The degradation of the Y chromosome follows a long history of sex chromosome turnover. Even if it disappears, males will still be produced. But how? Evolutionary genetics provides us with answers.

*Illustration by Cynthia (@PTElephant). Custom illustrations below were provided by the author and used with her permission.*

Almost every single aspect of our physiology is determined by our DNA—from the color of our skin to the way we think and even our chances of developing certain diseases. DNA influences the development of our bodies throughout life, and especially during the crucial first weeks of embryonic growth, when we undergo sex determination.

As any basic biology textbook will tell you, mammalian DNA is organized into several long strands known as chromosomes. Humans have 23 pairs of chromosomes; a set of 22 identical twins (autosomes) and one fraternal twin pair that look almost nothing alike (our sex chromosomes). If you imagine every letter of your DNA typed out into a series of books, each gene would comprise a chapter and each chromosome would be a separate volume. This view of our genetic code doesn't need to just be trapped in your imagination either; if you're ever in London, I'd highly recommend visiting the Welcome Collection and gazing in astonishment at the Library of the Human Genome —an expansive bookcase filled with these letters of life.

*The letters of life that encode our genes.*

What a textbook might neglect to mention, however, is that our chromosomes are far from organized collections of information. Geneticists can only dream of genes being neatly grouped based on function. Instead of one chromosome controlling our eye development and another determining our brain biology, genes are littered haphazardly throughout each chromosome—messy manuscripts that take decades to decipher. The only striking exception is the Y chromosome with its streamlined profile of genes, almost all of which are responsible for maleness. We now know that the key player of male sex determination is a small sequence of DNA on the Y chromosome: the SRY gene.

How can one tiny gene flip the switch on sex? Although our chromosomes signpost our sex from the moment of fertilization, early embryos are actually 'sex indifferent' until the SRY gene is activated. The cells that make up the initial reproductive organs exist in a bipotential state where they could either differentiate into ovarian or testicular tissue. The SRY gene codes for the testis-determining transcription factor (TDF) which serves to amplify the production of other proteins by binding to the neighboring non-coding 'junk' DNA.

It is easy to be lulled into believing that binding in biochemical reactions has a certain simplicity to it—like the smooth insertion of a key into the right lock. In the case of TDF binding, this could not be further from the truth. First, the amino acids of the TDF protein interact with the phosphate backbone of the DNA, gluing itself tightly to the grooves in the double helix. Strategically placed amino acids then jam into the minor groove of the DNA, contorting it into a sharp 80 degree bend which is held in place by attractions between the oxygen and nitrogen atoms in DNA and the hydrogens of the TDF protein.[1]

*The SRY gene with its transcription factor known as testis-determining factor (TDF) that kickstarts male sex differentiation.*

This bending is crucial to kickstarting a cascade of biochemical reactions leading to the differentiation of sexless primordial gonad cells into the sperm-producing cells of the testes. In fact, improper bending of the DNA at this stage can result in sex reversal mutations, causing intersex conditions in which a typical male karyotype produces female physiology.[2]

The Sex Chromosome Gap

Clearly, the Y chromosome plays a dominant role in sex determination. Yet, it seems to pale in comparison to its X counterpart in terms of its structure. It has fewer functional genes, a shorter stature and many more mutations. The journey to understanding its uniquely poor structure starts with tracing back to its emergence in our genome.

Prior to the evolution of mammals, sex determination did not follow a chromosomal blueprint. Rather it was decided by environmental factors. For example, alligators’ sex entirely depends on incubation and egg temperature at the time of hatching. As a result, every one of their chromosomes belongs to a matching set as they lack distinctive sex chromosomes. At some point, very early in the evolution of mammals, an ancient form of the SOX3 gene, involved in brain development pathways, randomly mutated to form the SRY on a single autosome.[3] This was the first step in a long path of mutations, a growing divide between the SRY-containing autosome and its counterpart—culminating in two very different sex chromosomes.

From comparing our genomes to those of early mammals, such as marsupials, geneticists have identified that the modern Y chromosome shares just four genes with its much larger autosomal ancestor. How did we get from an ancestral Y with 2000 functional genes to a stunted chromosome with just 55?

Mate or Mutate

The answer lies in the surprising fact that the sex chromosome (X or Y) doesn’t recombine with the X chromosome during cell division that produces sperm cells.

