The origins and history of human Y chromosome

Figure 1: The 23 pairs of chromosomes in the human genome

The human Y chromosome is fascinating not only for it harbors the major control gene that defines gender but also for the reason that of its rare evolutionary history (Soukup, pp 1967). The Y chromosome, therefore, evolved from an autosome, and its evolution has been regarded by enormous gene decay. In the human genome, there exist 23 pairs of chromosomes. In the 23 pair chromosomes, one pair of them is sexual chromosomes, which are also named allosomes, and the rest are called autosomes. Just as the names apply, a sexual chromosome can determine the human gender. The combination of allosomes is XY in male humans and is XX in female humans. However, when life initially appeared on earth, there was no sexual chromosome. At that time, sex determination all depended on the environment rather than genes. For instance, the sex development of reptiles such as snakes and turtles is reliable on the temperature of incubation.

Over different lineages, from one of the pairs of autosomes, the X and Y chromosomes are descended and, therefore, evolved many times. The X and Y chromosomes started to differentiate at least 180 million years ago with the acquisition of a testis-determining gene (TDF) to be proto X and Y chromosomes, which essentially is referred to us as the sex-determining region Y (SRY) (Hughes, 2012). Recombination between the X and Y chromosomes was subsequently a large input on the Y chromosome in creating more than four evolutionary strata, including the divergence of marsupials, rodents, new world monkeys, and old-world monkeys as shown in figure 2. Going through these evolutionary processes, this combination was largely suppressed (Ross, 2005). X and Y chromosomes are highly differentiated in modern human beings. Altogether, its length is around 156 Mb containing around 1100 genes and equals 5% length of X chromosome in the of human. [AY1] Although they look quite different, they share two small regions of homology termed pseudoautosomal regions (PARs), which are entirely located at the two ends of both the X and Y chromosome. The one named short-arm pseudoautosomal region (PAR1) (Skalctsky, 2003) ensures an obligatory recombination event to mediate the X and Y segregation that happens during the male meiosis. The other one is referred to as the long-arm pseudoautosomal region (PAR2), which no longer undergoes meiotic recombination. The rest part of the Y chromosome is known to be male-specific region (MSY), much of which consists of simple-sequence respective DNA, and it does not engage in regular meiotic recombination. In the deficiency of meiotic recombination, the Y chromosome is subject to evolutionary decay resulting in gene loss and deletion. Because of this, MSY has been substantially shrunken (Rice, 1996). The length of present-day MSY is just about 23 Mb, which is only 3% genes on the ancestral sexual chromosome survived.

Figure 2: The evolution of the human Y chromosomes. The left side represents the evolution of human X chromosome; the right side represents the differentiation and degeneration of the Y chromosome. The top is the pair of ancestral autosomes, from which the human X and Y chromosomes descended; the bottom is the completely differentiated X and Y chromosome in modern humans. The short-arm pseudoautosomal region (PAR1) is marked by dark green,and the long-arm pseudoautomal region (PAR2) is marked by light green. The light gray part in male-specific region in Y chromosome (MSY) represents the region differentiated from the X chromosome. The dark gray part in MSY is the major heterochromatic region. Arrows indicate evolutionary strata from inversion events. X-added region (XAR) represents the chromosomal part which was inverted to pseudoautosomal region in an ancestral eutherian. Abbreviation: Mya: Million years ago. [adapted image]8

1.3 The molecular structure of human Y chromosome

The Y chromosome is known well for the role of male sex determination and it was regarded as wastelands and imminent (Charlesworth, 2000). However, the enormous degeneration in term of loss of genes over evolutionary time was not only one reason that Y chromosome was considered generic wastelands. Additionally, the lack of recombination of Y chromosome makes classical linkage-mapping studied intractable and the highly repetitive sequence in MSY has disqualified them from the record of the genome sequencing projects (Aitken, 2002). These two issues both truly hindered genomic studies for the Y chromosome in humans. Investigation on the Y chromosome started in 1980s but most probably until the year 2003, the complete human Y-chromosome sequences has been revealed and fully overturned the long period “wastelands” view (Graves, 2004).

Human Y chromosome is composed of five characteristic classes of sequence. These classes are termed as pseudoautosomal, X-transported, X-generated, heterochromatic and ampiconic regions. Declarations have been made and only human’s Y chromosome harbors two PARs. During meiosis, genetic exchanges only happen in the PAR located in the short arm of Y chromosome (Yp). The second PAR located in the long arm of Y chromosome (Yq) is derived from recent inversion event (Hammer, 1995). Expect to two PARs, the remainder is generally termed MSY, which has no partner to pair in meiosis and thus it transmitted uniquely in male germ line. Therefore, MSY analysis takes a significant role in understanding of population histories and revealing human migration patterns. Heterochromatin is a heterochromatic large-scale block that has not been sequenced on the Yq, which is around 40Mb in length. The other regions constitute the euchromatin part of human MSY. The X-transposed region is 3.44 Mb in length and solely exist in human, which was transposed from X chromosome. Within X-transposed segment, only two genes functioned as protein encoder including TGIF2LY and PCDHIIY has been identified (Shamsi, 2011). As for X-degenerate region, it is originated but largely deteriorated from where the Y chromosome was formed by the ancestral autosome. The X degenerated region has 8.5 Mb combined length with 16 single-copy genes dotted, where most of these genes are expressed ubiquitously and have housekeeping function. For instance, the SRY determining gene, which is probably the key factor that activate male sexual differentiation located in the region of the X-degenerate. The ampiconic region in the euchromatin is the most complex region in the human Y chromosome that has a 10.5 Mb combined length. Being different with X-transposed and X-degenerate regions, the ampliconic region contains highly identical sequences which have substantial genes and special functions. The human ampliconic region contains approximately 60 genes that belong to different nine gene families, most of which are arranged in palindrome structures. In addition, human ampliconic region is significantly tend to have large scale sequence deletions, inversions and duplication, some of which can result in severe issues such as infertility of men in clinic. The 60 genes are repeated in a palindromic or inverted way, and the repeat copies are extremely identical (>99.9%) to each other. Thanks to the repetitive characteristics of ampliconic region, it might make a vital contribution to avert the disintegration of the genes located on this region.

