Review: Sex Chromosome Evolution and the Expression of Sex-Specific Genes in the Placenta
Article Outline
- Abstract
- 1. Introduction
- 2. Human sex chromosomes
- 3. Sex chromosome evolution
- 4. The gene content of the X chromosome
- 5. X chromosome inactivation
- 6. Male genes in a pregnant female
- 7. Conclusions
- Conflict of interest
- References
- Copyright
Abstract
Sex chromosomes have a disproportionate influence on health and disease. Both the X and Y are atypical in gene content and activity, as a result of their unique evolutionary trajectory. The X and Y chromosomes originated in a pair of autosomes, and differentiated as the Y chromosome degenerated progressively. The Y contains few active genes and is composed largely of repetitive DNA sequences. Most Y genes have copies on the X from which they evolved; this includes even the sex-determining gene SRY as well as several genes required for spermatogenesis. The X contains a disproportionate number of genes that affect reproduction and brain function (or both). It is also subject to inactivation in females, so that females are mosaics composed of patches of tissue that express only the genes on either the maternally or the paternally derived X chromosome. Several widely expressed genes on the Y chromosome code for male-specific proteins that provoke an immune reaction in females; this HY antigen has a measurable effect on maternal-fetal incompatibility. Imprinted paternal X inactivation in rodent extraembryonic tissues would be expected to mitigate the effect of foreign paternal antigens; however, paternal inactivation seems not to occur in the human placenta.
Keywords: Sex chromosomes, X chromosome, Y chromosome, Sexual antagonism, Brains-and-balls genes
1. Introduction
The placenta is the site of genome wars, in which maternally and paternally derived alleles battle over fetal growth and nutrition. This sexual antagonism is seen particularly in the large numbers of genes that show imprinted expression in the placenta – more than in any other tissue – and may have evolved because of the competing interests of the male parent in larger offspring, and the female parent in surviving to bear offspring from other partners (reviewed [1]). Mutations in these genes can result in fetal overgrowth or undernutrition, and might be responsible for some of the hazards of pregnancy such as pre-eclampsia [2].
Sex chromosomes are unique in the genome in that they are represented differently in males and females. Both the X and Y chromosomes are choice sites for the evolution of sexually antagonistic genes. In this review I explore the atypical gene content and atypical activity status of the human X and Y chromosomes, how this evolved and how it could affect maternal-fetal interactions.
2. Human sex chromosomes
In humans, as in other mammals, sex is determined in the embryo by a pair of sex chromosomes. Females have two copies of the X chromosome (XX), and males a single X and a small, male-specific Y chromosome (XY). The X is a medium-sized chromosome that contains about 1300 genes with a range of functions. The Y is a small heterochromatic chromosome with few active genes, being composed largely of simple-sequence DNA that is repeated many thousands of times, and thousands of copies of inactive virus genomes [3]. There may be regulatory signals hidden in this sequence, but much of it may be considered to be genetic junk.
Although the X and Y differ greatly in size, they share a small (2.5 Mb) “pseudoautosomal” region (PAR1) that is homologous between the X and Y, and pairs and recombines at male meiosis. The Y contains only about 45 unique protein coding genes [4], many in PAR1. Only 27 lie in the region that is male-specific, although many have been amplified into large families of genes and inactive pseudogenes. Many of the genes on the male-specific region of the Y are dedicated to sex and reproduction, making the Y quite unique in its “functional coherence” [5]. One of these genes is SRY, the sex-determining gene [6], which activates a testis-determining pathway that induces the genital ridge of tissue in the 10-week old embryo to form a testis, which then secretes hormones (androgens and the Mullerian inhibiting factor) that masculinize the embryo.
The mammal X and Y chromosomes also differ greatly in the extent to which they are conserved between species. The Y chromosome is poorly conserved, both in its gene content and arrangement, and the position of the pseudoautosomal boundary (reviewed [7]). In contrast, the X is by far the most conserved chromosome of the complement, as predicted decades ago by Ohno [8]. It has virtually identical gene content (and much the same gene order) in humans, mice, cats and even elephants [9]
Sex chromosomes are the cause of a lot of trouble. The Y chromosome, being full of repetitive sequence, often undergoes deletions and rearrangements that play havoc with sex determination and fertility. If pairing between the X and Y fails, sterility results because meiosis is disrupted. When the SRY gene is accidentally transferred to another chromosome (often the X), a sterile XY female results. If deletions remove one or more fertility genes, spermatogenesis is disrupted.
