SIZE MATTERS: THE IMPENDING DEATH OF THE Y CHROMOSOME
“And the LORD God caused a deep sleep to fall upon Adam, and he slept: and he took one of his ribs, and closed up the flesh instead thereof;
And the rib, which the LORD God had taken from man, made he a woman, and brought her unto the man.
And Adam said, This is now bone of my bones, and flesh of my flesh: she shall be called Woman, because she was taken out of Man.” (Genesis 2:21-23)
Biblical tradition tells the story of creation with man as the first sex, and woman the second, fashioned from Adam’s rib. Biology conveys a different tale for the evolution of the sexes, however, revealing that man, not woman, is the second sex. Recent research in genomics and molecular genetics has shed much light onto the elusive human Y chromosome, suggesting that man may not only be the second to arise, but the first to disappear.
The creation of the sexes begins with the evolution of the mammalian sex chromosomes. It is believed that the X and Y were originally a pair of identical autosomes: ordinary non-sex chromosomes, the same size, carrying the same genetic material. Then 300 million years ago, a chance mutation suddenly occurred on the ancestral Y, mutating the SOX3 gene to the SRY gene. It is at this point that the Y chromosome took on the sex determining role for maleness (SRY stands for Sex-determining Region of the Y). The ancestral X retained the unmutated SOX3. And thus, the sex chromosomes emerged. Between 80 to 300 million years ago, four different rearrangements (inversions) took place sequentially in the Y, further differentiating it from the X. The ultimate result: only the two distal ends of the X and Y remain identical to each other, known as the pseudoautosomal regions (PARs) [12].
The SRY gene on the Y chromosome is the master switch for sex determination. When present, it diverts the embryo onto the path towards male development by turning on testis differentiation, which whips out powerful masculinising hormones . Embryos carry 22 pairs of autosomes plus two sex chromosomes; an XX embryo will become a female, while an XY embryo will be male. It has been known for 45 years that people with a Y are male, no matter how many Xs they may also have. This explains why XXY embryos develop into males (Klinefelter’s Syndrome), while XO embryos produce females (Turner’s Syndrome). It is evident that the female can be regarded as the “default” sex: the fall-back developmental pathway for any fetus if the Y is absent. It is for this reason that Steve Jones, professor of genetics at University College London and author of The Descent of Men, considers females the first sex, and males, the second [4].
By all means, SRY is not the only gene carried by the Y; also spread out on the chromosome are a handful of other genes involved in spermatogenesis, expressed exclusively in the testis, and required for manufacturing fully operational sperm [5]. In addition, there are also a few genes that have absolutely no involvement in maleness, including one that codes for tooth enamel.
The emergence of the SRY gene on the Y was a bold and definitive move (albeit by chance) that allowed and enabled the manifestation of the male species. Ironically, this mutation may have also sealed the fate of the Y chromosome and quite possibly doomed it for extinction. Since that fateful event 300 million years ago, the Y has shrunk dramatically. Recall that the X and Y chromosomes began as the same size; today, the X is 165 megabases (Mb), while the Y is less than half of that (67 Mb) [6]. Something has been driving the Y to degeneration. Thus remain the controversial questions that have been debated for decades: What is the future of the Y chromosome? Will it continue to deteriorate to extinction? And what will this mean for the male species?
To put it plainly, the Y chromosome is a loner. Unlike all other chromosomes, the Y is genetically isolated; this is the central reason that it has shrunk so dramatically. The 22 pairs of autosomes are able to pair up, allowing for a process known as homologous recombination to occur in meiosis. During recombination, the two members of an autosome pair are able to cross-over, exchange genetic material with each other, and notably, swap faulty genes for good ones by using each other as templates. This process allows for the repair of damaged chromosomes that may have resulted from mutations. Like autosomes, the X chromosome is also able to engage in recombination, but only half of the time, namely, when it pairs with another X. The Y, however, is an isolated entity, because it is never in proximity with another Y; the only partner it can potentially pair up with is an X chromosome. Over the past 300 million years, however, because the Y has gradually become less homologous to the X, cross-over between the sex chromosomes has become drastically reduced. The result is that only the tiny PARs of the X and Y are able to recombine[2]. The 95% of the Y chromosome length that lies outside of the PARs, dubbed the male-specific region of the Y (MSY), is unable to recombine with the X. Thus, the vast majority of the Y suffers from the detrimental effects of suppression of recombination. In the non-recombining MSY, mutations accumulate, uninhibited and unrepairable. As a consequence, active genes on the Y are rapidly lost, and the Y is subject to considerable degradation and decay.
