Y Chromosome

		The human Y chromosome has now been sequenced and published in the June 19, 2003 issue of Nature (click for the Free Article by Skaletsky et al.). The article explains the evolution of the Y chromosome at genetic level. It also serves to illustrate the structure of a chromosome in general. The followings is an attempt to summarize the main features in the article.
Figure 01 Y Chromosome Structure [view large image]	Figure 02 Y Chromosome Evolution [view large image]

Y Chromosome Structure and Evolution:


• Cytogeneticists use stains to distinguish chromosomes. Dark-staining genetic material, called heterochromatin, is more highly coiled and has more repetitive DNA sequences than the lighter-staining euchromatin. Heterochromatin hugs the centromere and is present at the tips (telomeres). It is interspersed with euchromatin along the rest of the chromosome. The largest constriction is the centromere, which divides the medium size chromosome into a short arm (p) and a long arm (q). For short chromosome, the centromere locates near one end, while the long chromosome has an approximately centralized centromere. It is thought that heterochromatin only maintains the chromosome's structural integrity, all the genes are located in the euchromatin (see Figure 11-33 and Figure 01).
• Figure 01 shows that structure of the Y chromosome with each sub-structure represented by different colour. The short pseudoautosomal regions (~5%) are located at both ends. They are the only portions that are still identical to the corresponding regions of the X chromosome, reflecting the frequent exchange of DNA between these regions (crossover) that occurs during sperm production. Prioritization in the Human Genome Project had led to the sequencing for the heterochromatic regions of the Y and other chromosomes being set aside to be dealt with later, if ever.



The main interest is in the three euchromatic classes in the MSY (Male-Specific Region):


• The X-transposed region - The X-transposed sequences are 99% identical to DNA sequences in Xq21, a band in the midst of the long arm of the human X chromosome. The X-transposed sequences are so named because their presence in the human MSY is the result of a massive X to Y transposition that occurred about 3-4 million years ago, after the divergence of the human and chimpanzee lineages (see Figure 02, the pink area in the lower left). Within the X-transposed segments, which have a combined length of 3.4 Mb, only two genes have been identified (see Table 01). Thus the X-transposed sequences exhibit the lowest density of genes (see part "c" of Figure 01). The rest of this region are populated with repeat elements including Alu (transposons - jumping genes, each consisting of 300 bases), retroviral (deposited by virus via reverse transcription), and LINE1 (long interspersed nuclear element 1).
• The X-degenerate region - The X-degenerate segments of the MSY are dotted with single-copy gene or pseudogene (DNA sequence closely resembles to a coding gene but is not expressed). They display between 60% and 96% sequence identity to their X-linked homologues, and seem to be surviving relics of ancient autosomes (non-sex chromosomes) from which the X and Y chromosome co-evolved. Figure 02 shows the ancient origins of these genes (the yellow strips) as Group 1-4 objects of age at least 40 million years old. The sex-determining gene SRY was introduced into this region 300 million years ago. The SRY gene product is a type of protein called a transcription factor that controls other genes. It switches on the genes that direct the development of male structures in the embryo. When it is expressed, the gonads specialize as testes, which in turn secrete two types of hormones that begin to mold a male.
• The ampliconic region - The ampliconic sequences exhibit by far the highest density of genes (see part "c" of Figure 01). In contrast to the ubiquitous expression of most X-degenerate genes, the ampliconic genes and transcription units ( sequence of DNA transcribed to a single primary RNA transcript) show highly restricted expression (exclusively in testes). Ampliconic genes were derived through three converging processes: amplification of X-degenerate genes (RBMY, VCY); transposition and amplification of autosomal genes (DAZ from chromosome 3); and retroposition and amplification of autosomal genes (CDY). Each of these genes has been amplified, one of them (TSPY) has multiplied itself 35 times. It is suggested that since these genes never received maintenance through "crossover" ("recombination"), the integrity is maintained via swapping between these copies in a process called "gene conversion". However, this gene-fixing technique comes at a price. When the chromosome makes a mistake in the procedure, it can delete stretches of DNA. Such deletions, occurring in one in every couple thousand boys, are a recognized cause of male infertility.

Palindromes - It is a segment of DNA in which the nucleotide sequence in one strand read from one end is the same as the sequence in the complementary strand read from the opposite end. For example, the sequence GGTACC is a palindrome when the complementary strand is CCATGG. The male chromosome contains stretches of DNA in such identical mirror copies of each other. If one of these sections makes a hairpin bend in the middle, it appears capable of donating an intact gene to fix a defective copy on the neighboring section (see Figure 03). In essence, the Y seems to have its own self-repair mechanism, a process called gene conversion, maintaining the integrity of the genes without crossover.