The single copy of the X in males poses two severe problems. One is that a mutation on the single X, having no back-up copy, will reveal its full effect in males. This is why so-called X-linked diseases like haemophilia or mental retardation are much more common in males than females. The other problem is that the dosage of X-borne genes is different in XX females and XY males. Humans and other mammals solve this problem by upregulating genes on the X to match the expression of autosomal genes, then inactivating one X in females. This X chromosome inactivation is an extraordinary example of epigenetic silencing on a grand scale.
Why are sex chromosomes so atypical? Have they been shaped to work optimally? Or are they the result of a genetic accident? I will argue here that they are a splendid example in which part of the genome is shaped by forces beyond those that select for optimal function. Thus sex chromosomes can be understood best in terms of the forces that drove their evolution.
3. Sex chromosome evolution
Although human X and Y chromosomes are morphologically and genetically very distinct, there is good evidence that they were once an ordinary autosomal pair (reviewed [4]). The shared pseudoautosomal region at one end is consistent with this explanation. So, too, are the homologies of most Y genes with partners on the X from which they diverged. Even genes that we know have male-specific functions, such as the sex-determining gene SRY and several genes required to make sperm, have partners on the X from which they obviously evolved.
So what happened to differentiate the X and Y chromosomes? The X chromosome is seen to have diverged rather little from the original autosome from which it evolved. It is highly conserved in all placental mammals, and is present as two autosomal blocks even in the chicken genome. Genes on the long arm of the human X comprise the short arm of chicken chromosome 4, and genes that lie on the short arm of the human X reside, in much the same order, on chicken chromosome 1. Remarkably, the human X is an autosome also in the platypus, which has a complex multiple XY system that has homology, not to those of other mammals, but to the ZW sex chromosome pair of birds. The homology of the human X to autosomes in the platypus, which diverged only 166 million year ago from the therian mammal lineage, shows that its evolution into sex chromosomes was relatively recent.
In contrast, the Y chromosome has evidently changed rapidly in mammalian evolution (Fig. 1). Its unique structure, the paucity of genes on it and the high content of repetitive elements all testify to a rapid loss of active genes and accumulation of repetitive sequence. This occurred independently in different lineages, giving rise to the observed variability. This loss is thought to have been driven by the acquisition of a novel male-determining gene (SRY?), followed by acquisition of male advantage genes (eg spermatogenesis genes) nearby; recombination was suppressed to keep together the male-specific package of genes, and the absence of recombination with the X promoted accumulation of mutations and deletions because of drift and inefficient selection [10].
Fig. 1
Evolution of the X and Y chromosome from an original autosome. The X chromosome has stayed more-or-less intact, while the Y has degenerated progressively.
Marsupials reveal that the human X is made up of two evolutionary blocks that were fused together rather recently [11]. The marsupial X chromosome is about 2/3 the size of the X of placental mammals and the Y is tiny. Comparative gene mapping (Fig. 2) shows that the marsupial X is equivalent to the long arm and centromeric region of the human X, the same genomic region that is represented by chicken chromosome 4 p. The short arm of the human X (represented by a region of chicken chromosome 1q) is homologous to part of the kangaroo chromosome 5. This implies that the original mammal XY chromosome pair was smaller, and a large region of an autosome was added to it early in eutherian evolution, after divergence of marsupials, but before the divergence of Afrotheria 105 million year ago.
Fig. 2
Comparative mapping of genes on the human X in distantly related mammals, and other vertebrates. Blue denotes the X conserved region shared by the X chromosomes of marsupials and placental mammals, and green the recently added region that is autosomal in marsupials. The blue and green regions represent two evolutionary blocks of the genome that are highly conserved in all vertebrates. However, they are both autosomal in the chicken, and also the platypus, dating the evolution of our X and Y at 166 million year ago. The human Y chromosome, too, is made up from the same two evolutionary blocks, but there is almost nothing left of the original (blue) Y chromosome.
The hypothesis that the X and Y chromosomes differentiated from an ancient autosome pair as the Y degenerated predicts that the gene content of the X has not changed since it was an autosome. This is not quite true; the X has a strongly biased gene content that reflects its evolution.