Jennifer Graves from the Research School of Biological Sciences at the Australian National University is one of the leading experts convinced that the Y is on the road to extinction. She estimates that since the Y took on its sex-determining role, 1393 out of 1438 genes have been lost, leaving a measly 45 genes retained on the Y. (Compare this to the large 1438-gene-bearing X.) Of these 45 genes, 27 are in the non-recombining MSY. The gene paucity of the Y is also evident in its density of active genes: 0.5 genes per Mb, compared to 10 genes per Mb on the X[6]. Graves argues that the Y chromosome’s significant rate of gene loss (4.6 genes every million years) guarantees its future demise. In 2002, she predicted that the last 45 genes, and thereby the Y chromosome, will be gone within another 10 million years [7].
Needless to say, Graves’ prediction has been vigorously opposed. On the other side of the argument is David Page of the Whitehead Institute at the Massachusetts Institute of Technology. In 2003, he and a team of 40 researchers completed the sequencing of a human Y chromosome from an anonymous donor. They claim that the Y chromosome does not have only 27 genes in the MSY, but 78. Furthermore, they argue that the Y’s powers of self-preservation have been greatly underestimated [8]. Complete sequencing revealed that the Y contains eight large palindromes, regions that read the same both forwards and backwards (think “RADAR”); the Y is a “hall of mirrors,” as Page describes it [9]. These palindromes can form internal hairpin loops within a single Y chromosome, within which internal pairing and recombination can take place. This process, named gene conversion, involves a gene copy on one palindrome arm non-reciprocally replacing the homologous gene copy on the other arm [10]. In this way, by converting mutated gene copies to active copies via gene conversion, the Y chromosome may be capable of self-repair.
The role of gene conversion in sustaining the Y has been argued at the forefront by researchers involved in genome sequencing at the Whitehead Institute, including Page and Helen Skaletsky. They believe that gene conversion occurs in the MSY as frequently as recombination in autosomes. All eight palindromes of the Y are located in a euchromatic (genetically active) region of the MSY, of which they constitute 25%. All 27 genes of the MSY are also found within this euchromatin and are highly concentrated within the palindromes. The arms of each palindrome are over 99.9% identical, strongly facilitating pairing. Furthermore, for all the known genes on palindromes, identical or nearly identical gene copies exist on the opposite arm. It is therefore no surprise that there is evidence of gene conversion occurring routinely in 30% of the MSY euchromatin; calculations suggest that multiple conversion events take place every generation[10].
Interestingly, I noticed that most of the literature arguing the Y chromosome’s destined oblivion cites the number of genes in the MSY as 27 (plus 14 in the PARs, totaling 45 genes). In contrast, almost all the literature arguing that the Y is here to stay cites 78 genes in the MSY. This apparent discrepancy is due to the ambiguous, flexible definition of a gene. There are 78 protein-coding genes within the MSY, but collectively, they encode only 27 distinct proteins. Graves chooses to define the number of genes as the number of distinct proteins encoded, no doubt to emphasize how puny the Y is. In contrast, Page and Skaletsky take into account duplicated and amplified genes, presumably to demonstrate that the Y is not deteriorating as fast as one might think from listening to Graves. This just goes to show that even apparent scientific “facts” can be manipulated for any slant; after all, the numbers can tell whatever story one wants them to tell.
Graves, for one, remains adamant that the Y chromosome is running out of time, despite Page’s 2003 discovery of its eight palindromes. In 2004, she restated her unchanged predictions for the future of the Y, unconvinced that gene conversion will save it. She agrees that if mutated copies of a gene are continually converted back to active copies, then clearly, the Y will not decay[6]. But, unfortunately, gene conversion is not directional; there is equal opportunity for mutated gene copies to overwrite active ones. This “incestuous swapping might be a double-edged sword,” warns Rick Wilson, director of the Genome Sequencing Center at Washington University School of Medicine . In fact, the current state of the Y suggests that there may even be more casualties of the process than successes, judging from the numerous inactive pseudogenes (genes that cannot be transcribed) within palindromes. Graves believes that “gene conversion within palindromes is more like genetic masturbation than real sex [homologous recombination between two chromosomes]. It does not offer interaction between different Y chromosomes, which is essential for […] genetic health”[6].
