The structure of the human Y chromosome features are shown approximately to scale. The black regions at each end of the Y chromosome are the pseudoautosomal regions, which cross over with homologous sequences on the X chromosome. The gray regions are heterochromatin. The white region contains the 23 megabase portion of the Y chromosome sequenced by Skaletsky et al. The first complete sequence of a 23 megabase Mb euchromatic non-heterochromatic portion of a human Y chromosome, from a single male, has recently been published by David Page's group [ 7 ].
This is a considerable achievement, given the difficulties of sequencing chromosomes that are rich in repeats, as is the case even for the euchromatin of the human Y. The researchers exploited the fact that a single Y chromosome provided the material for sequencing: this allowed them to attribute slight sequence differences between similar tracts of DNA to within-chromosome rather than between-individual variation, and hence facilitated the identification of repeats.
The results provide a uniquely detailed picture of the organization of a Y chromosome - not yet available for other species - which confirms many previous findings but modifies others.
The sequenced region is nearly the entire portion of the euchromatic Y chromosome that does not cross over with the X, together with some of the repeat-rich heterochromatic part of the Y chromosome. Skaletsky et al. We now have a list of putative transcription units within the MSY that is considerably larger in number than was previously thought, but this is still a small fraction of the number of the 1, or so on the Mb of the X chromosome [ 6 ].
Many of the ones on the Y probably do not code for proteins. The identifiable coding sequences among the predicted genes on the Y chromosome can be divided into two categories. The first comprises 27 genes with clear signs of homology to genes on the X chromosome, betraying the common origin of these two chromosomes; 13 of these have degenerated into pseudogenes.
The remaining 14 active Y-linked genes within this category tend to have a broad range of expression in many different tissues, with the notable exception of the male-determining gene, Sry , which is expressed early in development in the germ cells of males, and has an X-linked counterpart, Sox3.
There is considerable variation among these 14 genes in the extent of their silent-site sequence divergence K s [ 8 ] between the copies on the X and Y chromosomes, although it is not clear that they can be sharply divided into four 'evolutionary strata', representing discrete phases in the differentiation of the X and Y chromosomes, as was previously proposed for a subset of these genes [ 9 ].
There are two possible explanations for the range of differences in divergence: one is that the more highly diverged genes have been isolated from recombination with the X chromosome for longer than the less highly diverged genes; and the other is that there are different rates of genetic exchange via gene conversion between X and Y for different genes.
The first hypothesis is consistent with the fact that genes with different K s values tend to cluster together on the X chromosome in contiguous blocks, with K s values increasing from the distal short arm to the distal long arm of the X. The order of these genes differs greatly between X and Y chromosomes, suggesting that there have been rearrangements involving chromosomal inversions that would have helped to suppress crossing-over between the evolving X and Y chromosomes.
The evolutionary advantages to such suppression of crossing-over have long been discussed [ 1 , 3 , 10 ]. Sry and Sox3 have the highest K s value, as would be predicted from such evolutionary considerations for descendants of a gene that must have been involved in early stages of the evolution of the Y chromosome, equivalent to a time of isolation of over million years ago. The second hypothesis - that different genes have different rates of genetic exchange between X and Y - is supported by the fact that gene conversion between genes on the X and Y chromosomes has been detected in the cat family [ 11 ], and seems also to be occurring at a high rate within the human Y chromosome discussed below , but this does not explain the ordering of K s values along the X chromosome and the very ancient origin of several Y chromosome genes.
The second category of Y-linked genes consists of nine gene families that mostly have no resemblance to genes on the X chromosome. These are organized into repeats of two or more units, and show testis-specific expression. They seem to comprise genes whose functions are important for males but possibly deleterious for females; seven out of the nine have originated by transposition from an autosome, and two come from the X chromosome. Genet Mol Res. The human Y chromosome: a masculine chromosome.
Curr Opin Genet Dev. Epub May 2. Am J Med Sci. Genetic variants of Y chromosome are associated with a protective lipid profile in black men. Arterioscler Thromb Vasc Biol. Epub May The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. A new look at XXYY syndrome: medical and psychological features.