4. The gene content of the X chromosome
In contrast to the Y chromosome, which specializes in male sex and fertility, the X chromosome contains genes with a wide range of functions, such as blood clotting factors, visual pigments and housekeeping enzymes. However, even as early as the 1980s, the large number of X-linked mental retardation conditions that manifested in boys suggested that the X chromosome contained a disproportionate number of genes involved in brain development and function (reviewed [12]). There was also the suspicion that the X chromosome is disproportionately rich in genes whose products are required for – usually male – gonadogenesis and fertility. Interestingly, these are often the same genes, as shown by the numerous mental retardation syndromes accompanied by sex reversal (eg ATRX syndrome) or gonad abnormalities (eg fragile X).
Now we have a complete readout of the human genome, both these suspicions have been confirmed. There are at least five times too many genes on the X that are expressed in the brain, and at least three times sex and reproduction related genes. And, indeed, there is a class of genes that is expressed in the brain and the testis (e.g. ATRX, FMR1) that do both. Why?
It is easy to see why genes retained on the shrinking Y chromosome would be selected for a male-specific function; there is not much option because this chromosome is limited to males. But it is not so obvious why the X chromosome should be similarly biased, since this chromosome is present in XY males as well as XX females. However, as long ago as the 1930s, it was proposed that the X chromosome should accumulate male advantage genes [13]. This is because a new recessive allele which confers some advantage to the male carrying it (e.g. bigger, faster, more sperm) is exposed on the single X and will be immediately selected in XY males. Even if it is deleterious to females (as “sexually antagonistic” genes often are), this effect will not be felt until the allele is sufficiently frequent to produce female homozygotes. By this stage, there is strong selection to restrict expression of the gene to the testis, to mitigate disadvantage to females.
The X chromosome is generally thought to be conservative, and to change more slowly in evolution than the Y or the autosomes. There are two reasons for this; firstly the single copy of the X is present in the testis and sperm less frequently than the Y or the autosomes, so it is less frequently exposed to male-biased mutation [14]. Secondly, the X chromosome appears to have been sacrosanct from rearrangements that would be selected against if they disrupted the whole X chromosome inactivation system. However, there are classes of genes on the X that have evolved very rapidly, including microRNAs [15] and a histone that is involved in spermiogenesis [16]. Strong selection for male advantage genes on the X seems also to have selected for amplification of “cancer-testis antigens” coded for genes that are required for fertility [17]. This has altered the structure of the X chromosome, which contains arrays of so-called “testis-cancer antigen” genes that lie in large palindromic loops.
Can this explanation work also for the accumulation of “intelligence genes”, mutations in which cause mental retardation? The most convincing explanation for the accumulation of intelligence genes on the X is that, over the last few million years of hominid evolution, females have selected smart males to mate with. This could have been either because smarter males are better breadwinners (or meat-winners), or because their bigger brain is viewed as an expensive ornament that, like the peacock's tail, is a badge of good genes. This “sexual selection” can be extremely rapid, and would explain why the brain underwent such amazing expansion in early hominids.
Genes that are expressed in brain and testis are hard to explain by the hypothesis that they carry out similar functions in the two tissues, since they are not obviously connected by ontogeny or function. I have suggested that their expression in brain and testis function is the result, not of function, but of evolution. The starting material is a large ancestral gene that codes for a multifunctional protein, which becomes subject, independently, to both direct selection for a trait that improves fertility, as well as sexual selection for intelligence [4].
Thus the X chromosome, as well as the Y, has a very atypical structure and a gene content strongly biased in functions.
5. X chromosome inactivation
A consequence of the differentiation of the X and Y chromosomes is that most of the 1300 + genes on the X have lost their partners on the degenerating Y. They are therefore subject to 2:1 dosage differences between the female and male. This may not matter much for genes that code for housekeeping enzymes like HPRT or blood clotting factor F9, which are subject to controls at many levels – after all, women who are carriers for HPRT- or F9-deficiency (so have only one functional gene copy) are normal. However, there are many genes for which haploinsufficiency is disastrous. Loss of a copy of even the smallest autosome is incompatible with life, and even an extra copy (e.g. trisomy for chromosomes 23 or 15) causes profound phenotypic abnormalities. Dosage compensation would therefore seem to be essential, and indeed, most animals with differentiated sex chromosomes subscribe to one or another method of compensating for the dosage difference between males and females.