I agree with Graves; there must be a critical flaw in the process of gene conversion if it has already allowed the Y to lose nearly 97% of its genes. I presume that the other side of the camp may argue that the Y has allowed itself to lose those 1393 genes because they were unnecessary, but the remaining 45 genes will be actively retained because they are essential. In other words, the Y has decayed to an optimal size and will remain stabilized at this state, perhaps akin to the human appendix. I find no evidence for this, however; after all, it is often said that the best predictor of the future is the past. If the Y has the capability to retain genes, it has evidently been out of practice, and it will likely be unable to successfully step up to the task when it counts. Ziny Yen, a medical genetics graduate student here at the University of British Columbia (UBC), believes that gene conversion has not proven to be a powerful enough compensatory mechanism: “Gene conversion may help to slow down the degeneration, but I do not believe that it can prevent the decay altogether” [12].
It may be argued that natural selection could assist gene conversion by providing the directional bias that will select for more active copies of genes. Natural selection, however, works very poorly on the Y chromosome, because it requires a large population to be effective. The Y is essentially a small population, 4-fold lower in frequency than autosomes, since only half the population carries a Y, and only one copy of it at that. Selection is therefore a very weak force on the Y. Furthermore, selection is confounded by the forces of genetic drift and genetic hitchhiking, which prey on small populations especially in the absence of recombination; they exert powerful influences on the Y and drive it to degrade[6]. Genetic drift acts on the Y in a ratchet-like way (a mechanism dubbed Muller’s ratchet). When there is no recombination, the class of Y chromosomes with no mutations could be accidentally lost simply because its bearers have no sons; once this class is lost, it can never be salvaged. Subsequently, the class of Y chromosomes with one mutation may be randomly and permanently lost. The “ratchet” can continue to turn, with the two-mutation class disappearing next[2]. Similarly, damaged Y chromosomes can easily and randomly propagate simply if the bearer happens to have many sons. Genetic hitchhiking is another powerful force driving the decay of the Y. This occurs when a mutation conferring a major benefit on male fitness happens to pop up on a particular Y chromosome. This Y will spread through the population, regardless of whether there are detrimental genes carried on it as well [13]. Together, the forces of drift and hitchhiking can counteract selection for a “perfect” Y chromosome that carries all functional genes.
So altogether, the palindrome discovery may have revealed that the Y can keep afloat for a while longer, but inevitably, it will still sink. As Bryan Sykes, head of Human Genetics at Oxford University, so scathingly puts it: “…sadly, the Y chromosome is just as lonely as ever – though we now know that it talks to itself as it spirals towards oblivion” [14].
Lack of recombination, drift, and hitchhiking all render the Y extremely susceptible to the propagation of mutations. This may have been manageable if the Y chromosome rarely suffered such mutational wounds, but this is not the case. On the contrary, out of all the chromosomes, the Y is the one under the most constant bombardment[6]. So not only is it defenseless, but it must deal with an elevated level of mutations hitting it in the first place. Studies have compared genes that are shared by the X and Y, and in each case, the Y-borne copy is much more rapidly mutated than its X-borne partner [15]. This is not surprising given that the Y chromosome is immersed in layer upon layer of danger and opportunity for error. Firstly, the Y alone is permanently locked in the germ cells of men, passed from generation to generation through the testis. This is a perilous place for a chromosome; the testes are located in the scrotum, which encounters many more harmful environmental mutagens than do the ovaries [16]. Secondly, spermatogonia undergo many more division cycles in the testis (300 to 700) than do oogonia in the ovary (~20)[16]. Over 150 million sperm are created daily, brought about by a tumult of cell division and extremely error-prone DNA replication. The chances of errors, and thus mutations, occurring in these conditions are astronomical [17]. Thirdly, sperm itself is a harsh environment for a gene, being a breeding ground of oxidation and lacking enzymes for repair [18]. True, all the other chromosomes must also pass through the testis and the sperm, but the Y is the only one found solely in these locations, rendering it much more fragile.