During sex cell production, each autosome ‘crosses-over’ with their twin, swapping segments of DNA between themselves to create unique, new chromosomes for future offspring. This chromosomal mating, termed recombination, also serves a vital role in eliminating mutations in the autosomes of sex cells—preventing mutations from being passed onto future generations.

Recombination works well in autosomes and in XX chromosome pairs as they each have an identical twin. However, since the development of the SRY gene, X and Y chromosomes have been unable to fully recombine during sperm cell production as they aren’t identical. While X chromosomes can recombine with each other over their full length, all that modern X and Y chromosomes have left are little regions at their tips that are capable of crossing over.

Without recombination, our Y has gradually acquired a slew of deleterious mutations—filling the chromosome with ‘junk’ DNA and shortening it through deletion mutations. As the Y chromosome mutates, it becomes less able to recombine with its X counterpart and continues to lose genes: a vicious cycle of shrinkage.[4]

*An illustration showing how the sex chromosomes, X and Y, cannot recombine fully.*

*An illustration showing the cycle of sex chromosome turnover, the Y degrading because of its lack of ability to fully recombine with the X, only to remerge later.*

Chromosomal Kismet

Trapped in this cycle of mutating without much recombination, is the Y chromosome headed for extinction? Again, we can turn to our marsupial ancestors for answers. Dasyurid marsupials, such as the Tasmanian devil, have a Y that has been whittled down to just 10 megabases in length—a little genetic fragment containing just SRY and a few sperm-producing genes. This degradation is taken to the extreme in bandicoots. These marsupials use their miniscule Y chromosome (holding nothing but SRY, the last in a long line of seemingly disposable genes) for sex-differentiation and gonad formation, before eliminating it entirely from all other embryonic cells. Such a small chromosome, essentially a single gene, is at great risk of further loss.

Some species have ventured beyond this point in chromosomal evolution. Two examples are the Transcaucasian mole vole and the Ryukyu spiny rat.[5][6] Their Y chromosome and the SRY gene have disappeared completely. In the Ryukyu spiny rat, males and females are both XO (one X chromosome, no Y). But they still produce males in abundance. How? The answer is gene duplication. Males inherit a small duplicate genetic sequence located on Chromosome 3 that upregulates a gene required for testes differentiation known as SOX9. For this species, other genes required for spermatogenesis (sperm creation) are located on the X chromosome, translocated from the lost Y.

When a chromosome acquires sex determining properties, holding a single gene locus for sex determination, it will not be able to entirely recombine with its pair, and over a long period of evolutionary history, it may accumulate mutations—diverging in function and shortening to produce a new Y chromosome. In this way, the same Y chromosome evolution described earlier can renew itself cyclically in a sex chromosome cycle.[7]

Fast-forwarding a couple hundred million years, human sex-determination may morph entirely, doing away with the Y chromosome or forming an entirely new one.

One thing is clear, however: the male sex is here to stay.

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References

[1] Kashimada, K., Koopman, P. (2010). Sry, the master switch in mammalian sex determination. Development, 137.

[2] Weiss, M., et al. (2013). Molecular Mechanisms of Male Sex Determination: The Enigma of SRY. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

[3] Lahn, B. T., Pearson, N. M., & Jegalian, K. (2001). The human Y chromosome, in the light of evolution. Nature Reviews Genetics, 2(3), 207–216.

[4] (n.d.) Evolution of the Y chromosome. Biointeractive.

[5] Matveevsky, S., Kolomiets, O., Bogdanov, A., et al. (2017). Chromosomal Evolution in Mole Voles Ellobius (Cricetidae, Rodentia): Bizarre Sex Chromosomes, Variable Autosomes and Meiosis. Genes, 8(11).

[6] Terao, M., Ogawa, Y., Takada, S., et al. (2022). Turnover of mammal sex chromosomes in the Sry-deficient Amami spiny rat is due to male-specific upregulation of Sox9. PNAS, 119(49).

[7] Furman, B., Metzger, D., Darolti, I., et al. (2020). Sex chromosome evolution: so many exceptions to the rules. Genome Biology and Evolution, 12(6).

(Extra Citation included by the author: Jennifer A. Marshall Graves, Human Y Chromosome, Sex Determination, and Spermatogenesis—A Feminist View. Biology of Reproduction, Volume 63, Issue 3, 1 September 2000, Pages 667–676).