In the summer of 1925, Russian geneticist Sergey Gershenson collected 19 female fruit flies of the species Drosophila obscura from a forest near Moscow. He brought the captured flies back to his laboratory and mated them with normal males to study their offspring. By the second generation of matings, Gershenson noticed a puzzling trend: some of the male flies were producing almost all female progeny. He repeated the matings to confirm that this was not just an extraordinary coincidence, but the result remained the same. These otherwise healthy males exhibited a shocking propensity to sire daughters (1).
Gershenson resolved that this abnormality was related to the fertilization of the egg. During mating, a male fly fertilizes the egg with a sperm cell that contains either an X chromosome or its homologue, the Y chromosome. The egg always has an X chromosome, and the content of the sperm determines the gender of the offspring. If the sperm has an X chromosome then the fertilized egg will develop into an XX female, and if it has a Y chromosome it will become an XY male.
The mutation in Gershenson’s flies exploited the diploid nature of the fly genome. Like most organisms, fruit flies have two copies of each chromosome, and pass either one to their offspring with approximately equal probability. Gershenson’s flies, however, carried a mutated chromosome that distorted the transmission probability in favor of itself, a mechanism that is known as “meiotic drive” (2, 3, 4, 5). In this case, the affected chromosome was the X chromosome, leading to the sex-ratio bias.
The meiotic driving X chromosome mutation, known as Xd, was attacking and destroying Y-bearing sperm, leaving a vast majority of X-bearing sperm to fertilize the egg. As a result, nearly all of the fertilized eggs received an X chromosome and developed into XdX females. The mutation then lurked in the genome of the daughters, who would mate with healthy males and pass the defective X chromosome to their offspring. As the generations progressed, the number of fathers with the ability to sire sons plummeted, nearly eliminating males from the population entirely (1).
While the destructive and selfish nature of the X-linked meiotic drive mutation is detrimental to the species as a whole, evolution actually favors it, at least in the short term. Since females have two X chromosomes and males only have one, the X chromosome spends two-thirds of its existence in females (4, 6). So if an X chromosome has a gene that poisons and kills Y-bearing sperm, it increases its own chances of being transmitted to progeny. In pursuit of this advantage, the X chromosome has no qualms about wiping out males entirely, even if it means eventual extinction of the species. Evolution has no foresight and no plan. The only goal is propagation, and the Xd mutation was effectively forcing its own propagation through the destruction of its competitor.
The idea that evolution occurs on the level of the genes was most famously articulated by Richard Dawkins in The Selfish Gene: “Genes are competing directly with their alleles for survival, since their alleles in the gene pool are rivals for their slot on the chromosomes of future generations. Any gene which behaves in such a way to increase its own survival chances in the gene pool at the expense of its alleles will, by definition, tautologously, tend to survive. The gene is the basic unit of selfishness” (7). One way that a gene can triumph over its competing allele is to improve itself, but another, more devious method, is to sabotage its competitor.
Meiotic drive requires several factors to accomplish this feat. First, the affected pair of chromosomes must each contain both a driving and a target locus. In the hostile chromosome, the target locus becomes resistant to the driving locus, which prevents the chromosome from destroying itself. In the susceptible homologue, the driving locus is inactive and the target locus has no protection against the attack, leaving it at the mercy of the hostile chromosome. Meiotic drive also requires that the driving and target loci have a low recombination frequency, since recombination may lead to the suicidal pairing of driving and target loci on the same chromosome (3).
Since the sex chromosomes do not undergo recombination, they are hotspots for meiotic driving mutations (3). The long and widespread history of sex chromosome antagonism may have shaped the structure of the genome. In a paper published in the Philosophical Transactions of the Royal Society of London, William Amos and John Harwood hypothesize that evolutionary pressure from meiotic drive genes on the X chromosome is responsible for the reduced content of the Y chromosome (4, 8). The human Y chromosome, (~60 million nucleotides), is less than half the size of the X chromosome (~165 million nucleotides) (9, 10). Homologies in the X and Y DNA sequences suggest that they originally descended from a pair of identical autosomes, but the X chromosome repeatedly targeted loci specific to the Y chromosome. To escape these attacks, the Y chromosome shed all non-essential genetic material that the X chromosome could lock on to. Little by little, the Y chromosome grew shorter, eventually assuming its current abbreviated and specialized form. In humans, today’s Y chromosome has lost all but 45 of its original 1000 genes, and the majority of surviving genes are those involved in the development of male traits (9).