The effect of the Y chromosome’s vulnerability to mutations has clear manifestations. Almost all de novo (new) mutations are derived from the father, not the mother [19]. Most prominent are the implications on male fertility. Severely declining sperm counts have been reported in the United States and Europe over the last half-century, in which the Y may play a role. A landmark paper was published by Elisabeth Carlsen et al. in 1992, a historical analysis of 62 separate sperm-count studies from around the world; she concluded that sperm count among men in the industrialized world declined by about 50% in the past 50 years [20]. These results were questioned, however, criticized for purported erroneous statistical methods. Furthermore, a flurry of studies in subsequent years presented contradictory conclusions [21]. In 1997, University of Missouri epidemiologist Shanna Swan revisited the data from the 62 studies and confirmed Carlsen’s conclusions; moreover, she found the dramatic decline to be even greater than previously estimated. Sperm counts among healthy American men were found to have dropped by 1.5% per year from 1938 (120 million sperm per mL of semen) to 1988 (50 million sperm per mL of semen). In Europe, Swan found that they had been dropping at double that rate (3.1% each year) between 1971 and 1990 [22].
The World Health Organization currently designates a minimum of 20 million sperm per mL of semen as normal [23]. Many clinical groups have had to adapt this criterion to accommodate widespread declining sperm counts. According to Fouad Kandeel, a fertility expert and chairman of the department of Diabetes, Endocrinology and Metabolism at the City of Hope Medical Center, 20 million sperm per mL used to be considered subfertile[24]. As of December 2004, Surrey’s own BC Biomedical Laboratories, which conducts medical diagnostic services including semen analyses, has used 14 million per mL as its standard for subfertility [25].
These decreases in sperm count have been attributed to a range of factors, including age, ozone levels, pesticides, smoking, tight underwear, hot tubs, driving, and most recently, laptop computers. Not surprisingly, genetic defects, namely in the Y, are also incriminated. Between 10 to 25% of male infertility cases have been traced to a region on the long arm of the Y called the AZF (azoospermia factor), which is involved in sperm production[24]. Studies have revealed that microdeletions in regions AZFa, AZFb, and AZFc do indeed lead to both azoospermia (the absence of sperm) and, more commonly, oligozoospermia (decreased sperm count) [26]. One study conducted by researchers at the Whitehead Institute and the Howard Hughes Medical Institute looked at the Y chromosome of 35 men with extremely low sperm counts, and found that two had a deletion in AZF. This mutation was not found in their fathers, proving that the deletion was the cause of the condition. A follow-up study found similar deletions in 12 of 89 men who produced few sperm; their fathers also had intact Ys [27]. The first specific gene mutation on the Y conferring infertility (USPY9) was identified by Page in 1999 [28].
Sykes, the cynical Oxford professor mentioned earlier, is the author of the controversial Adam’s Curse. In this text, he argues that, based on the observation that 1% of men are infertile because of a deletion on the Y, human fertility will decay to 1% of its present level in 125 000 years[14]. His prediction is evidently much more looming that Graves’. Recall that based on a loss of 4.6 genes per million years, Graves estimates that the Y will be gone within another 10 million years. She adds that this is likely a conservative estimate, however, since the rate of gene loss may very well be non-linear. There is evidence that as the Y becomes further degraded, its stability declines even more. Studies have looked at male babies born from intracytoplasmic sperm injection (ICSI), the now popular technology of injecting a single sperm into an egg to circumvent low sperm counts, and found that they have more Y deletions than their subfertile fathers [29]. Thus, the Y could disappear much faster and earlier than Graves originally predicted.
The idea of inheriting infertility seems to be quite the oxymoron. This is an argument used by the “Y will survive-ers,” who claim that any mutations severely affecting the Y cannot be passed on since the bearer will be infertile. Predisposition to subfertility, on the other hand, can be inherited, as mentioned above in male babies born from ICSI. Nonetheless, there appears to be an exceedingly high rate of a recurrent deletion of a 1.6-Mb region containing genes required for spermatogenesis; this mutation confers infertility, yet it occurs at such a high rate that it is maintained as a polymorphism in the human population [30]. Thus, even though bearers of this deletion are infertile, the mutation crops up in so many males that it appears to be inherited, rather than de novo.