Am J Med Genet A. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. Birth Defects Orig Artic Ser. Semin Cell Dev Biol. Epub Feb Tales of the Y chromosome. Citation on PubMed. Mosaic LOY disrupts such balances and predisposes men to pathogenesis, resulting in sex differences in the various diseases. Studies on individual Y chromosome genes have provided information suggesting that they could exert positive actions on the pathogeneses of various human diseases, including cancers and neurodevelopmental diseases, thereby preferentially affecting males [ 6 , 20 ].
Studies on the spontaneously hypertensive rat SHR indicated that the rat Sry up regulates genes in the renin-angiotensin system, resulting in higher blood pressure in the male SHRs [ 22 ]. The human SRY could upregulate the monoamine oxidase A MAOA gene, whose expression levels are associated with various neurological and psychological disorders [ 23 ].
Further, aberrant expression of SRY could compete against the proper functions of a family of related transcription factors, encoded by the SRY-box SOX genes, which play critical roles in numerous developmental, physiological and pathogenic processes [ 24 , 25 , 26 ]. Importantly, aberrant activation of a human SRY transgene during embryogenesis in transgenic mice impairs the normal development of various vital organs, resulting in postnatal growth retardation and lethality [ 27 ].
Hence, these studies suggest that aberrant activation of Y chromosome genes, in this case SRY , could disrupt normal development and exacerbate the disease processes, thereby contributing to sex differences in a positive manner s. These findings are in contrast to those of mLOY studies, in which loss of genes on the Y chromosome potentiates the disease processes [ 13 , 15 , 18 , 19 ]. To understand the roles of the Y chromosome in human health and diseases, it is crucial to discuss a few basic aspects of the genetics and biological functions of the genes on this male-specific chromosome.
In humans, men and women are genetically identical with 22 pairs of autosomes, except their sex chromosomes, i. X and Y chromosome. Men possess XY while women possess XX sex chromosome constitution. The gene dosage differences for the X chromosome is compensated by inactivation of the genes, with specific exceptions, on one of the X chromosomes during early development in females [ 28 , 29 , 30 ]. The mammalian X and Y chromosome originated from a pair of autosomes. One of them had acquired a male sex-determining gene, i.
SRY , postulated to occur over million years ago, and became the Y chromosome while the other homologue maintained the genetic content and structure of the ancestral chromosome and evolved to be the X chromosome [ 31 ]. The human Y chromosome is Cytogenetically, the heterochromatic long arm is highly variable, mostly involving either amplification or deletion of the heterochromatin and possibly the PAR2 at the telomere of the long arm [ 33 , 34 ].
There is an obligatory crossover s between the X and Y chromosomes at their PARs during male meiosis [ 36 ], and hence genes on PARs behave similarly as those of the autosomes.
Interestingly, there are 5 receptor genes, i. Initial sequencing results suggested that there are 78 protein-coding genes on the MSY, corresponding to 27 distinct proteins [ 10 ]. This number varies due to microdeletions and copy number variations CNV of ampliconic genes among the general population [ 37 ]. There are 22 MSY genes, of which 17 are evolutionarily conserved with corresponding X homologues, widely expressed Additional file 1 : Figure S1B-C and postulated to serve dosage-sensitive regulatory functions in chromatin modification, transcription, translation, RNA splicing and protein stability [ 9 , 10 ], which likely exert global effects on gene expression and modification of protein functions.
They are primarily expressed in the testis and serve vital functions in the differentiation and physiology of this male-specific organ [ 38 , 39 , 40 ]. Further, the respective encoded proteins could possess structural divergence s , suggesting that they might serve different functions in various biological systems [ 24 , 25 , 41 ]. They represent a pair of homologues on the sex chromosomes, which could oppose each other in various biological processes [ 41 ].