The mammal X chromosome has a unique system, in which one X chromosome in the somatic cells of females is inactivated early in embryogenesis, and stays stably repressed throughout many subsequent cell divisions [18]. Transcriptional repression [19] is accomplished by epigenetic changes to the chromatin, including DNA methylation and histone modification (reviewed [20]). In humans and other placental mammals these are orchestrated by a controlling gene called XIST [21], which produces a non-coding RNA that binds to the inactive X and sets off a chain of structural changes that result in transcriptional repression. This extraordinary system is the paramount model for investigations of epigenetic silencing.
In placental mammals, inactivation is random. The X chromosome derived from the mother or from the father is inactivated in a progenitor cell, and stably repressed in all cell progeny. Random inactivation produces a mosaic of two populations of cells that express genes on either one or the other X, which can be demonstrated by cloning. For instance, women heterozygous for a deficiency of HPRT have cell populations that express the gene or are deficient [19]. The final phenotype is normal because the cells that can make enzyme can supply the whole body. The same process in cats produces the tortoiseshell, in which different coat colour alleles on the maternal and paternal X are expressed in spots and stripes that reflect the movement of clones of skin cells.
More recently, X chromosome inactivation in humans has been shown to be incomplete, for some 150 loci escape inactivation and are expressed from both X chromosomes [22], [23]. Unexpectedly, polymorphism for inactivation is detected at some of these loci; in some women, only one allele is active, whereas in other women, both are active. It is notable that most of the genes that escape inactivation are located on the short arm of the human X, in the region that was added to the X and Y chromosomes relatively recently. It is therefore proposed that escaper genes have not yet been fully recruited into the chromosome-wide X chromosome inactivation system.
Curiously, marsupial mammals, although they subscribe to X inactivation, always inactivate the paternal X (reviewed [24]), and also show tissue-specific and incomplete inactivation of the X. This inactivation is different from random inactivation in placental mammals at the molecular as well as the phenotypic level, occurring in the absence of XIST (reviewed [25]), and showing no signs of DNA methylation or some of the histone modifications [26].
Mosaicism for paternal and maternal X inactivation has many medical consequences (see detailed review in [23]). One of these may be to moderate maternal-fetal incompatibility by suppressing paternal antigens in the placenta of pregnant females.
6. Male genes in a pregnant female
Sex chromosomes pose some special problems for pregnancy. The general problem faced by the placenta is how to mediate between the blood circulation of the mother, and the circulation of the fetus she carries, when at least half the genes are from her mate, and therefore could act as foreign antigens and provoke immune rejection. The special problems are posed by genes that are male-specific; either coming from the Y in a male fetus, or from the paternal X in a female fetus (Fig. 3).
Fig. 3
The expression of male-derived genes (blue) from the sex chromosomes in the placenta in mouse (top) and human (bottom). Placentas are represented as small ovals within pregnant mouse and human females (pink). Genes from the Y chromosome (left) are represented by blue patterns that are different in the two species (representing the products of different HY antigens in mouse and human). The paternally derived X chromosome (right) is inactivated in the extraembryonic membranes of the mouse, so the placenta expresses only the maternal X (pink), but in human the maternally and paternally derived X chromosomes are randomly inactivated or co-expressed in the placenta (pink and blue pattern).
The 27 male-specific genes on the human Y could pose a particular challenge. Although the female genome contains X-borne copies of many of these genes, the Y copies have diverged so extensively that there are major differences in the proteins that they encode, so the maternal immune system should detect major differences from “self”. This problem is not as bad as one might think, because many genes on the Y chromosome (and most genes on the mouse Y) are specific to the testis and not expressed in fetal blood or other tissues in touch with the maternal circulation. However, there are several genes on the Y that are widely expressed, and would be expected to act as histocompatibility antigens.
There is much evidence that there are, indeed, male-specific peptides that act as minor histocompatibility antigens. These HY antigens have a long and colourful history (reviewed [27]). First detected in the 1970s by immunizing female mice with cells from isogeneic males, the “HYA locus” was initially claimed to be the sex-determining gene, which was known to be located on the Y chromosome. Furthermore, it was claimed that the mouse reagent cross-reacted with male cells from a wide variety of animals, including birds and snakes. The claim that HYA was the testis-determining factor was disproved when it was shown that males were determined normally in a strain of mice with a deleted Y chromosome that lacked HYA (reviewed [28]).