At this point, I must call into question all the information, statistics and “facts” presented thus far. They may all very well be biased. The majority of research done on male infertility has been on men found through fertility clinics: men who are not typical, nor representative, of the general population. It is from them that all the mutations on the Y chromosome are discovered and analyzed, thus revealing a sampling bias. There may be men with mutations on their Ys, but who do not experience any fertility problems or realize they are subfertile; these men would never enter fertility clinics, and thus their Ys would never be considered. Studies on sperm counts are just as limited; they rely on data from sperm banks, which again, may not reflect the male population as a whole. It has been suggested that the decline observed in studies such as Carlsen’s and Swan’s may not have taken into consideration normal sperm fluctuations that can occur from year to year, from season to season, and between different regions. For example, one study found the sperm count in New York City to be much higher than that in Los Angeles. Another Los Angeles study in 2000 found no significant change in sperm count from a study conducted in the 1950s [31]. (Swan takes these apparent contradictions into account and defends her results, claiming that although temperature and climate can cause regional variations, the overall decline in sperm count is not an illusion; the United States National Institutes of Health agrees.)[22] To take this questioning one step further, I begin to suspect the validity of the alleged Y chromosome sequence itself. Page and his Whitehead Institute colleagues obtained this single Y from an anonymous donor. What a shock it would be to realize, 10 years later, that his sample was an anomaly. Laughable, maybe. But not as ridiculous and far-fetched as one might think; for 37 years, it was accepted as scientific fact that humans had 48 chromosomes. This was what Herbert Evans found in 1918 in the cells of a man who, as was realized later, just so happened to have a genetic abnormality. It was not until 1956 that J. H. Tijo and Albert Levan proved this wrong [32].
Another potential source of information for the future of the human Y is the Y chromosomes belonging to other mammals. “Rodents, which have much shorter generation times than primates, are indicative of what might happen after many more generations in humans,” says graduate student Yen[12]. In other words, because mice have undergone many more “cycles of evolution,” the current condition of their Y might provide a glimpse of that of the future human’s. In 1990, the mouse Y was reported to be 60 Mb; given that the human Y is 67 Mb, this would provide support for the degeneration of the Y. However, a 1999 study revised this number, claiming that the mouse Y is actually almost 95 Mb, larger than the human’s [33]. The marsupial Y has been found to be about 10 Mb, significantly reduced in size compared to that of the human’s. It contains no PARs, and therefore does not undergo homologous pairing or recombination with the X; this may explain why it is so small [34]. In contrast, the mouse Y does include PARs of about 0.7 Mb [35]. But this only makes up 0.7% of its Y, compared to the human PARs which encompass 5%. Thus, recombination with the X evidently does not explain how the mouse Y has managed to retain such a large size. Perhaps it has evolved some extremely successful compensatory mechanism, more efficient than gene conversion has been for humans.
Intuitively, it follows that if a gene is clearly essential for male development, function, and reproduction, then it cannot possibly disappear. The gradual loss of genes on the Y would inevitably lead to the loss of the SRY, which would surely mean the cessation of the male species, and thus of mankind. Not necessarily. The loss of the Y may not equate to the loss of the species if genes on other chromosomes could take over the job of male development. The question is whether all the crucial genes on the Y could translocate or be recreated elsewhere before the Y vanishes completely. The existence of human XX males reveals that the SRY master switch is indeed capable of smuggling itself onto another chromosome[6]. These XX males are sterile, however, since they are missing all the spermatogenesis genes also located on the Y. This strategy would therefore only work if one by one, each crucial Y gene is relocated or replaced by an autosomal gene, facilitating the loss of the former. Step by step, the Y would become less and less necessary for male function[6]. In 1995, male mole voles were discovered to have no Y and no SRY. These burrowing rodents who live in the foothills of the Caucasus mountains have roughly equal proportions of males and females, meaning that they have managed to invent a new form of sex determination [36]. The discovery of the identity and location of a supposed new sex-determining gene is currently in progress. It could be an already known gene that has been altered, or a newly-created gene. Japanese spinous country rats are also Y-less and SRY-less [37]. These rodents may very well be a vision of the future of human sexes.
