million bases, including 30 million that had never been sequenced before.


However, the team did not stop there. Once they had put together the structure of the Y chromosome, they sequenced it for 43 men from 21 different populations all over the world. Thanks to the 1000 Genomes Project, they knew that even within humans, there is a great deal of genetic variation.


The results of the analysis were quite surprising. Even within two healthy people, the Y chromosomes could look quite different. One person had, for instance, 23 copies of the gene TSPY, which is important for sperm formation. Another person had 39 copies of the same gene.


What scientists do not know yet is whether all this variation between different people could affect traits like fertility. Having the entire genome sequenced, as well as all the new data, is helpful because it has laid a foundation for future work.


Now, scientists will find it easier to look at how genes are passed down through generations and see how they change over time. In fact, it is not just the genes that are evolving and mutating, but the genome as a whole.


Going forward, researchers can examine whether chromosomal differences are associated with health problems such as infertility or certain kinds of cancers. For example, many people can lose genetic material in their Y chromosomes as they get older. Working on these issues can lead to breakthroughs for in vitro fertilization and reproductive treatments.


The human Y chromosome will be added to the pangenome  (Human Pangenome Reference Consortium), which combines the genomes of people from many different ancestral backgrounds. Scientists hope that this will encourage more equitable research into diagnosing diseases, predicting medical outcomes, and guiding treatments.


Because the genes in the Y chromosome have multiple copies and are organized at a very high level, the “gene content” of the chromosome stays essentially the same. Earlier, scientists thought that the Y chromosome might get smaller and smaller until it disappears altogether.

Some rodents have lost their Y chromosome! Waldron

This has happened in other animal lineages, such as species like the Amami spiny rat and the creeping vole. However, findings from this exciting new research seem to say that the Y chromosome is here to stay.


Flesch Kincaid Grade Level: 9.2


Flesch Kincaid Reading Ease: 56


Base pairs: A unit of two bases that have combined. The base adenine always pairs with thymine, while cytosine always pairs with guanine.

Chromosome: Threadlike structures which are made of protein combined with a single molecule of DNA. They carry important genetic information between cells.


Deoxyribonucleic acid: The molecule that carries genetic information that is crucial for organisms to develop and function. Deoxyribonucleic acid or DNA consists of two strands that wind around, looking like a twisty ladder. This shape is known as a double helix.

Genome: All the set of DNA instructions in the cell. For example, humans have 23 chromosome pairs in the nucleus of the cell.

Inversion: Chromosomes have inversions when some part breaks off and reattaches – but in the opposite direction. Some DNA might be lost during this process.

Palindrome: Sequences whose complementary strands read the same in the opposite direction. They can either be exact or approximate palindromes. An example of an exact palindrome is 5′-CGATCG-3′ – the reverse complement 3′-GCTAGC-5′ reads the same!

Pangenome: All humans share a core genome, but some sequence information is unique to each person. This is the variable genome. The pangenome includes the core genome and the variable genome, allowing us to understand our shared genetic character and history.

Proteins: Naturally occurring complex chemicals made up of amino acids and peptide bonds.

Traits: Specific characteristics of an individual. Traits are determined by a combination of genetic and environmental factors. Eye color, blood pressure, height, and complexion are all traits.

Couger, Matthew B., et al. “Sex chromosome transformation and the origin of a male-specific X chromosome in the creeping vole.” Science 372.6542 (2021): 592-600.


Hallast, Pille, et al. “Assembly of 43 human Y chromosomes reveals extensive complexity and variation.” Nature (2023): 1-10.

Kuroiwa, Asato, et al. “Additional copies of CBX2 in the genomes of males of mammals lacking SRY, the Amami spiny rat (Tokudaia osimensis) and the Tokunoshima spiny rat (Tokudaia tokunoshimensis).” Chromosome Research 19 (2011): 635-644.

Lahn, Bruce T., and David C. Page. “Four evolutionary strata on the human X chromosome.” Science 286.5441 (1999): 964-967.

Rhie, Arang, et al. “The complete sequence of a human Y chromosome.” Nature (2023): 1-11.

Watson, James D., and Francis HC Crick. “The structure of DNA.” Cold Spring Harbor symposia on quantitative biology. Vol. 18. Cold Spring Harbor Laboratory Press, 1953.


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