TSPY is specifically expressed in the testis Additional file 1 : Figure S1E and could serve important functions in spermatogonia stem cell renewal and male meiosis [ 46 ]. It is located on and is the putative gene for the gonadoblastoma locus on the Y chromosome GBY [ 47 , 48 ]. It is frequently and aberrantly activated in various cancers, including gonadoblastoma, testicular germ cell tumors, melanoma, liver, head and neck and prostate cancers and promotes cell proliferation [ 48 , 49 ].
Importantly, TSPY is an androgen-responsive gene, and hence TSPY and AR form a positive feedback loop in amplifying their respective biological functions in male-specific manners [ 41 ]. It retards cell proliferation and suppresses AR transactivation activities [ 45 ]. This peculiar situation raises some very interesting scenarios on the roles of the X—Y homologues in cancers. If under certain conditions, TSPX escapes X-inactivation, it could increase the tumor suppression functions in females [ 29 , 50 ].
Collectively, such aberrations could disproportionally exacerbate cancer initiation and progression in males. Since the Y chromosome includes the pseudoautosomal and male-specific regions, the loss of the PAR genes and those on MSY with dosage-sensitive functions could result in gene dosage deficiency in various biological systems. On the other hand, the testis-specific MSY genes are important for male-specific functions, and their loss might be less critical in such mLOY-mediated disease predispositions, except those associated with reproductive tissues.
Understanding the biology and genetics of individual genes on the Y chromosome could provide some clues on which genes are likely to be important for the maintenance of homeostasis and their losses or aberrant activations could contribute to disease predisposition in men.
The laboratory mouse has been widely used as experimental models for human diseases using transgenic means [ 53 , 54 ], including male and female animals with different sex chromosome constitutions [ 55 , 56 ]. Beside sex determination, the genetic contents of the human and mouse Y chromosome are quite distinct [ 10 , 57 ]. Asmt , Sts pseudogene and Mid1. Other orthologues of the human Y chromosome genes are located on either the X chromosome or autosomes of the mouse.
Significantly, only two MSY genes, i. Sry the sex-determining gene and Eif2s3y absent on the human Y chromosome , are sufficient to generate male mice with spermatogenesis [ 58 ]. Further, these two MSY genes could be replaced by the activation of Sox9 the Sry downstream gene [ 26 ] and Eif2s3x the X-homologue of Eif2s3y to produce similarly functional male mice without a Y chromosome [ 59 ].
Although transgenic mouse studies have provided critical information on the functional aspects on some of those conserved MSY genes [ 54 , 58 , 59 , 60 , 61 ], studies on the other MSY genes of the human Y chromosome with the laboratory mouse might require some retrofitting of the mouse Y chromosome. In particular, the mouse Tspy is a recently evolved pseudogene, harboring numerous in-frame mutations disrupting its open reading frame.
Since TSPY is tandemly repeated 30—60 times on the human Y chromosome [ 40 ], such tandem integration of the human transgene on the mouse Y chromosome resembles the organization of the human endogenous gene. Characterization of animals from this transgenic line showed that the human TSPY transgene is expressed in similar patterns as those of the human endogenous gene, including normal expression in spermatogonia and spermatocytes in the testis [ 62 ] and aberrant activation during oncogenesis [ 63 ].
Accordingly, with the recent advances of genome editing and transgenic technologies [ 64 , 65 , 66 , 67 ], targeting the integration of human MSY gene s onto the mouse Y chromosome could be viable strategies to model and study their functions in biological processes, involved in various aspects of development, physiology and disease pathogeneses.
Regitz-Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev. Author information Copyright and License information Disclaimer.
Corresponding author. This article has been cited by other articles in PMC. Open in a separate window. Figure 1. Anti-Turner syndrome effect Turner syndrome is characterised by a female 45 X karyotype or monosomy X. Genes controlling spermatogenesis Tiepolo and Zuffardi [ 4 ] reported the occurrence of grossly cytogenetically detectable de novo deletions in six azoospermic individuals, describing for the first time the role of the Y chromosome in spermatogenesis.
Oncogenic role of the Y chromosome The implication of the Y chromosome in cancer remains still speculative. References Polani PE. Experiments on chiasmata and nondisjunction in mice.
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