Figure 3: The five main sequence classes and genes located on the human Y chromosome (a). The composition of the Y human chromosome (b). MSY shows with some more comprehensive gene locations but excludes the Yq. The repeated sequence copies are displayed as a pair of dark blur triangles identical sequence are shown by the adjacent and opposite facing triangles [adapted image]8

Chapter 2. The mutations and diversity on the human Y-chromosome

2.1 Significant genes on the human Y chromosome

On the Y chromosome, SRY is the known best gene, since it is the master factor of the differentiation of testis. The location of gene SRY was revealed by genomic deletion and translocation analysis. The XY chromosomes in females resulted from the deletion of the short distal arm of the Y chromosome (Vogt, 1996)[AY2] . XY gonadal dysgenesis is referred as the phenotype that embryonic gonads can develop into neither testes nor ovaries, which resulted from the loss of gene SRY or point mutation of the SRY gene. WDR5 has been discovered to be a direct target of SRY, through binding to WDR5’s promoter. SPY starts up the expression of WDR5. Subsequently, WDR5 acts as a co-worker to initiate the expression of SOX9, which is responsible for Sertoli cell formation, and to repress the expression of b-catenin, which plays an essential role in ovaries growth and development (Ferlin, 2003)[AY3] . SOX9 is necessary and sufficient for the activation and preservation of one enzyme named prostaglandin D synthase. Prostaglandin D synthase enzyme turns prostaglandin H2 into prostaglandin D2, which then enhances the formation and secretion of the masculine. In addition, SRY also has been found to be articulated in the brain system. SRY regulates the expression of monoamine oxidase A in the brain. Moreover, it activates the catalytic activities of MAO A by binding the MAO A-promoter. MAO A can catalyze the oxidation of monoamine neurotransmitters, including serotonin, norepinephrine, and dopamine (Tse, 2003)[AY4] .

Another type of important genes on the human Y chromosome, which are termed as the azoospermia factor region (AZF), are associated with male germ cell improvement and preservation. The AZF is usually composed of approximately three non-overlapping regions, including the AZFa, AZFb, and AZFc. In the AZFa, there are two genes that are mainly located in it, and they include USP9Y and DDX3Y (Wong, 2002[AY5] ). USP9X expression only can be observed at the spermatid stage of the male germline, and deletion of this kind of gene will cause Sertoli-cell-only syndrome (SCOS), whose symptom is lacking germ cells in the theists’ seminiferous tubules. DDX3Y, reported as an RNA helicase, plays an important role in switching on translation, exporting mRNA from nuclear and mediating transcription (Stone J. F, 1995[AY6] ). Apart from that, DDX3Y has been conveyed to play a simple role in neural cell formation. Inhibition of DDX3Y would lead to the downregulation of CDK4, which is the key transitional factor for G1/S progression (Bishop, 2011[AY7] ). The downregulation of CDK4 can result in the arrest of the neural cell cycle during the G1 phase of mitosis. RBMY and PRY are two important genes located in the AZFb region. They work significantly during spermatogenesis. RBMY, as an RNA motifs recognition at N terminus, is responsible for mRNA transport from the nucleus in spermatogenesis. For PRY, it encodes a protein phosphate, which is indispensable to regulate apoptosis when there is nonfunctional spermatozoa needed to be eliminated. DAZ genes located AFZc, have been reported to significantly play a role in the development of sperm (Dada, 2012[AY8] ). Their expression can be observed at all stages of spermatogenesis from primordial germ cells to eventually sperms. On the other hand, the overexpression of DAZ will lead to the variation of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into primordial germ cells like cells (PGCLCs), and even further maturation of them. As another important gene located in AFZc, BPY2’s expression can also be in the processes of spermatogonia, spermatocytes, and spermatids (VanGompel, 2011[AY9] ). It has been deduced that BPY acts as a co-worker with ubiquitin-protein ligase E3A, which is responsible for preserving human sperm fertility.

Apart from these well-known genes and their functions on sex-specific gonad development, there are still a large number of genes in co-expression with their X counterparts acting in different organ development, including the nervous system as well as cardiac and kidney development. For example, NLGN4Y, as a Y-chromosome-specific gene, encodes a protein belonging to the neuroligin family and acting as a postsynaptic transmembrane communicator, which interrelates with neurexin. A mutation in this gene is possible to cause neurological disorders such as autism (Bottos, 2011[AY10] ). In conclusion, the Y chromosomes usually govern not only the male-specific features but also genes on the Y chromosome that can exhibit significant functions during organ development. Here, just a few examples about them can be shown in the table below.