But the Y chromosome has other methods of recourse than to simply retreat. It can also take the offensive against the X chromosome, and sometimes even beat the X chromosome at its own game. The stalk-eyed fly (Cyrtodiopsis dalmanni) population is 33-35% male as a result of a meiotic drive gene on the X chromosome. This particular Xd mutation exerts its destructive power during spermiogenesis, the last stage of sperm formation. During spermiogenesis in stalk-eyed flies, the immature X- and Y-bearing spermatids are arranged into sperm bundles. Males that carry the Xd mutation exhibit varying levels of sperm bundle degeneration. In some bundles, all spermatids are degenerate, while in others only a portion is affected. It is believed that in partially degenerate bundles only the Y-bearing spermatids are destroyed, while the X-bearing spermatids are protected by a resistant locus. But 66% of the sperm bundles are completely degenerate, and X- and Y-bearing spermatids alike are destroyed. Hence, the Xd mutation fights a semi-kamikaze mission against the Y chromosome, destroying many of its own in its quest to eliminate Y-bearing sperm. Though it suffers heavy losses, the X chromosome, along with the Xd mutation, is carried by nearly all sperm that emerge from the battle (3).
As an adaptive response to the Xd mutation, some male stalk-eyed flies carry a Y chromosome resistance mutation (Ym) to protect Y-bearing sperm. The Ym mutation makes the Y-bearing spermatids strongly resistant to the Xd attacks. In fact, it appears that the Ym mutation is better at protecting the Y-bearing sperm than the Xd mutation is at protecting itself. In the face of the Ym defense, the Xd mutation causes more collateral damage than directed damage. This resistance actually reverses the drive to produce fewer X-bearing sperm than Y-bearing sperm, resulting in a 63% male-biased progeny for carriers (3).
But the Y chromosome has another secret weapon in its defense. The autosomes enter the war as its allies, and offer reinforcements against the X chromosome. There is good reason for this behavior. Once the population becomes heavily female biased, males enjoy a huge evolutionary advantage (11). The rare males are surrounded by eligible females clamoring for a chance to mate. This evolutionary pressure affects not only the Y chromosome, but the autosomes as well. An autosome that finds itself in a male is assured of plentiful matings and transmission to many progeny. Thus, an autosome that develops resistance to the Xd mutation would be increasing its own propagation in its defense of the Y chromosome. This alliance between the embattled Y chromosome and the autosomes has been observed in the stalk-eyed fly of Malaysia (12, 13, 14).
In Malaysian stalk-eyed flies, the eyes are positioned on the tips of antenna-like eye stalks. These eye stalks extend far from the body, and in some species the width between the eyes exceeds the animal’s entire body length. The Ym suppressor is closely linked to an allele that is responsible for wide eyes. Because of the chromosomal linkage, males with wide eye stalks are likely to also carry the Ym mutation. Females that have a sexual preference for wide-eyed mates are indirectly attracted to the drive suppressing mutation. These mothers pass the autosomal preference gene to their sons who, by way of female mating demand, flood the population with wide eye preference. Once it establishes itself in the population, the female preference enters the feedback loop of runaway sexual selection. The males, reinforced by mating success, develop wider and wider eye stalks, leading to the comically exaggerated width in today’s flies. In closely related species that lack the X-linked meiotic drive however, female eye width preference never evolved, and these flies have normal eyes. Thus, X-linked meiotic drive may be the basis for female sexual preference in some species (14).
But even with this valiant defensive effort, the Y chromosome may be fighting a losing battle. An analysis of the chromosome’s history reveals that it has been losing genetic material at an alarming rate. In humans the Y chromosome may eventually be eliminated entirely. Estimates for Y chromosome extinction vary widely, from 125,000 years to 14 million years to never, but other species have shown that Y chromosome loss is certainly possible. In the Japanese spinous country rat (Tokudaia osimensis), both males and females are XO, meaning that they have a single X chromosome and no Y chromosome (15). In a species of mole vole (Ellobius tancrei), both males and females are XX (9).
From the Gershenson’s Drosophila to stalk-eyed flies to humans, many animals may be in danger of Y chromosome loss. Or perhaps this process is cyclical, and the Y chromosome is replaced by another autosome that follows it on the path to complete deterioration. Whatever the fate, the X and Y chromosomes will continue their blind evolutionary battle for propagation, selfishly teetering the gender balance on the brink of disaster.
Acknowledgments
The author would like to thank Professor Ryan Calsbeek for his consideration and guidance in this manuscript.
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