This is one of the best known genetic data: women are XX and men XY. In humans, the chromosomes determine gender, and this particular pair, the 23e, is the most surprising. It is the only pair of chromosomes where two versions with huge differences coexist. So much so that it is even difficult to recognize in this pair two ancestrally very close chromosomes, but which, over millions of years of evolution, have become unrecognizable.
Why have the sex chromosomes evolved to become so unique? This question has plagued geneticists for almost a century. Several hypotheses have been proposed over time, and a theory has gradually been consolidated. However, this long theoretical construction has just been turned upside down by a new model that challenges this edifice.
The XY dichotomy
The X is a fairly common chromosome, with nearly 800 protein-coding genes. The Y, on the other hand, is much stranger: smaller (regarding a third of the length of the X), it only has regarding sixty genes left. These two chromosomes do, however, form a “pair”. During the production of spermatozoa, they pair up and recombine on a small portion (recombination is an exchange of genetic material, here between the two chromosomes of the same pair), testifying to their ancestral homology. But 95% of Y no longer recombines at all. The X recombines along its entire length in XX females during egg production.
Finally, another oddity, a only X is expressed in females. That is to say that the genes are read to give proteins from a single X, either that inherited from the father, or that inherited from the mother, randomly according to the cells. This allows “dosage compensation”, so that the genes carried on the X are expressed at the same level in males and females.
Widespread differences in life
One might think that these eccentricities are unique to humans. This is not the case: they are in fact extremely widespread in animals, and even plants, although the details vary.
But, very regularly, we observe a recombination arrest on the sex chromosomes, a non-recombinant chromosome (Y) which contains few functional genes (it is “degenerate”), as well as dosage compensation.
These regularities soon caught the eye of geneticists, who began to search for a theory explaining why recombination stops on these chromosomes, and why this recombination stop is associated with degeneration. These same geneticists also quickly realized that answering this question might also help to lift the veil on a general question that tormented them even more: the role of recombination in evolution.
The role of recombination
Recombination, during the production of gametes, allows genetic “mixing”. It is an essential feature of sexual reproduction, and arguably the key factor explaining the advantage of sex over clonal asexual reproduction. The degeneration of non-recombinant sex chromosomes seems to be life-size proof of the importance of recombination for maintaining the integrity of genomes, in the face of the constant flux of deleterious mutations altering genetic information.
Indeed, most chromosomes carry mutations, which can be transmitted from one generation to another when their effect on the survival or the fecundity of organisms is not too great. The mutation-free version of a fragment of chromosome can be quite rare within a population, and can even disappear if the individuals carrying it leave no descendants. When this happens, a mutation-free fragment can only be recreated by recombination between chromosomes carrying mutations in different places. Due to this process, the non-recombinant areas of the chromosomes are expected to gradually accumulate mutations.
The absence of recombination might therefore explain the degeneration of the Y. But this does not entirely resolve the question: why the hell do the sex chromosomes stop recombining if this stop leads to degeneration?
The sex-antagonist gene theory
Until our work, this was explained by the sex-antagonist gene theory. Males and females differ for many characters: this is sexual dimorphism. For many genes, therefore, there are versions (‘alleles’) which are advantageous for one sex and disadvantageous for the other.
If these “sex-antagonist” genes are frequent, we can expect to find them on the sex chromosomes. Suppressing recombination (and therefore the exchange of alleles between the X and Y chromosomes) can then become advantageous. If an advantageous allele in males is found on a Y that no longer recombines, it will remain on this Y: it will always be found in males but never in females.
A comprehensive theory of sex chromosome evolution in three stages thus imposed itself. Stage 1 is recombination arrest on the Y, caused by the presence of sex-antagonist genes on the sex chromosomes. Stage 2 is the accumulation of deleterious mutations (degeneracy), following recombination arrest. Stage 3 is the evolution of dosage compensation to compensate for the X gene expression deficit in males.
This theory had the advantage of being very elegant, because it was very general. However, several subsequent observations have gradually questioned this structure, and have reopened the theoretical debate.
A new theory
For this, we started from the only “ingredients” which seem essential to explain the evolution of the sex chromosomes: recombination arrest events on the Y (but which are not irreversible), deleterious mutations (degeneration cannot take place without them), and gene expression regulators that can modulate their expression levels (dosage compensation cannot take place without them).
To our great surprise, these ingredients, and in particular the last one which had never been formally integrated into the classical theory, turned out to be sufficient. Our research has uncovered an overall process that is entirely different from the “classical” theory, where the set of causal relationships is reversedand the “sex-antagonist” genes become useless.
Like the classic theory, this new theory assumes an ancestral situation in which a gene carried by a pair of “normal” chromosomes (autosomes) determines the sex of individuals. Two different forms of this gene (or alleles, which will be noted M and F) coexist, the MF individuals developing into males and the FF individuals into females.
It is then assumed that chromosomal inversions can occur: an inversion corresponds to a “turning over” of a part of the chromosome, the genes located in this part then finding themselves in an inverted order. These inversions correspond to a form of mutation that is quite rare, but nevertheless occurs from time to time within populations. They have the effect of preventing (at the level of inversion) recombination between inverted and non-inverted chromosomes. Indeed, the different order of the genes prevents the correct pairing of the chromosomes in this area.
When an inversion encompassing the M allele (determining the male sex) occurs, this can be favored if the genes it contains carry fewer deleterious mutations than the average. In this case, it will increase in frequency over generations, until all male individuals carry this inversion. As a result, the chromosomes carrying the F and M alleles become X and Y “proto-chromosomes”, no longer recombining over part of their length (in the inversion zone).
However, stopping recombination ultimately causes an accumulation of deleterious mutations on the chromosome carrying the M allele (the one carrying the F allele continuing to recombine in females). This accumulation of mutations can favor either a return to recombination (for example, by a new chromosomal inversion restoring the initial order of the genes), or a reduction in the expression of the mutated genes carried by the proto-Y, which will be compensated by an increase in the expression of proto-X genes: this is the start of dosage compensation. When this takes place quickly enough, it prevents any backtracking: restoration of recombination will have the effect of destroying this delicate balance between the expression levels of the X and Y genes.
The computer simulations that we have carried out thus show a progressive cessation of recombination, by successive “strata” corresponding to different inversions stabilized by the evolution of the dosage compensation, without there being any need to invoke the existence of sex-antagonist genes.
By completely renewing our view of the possible scenarios for the evolution of the sex chromosomes, this new theory opens up a vast field of experimentation and empirical testing. It also shows the importance of taking into account the mechanisms of regulation of gene expression in the theory of evolution. Finally, she might suggest that taking into account the evolution of regulators might be one of the keys to solving the mystery of how sexual reproduction is maintained in plants and animals.
The original version of this article was published on The conversationa non-profit news site dedicated to sharing ideas between academic experts and the general public.
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Denis Roze has received funding from the ANR.