The search for the HYA locus resumed (albeit at a slower pace), but it was not until other genes on the human and mouse Y chromosome were identified that it was realised that “HY antigen” was a mixture of epitopes encoded by different widely expressed Y genes. Several Y genes have been identified that contribute to the human version of HY antigen; SMCY, UTY, DBY, DFFRY, EIF1AY, DDX3Y and RPS4Y (e.g. [29], [30], [31], [32]). These genes are not necessarily the same in mouse and human, since the gene contents of their Y chromosomes differ considerably. For instance, the RPS4 gene is present on the human, but not the mouse Y, whereas Ube1y is on the mouse, but not the human Y. There can be no correspondence at all between the HY antigen in mouse or other mammals and the sex-specific products in other vertebrates that do not share the same sex chromosomes.
Although these peptide epitopes are classed as minor, they have very measurable effects on the success of transplantation (e.g. [33], [34]; reviewed [35]). For instance, donor kidneys from males have a 12% higher rate of rejection in female hosts than do kidneys from female donors. These epitopes also evidently have an effect on the outcome of pregnancy, with the failure of pregnancy after miscarriages being much higher after a firstborn male [36]. However, it is clear that a pregnant female will tolerate a male fetus much better than a male skin graft, suggesting some kind of immune tolerance, whose mechanism is still poorly understood [37].
Allelic differences between the maternal and paternal genomes are less likely to cause drastic immune reactions than are male-specific genes. Nevertheless, it would be expected that some different peptides the mother is exposed to will be recognised as foreign. Hence it was of great interest to discover that X chromosome inactivation, while random in the embryonic tissues of female rodents, was paternal in the extraembryonic membranes (reviewed [38], [39]). This paternal X inactivation is somewhat different at the molecular level [40], [41], showing many similarities with paternal inactivation in marsupials such as independence of XIST and absence of differential DNA methylation [42], [43]. Indirect evidence for paternal X inactivation has also been observed in bovine chorion [44]. Such paternally imprinted inactivation would shield the mother from exposure to alleles on the paternal X chromosome, which represents some 5% of the genome.
However, whether the paternal X is preferentially inactivated in the human placenta has been very controversial. Although early observations were interpreted as paternal inactivation [45], [46], others observed randomness [47], [48], [49]. Migeon et al. [23], [50] have shown that at least some loci are actually 2X active in human chorionic villi, and Cotton et al. [51] reported inactive X-specific loss of methylation in the placenta.
What can we make of these species differences? The occurrence of paternally imprinted X inactivation in the extraembryonic membranes of rodents and cattle, as well as marsupials, suggests that paternal inactivation was the original mechanism by which one X was inactivated. Random inactivation of the later differentiating embryonic lineages is therefore seen as an evolutionary innovation that confers mosaicism, a kind of quasi heterozygosity. Why, then, have humans embraced random inactivation of the extraembryonic membranes as well as the embryo? Perhaps this is simply because the trophectoderm differentiates later in humans [23], and reflects, rather than a different selective regime, a mere side-effect of evolution for other characters.
There is mounting evidence that the sex of the embryo-derived tissues of the placenta is significant in determining fetal size and nutrition, morbidity and survival. Differences in the expression of genes in several pathways (eg insulin-like growth factor, cortisol) have been observed that alter the outcome of several insults to the pregnancy [52]. Some of these genes are imprinted, such that they are expressed only if they come from the father (eg IGF2) or the mother (eg IGF2R), but others may lie in pathways mediated by genes on the sex chromosomes.
7. Conclusions
The human X and Y chromosomes are unique in the genome in that they are represented differently in XY males and XX females. This difference in representation has led to the evolution of sexually antagonistic genes and endowed both chromosomes with atypical gene content and special mechanisms to control their activity. The presence of male-specific genes on the Y chromosome sets up the possibility for maternal-fetal incompatibility, and there is evidence that several Y genes contribute epitopes to HY antigens that affect pregnancy outcomes as well as the success of tissue transplantation between male donors and female recipients. The inactivation of the paternal X in the extraembryonic membranes of female embryos would provide an opportunity to minimise the exposure of the pregnant female to paternal antigens. However, such imprinted inactivation, although observed in mouse and cattle embryos, seems not to occur in humans, and it appears that alleles derived from the father are expressed randomly, or even biallelically.
Given the biased and sexually antagonistic functions of many genes on the X and Y chromosomes, it is not surprising that the expression of genes on the sex chromosomes in the placenta could have a disproportionate effect on the outcomes of pregnancy.
Conflict of interest
The authors do not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in this paper.
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PII: S0143-4004(10)00007-X
doi:10.1016/j.placenta.2009.12.029
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