So why should anyone, other than researchers fixated on the topic, care about the degeneration of the Y chromosome? Even if Graves is on track and the Y ceases to exist in 10 million years, that is still a long time away. After all, humans have evolved from apes in less than that time. Dixie Mager of the Medical Genetics Department at UBC agrees that although the Y “will continue to degenerate, […] humans will likely have exhausted earth’s capacity to sustain life long before the Y has a chance to change very much” [38]. So why then should it matter? The implications of the decrepit Y do, in fact, affect today’s world. Intracytoplasmic sperm injection (ICSI) is becoming an increasingly popular procedure to help men with low or zero sperm counts father children. A few sperm are extracted from their testicles and injected into eggs, which when fertilized, are placed back into the woman’s uterus [39]. Given that the fathers have fertility problems, there is a chance that their sperm carry defective Ys. Thus, such sophisticated assisted reproductive technology may well be contributing to the overall problem of infertility by allowing otherwise infertile and subfertile men to produce male offspring who will have the same problems as their fathers. Studies by Page have shown this to happen; genes controlling sperm production are able to be passed on to children via ICSI [27]. Therein lies the dilemma. There is an evolutionary reason that certain men have fertility problems. Spermatogenesis involves numerous checkpoints to ensure sperm quality during various stages of production[16]. If there is a flaw in the Y’s AZF region, for example, no or few sperm would pass the checkpoints, and the defect would have a hard time being passed on. Enter ICSI, and sperm carrying imperfect Ys no longer have to fight uphill battles. Nature has disallowed men with Y chromosome abnormalities to reproduce, and there is evidently a price to circumventing this.
About one in 1000 men have azoospermia, while a staggering one in 30 have oligozoospermia[27]. As previously mentioned, 10 to 25% of these cases involve a Y chromosome mutation not present in their fathers. With the Y continuing to degrade, these numbers are expected to rise; with the explosion of ICSI use, they may inflate even further. Thus, attempting to circumvent male infertility may, at the same time, increase its incidence and speed up the decay of the Y. Should this be taken into consideration by scientists? By physicians? By infertile couples? In the United States, up to 20 000 couples a year seek assisted reproductive technology to help them conceive; sperm production deficiency is the culprit in a fifth of these couples[27]. Page advocates that in these cases, genetic counseling is strongly recommended [27]. Thus the question arises of whether an infertile couple would continue to pursue conception via ICSI knowing that their son would have a chance of being subject to the same difficulties. Granted, not all forms of infertility or subfertility are heritable, but rather, only when the condition is Y-linked. Consequently, should all men contemplating ICSI be tested for Y chromosome abnormalities? Should Y screening be offered, recommended, or enforced? Should men who harbor mutated Ys voluntarily refrain from using ICSI? Should they be strongly advised by genetic counselors not to use ICSI? Should the government step in and legally prevent them from using ICSI?
These questions do not stray far from the current debate on the ethics of pre-implantation genetic diagnosis (PGD). This is a procedure available for prospective parents concerned about passing on genetically inherited diseases (of which they are carriers) to their children. The woman’s eggs undergo in vitro fertilization, and embryos are grown to the 8-cell stage. At this point, one cell is removed and tested for a number of diseases; if affected, the embryo from which it originates is discarded[16]. PGD is intended to weed out genetically defective embryos before they have a chance to develop. In this light, defective Y chromosomes could be weeded out as well before they are passed on to male offspring; this would prevent the spread of infertility, as well as artificially select for perfect Ys, which may, in turn, slow down the decay of the Y. The dangers of such methods, however, are that they begin to sound a lot like modern eugenics. If PGD can be used to select against diseases, it can also be manipulated to select for certain “desirable” traits: fast metabolism, height, perfect vision. Then again, there are cases where a deaf mother and deaf father find a way to purposely select for a deaf child, purely because they consider deafness “a beautiful thing,” as UBC medical genetics professor Robert Kay explains [40]. Similarly, infertile couples could want their sons to be infertile as well, for whatever reason. Graves proposes that Y chromosome manipulation could be used to control the possum pest situation in New Zealand forests; by engineering sterile male possums, the multiplying fertile ones would be driven out by competition [41]. No doubt, countries enforcing strict population controls may contemplate such genetic means on humans as well. Page has suggested that further knowledge on how mutations on the Y cause infertility can be used to create sterility at will; finding a way to antagonize the USPY9 gene, for example, could be used as a male contraceptive[28].
In the end, I am left with more questions than I began with. All I can do is scrutinize all the available information, however biased they may be, and attempt to form my own conclusions. I predict that the Y chromosome will continue to decay and lose genes. As this happens, male infertility will become more severe and widespread, whether this is assisted by ICSI or not. Before the Y has a chance to disappear completely, however, humans, as we know them, will have already left the earth. Perhaps they will have evolved into Y-less existence. Perhaps they will have become extinct. Or perhaps they will have been brought to Judgment Day by the same God who created Adam in the first place.
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