Figure 03 Palindromes [view large image]

• Figure 02 is the evolutionary map of the MSY. At the bottom is the euchromatic region of the MSY as shown in Figure 01 (b). Coloured rectangles extending above this schematic depict the estimated male-specific ages of the corresponding segments of the modern MSY. These ages are plotted on the logarithmic scale (a). It is found that the difference in X-Y gene pairs occurred in a stepwise fashion along the length of the X chromosome, in four "evolutionary strata". This suggested that at least four events had punctuated human sex chromosome evolution. These processes are represented by the four Groups in (b). Column (c) indicates the chromosomes from which the X-transposed or ampliconic sequences apparently arose through transposition during evolution. Column (d) shows the MSY genes that apparently arose at the indicated times. Column (e) shows the approximate times of divergence between the human and certain other vertebrate lineages.
• Three regions in MSY called AZFa, b, and c, are recognized to be vital for sperm development. Deletions of any of these regions will cause spermatogenic failure. AZFa includes the USP9Y and DBY genes (see Table 11-02), while AZFb and AZFc occupy about 1/3 of the MSY toward the end of the long arm section.

Table 01 MSY Genes and Gene Families

The detailed sequence of the human X chromosome has been published in the Spring of 2005. Followings list some observations:


• In the X chromosome, an unusually large number of its genes are coded for proteins important to brain function. According to one analysis, there are 221 known human genetic defects that can cause mental impairment, some 10% of which reside on the X chromosome, even though it carries less than 4% of known human genes. This is reflected in a survey of the US Census (starting from 1890), which shows more boys than girls were mentally disabled. It is because a woman uses only one of her two X chromosomes in each cell, there is always a backup if one of the pair has a defective gene. But men have only one X, so any defective brain genes from that chromosome are invariably expressed.
• Since females have two Xs and males have one X and a Y; to make the gene dosage equivalent, females inactivate almost an entire chromosome. Early in female development, cells randomly choose either the maternal or paternal X to be the active X chromosome. The other one then transcribes large amounts of a large RNA (XIST) from a gene in the middle of the chromosome. The other genes are silenced by a coating of this XIST RNA. This choice is permanent, and has certain consequences such as the coat colours of calico cats. It is found that the mechanism is not perfect, about 15% of the genes permanently escape inactivation (with fewer chance for escaping in older genes), meaning that they are expressed at twice the level in females as males. The consequence is unknown, but the possibilities are intriguing.

The X chromosome is very rich in repeats (56% compared with a 45% average for the whole genome). About 29% of the chromosome consists of DNA repeats known as "long interspersed nuclear elements" (LINEs), thought to be selfish bits of DNA that jump around the genome. The main constituents are members of the L1 family, which may serve as booster elements for the X inactivation signal. It emanates from around the middle of the chromosome (the reddest spot in Figure 04) with the transcription of XIST and spreads down the chromosome arms.

Figure 04 X Inactiva- tion[view large image]

Comparison of the human X and Y chromosomes: The length of the Y chromosome is about 51 Mb about three times shorter than the 155 Mb for the X chromosome. The euchomatic part of the X chromosome is six times longer than that of Y. Few genes on the X have an active counterpart on the Y, and the majority of these are contained in regions where XY homology (similar structure) is of relatively recent origin. There are 12 large homologous blocks as shown in Figure 05. They are descended from material that was added to the established sex chromosomes (XAR and YAR - X/Y added region). Note that the blocks inverted on the Y chromosome relative to the X chromosome are assigned red, negative numbers. It is thought that the XAR originally formed a large pseudoautosomal region with an equivalent YAR, which is now largely eroded. At a gross level, the homology between the XAR and YAR is continuous for 6 Mb. Beyond this, the remaining 38.5 Mb of the XAR detects few other remnants of the YAR. The tip of the short arm of the X and Y chromosomes comprises the 2.7 Mb pseudoautosomal region PAR1. Homology between the X and Y

Figure 05 X Y Comparison[view large image]

chromosomes in PAR1 is maintained by an obligatory recombination in male meiosis; gene loci in this region are present in two copies in both males and females and are not subject to dosage compensation by XCI (X Chromosome inactivation).

• At the tip of the long arm of X and Y is a second pseudoautosomal region, the 330 kb PAR2, which was created by duplication of material from X to Y since the divergence of human and chimpanzee lineages about 6 million years ago. Some genes in PAR2 are subject to XCI, presumably reflecting their status on the X chromosome before the duplication event.
• Outside the PARs, homologies between the X and Y chromosomes are in non-recombining regions, predominantly in other parts of the XAR, together with a large XTR (X-transposed region). The XTR arose by duplication of material from X to Y since the divergence of the human and chimpanzee lineages. The duplicated region spans 3.91 Mb on X, but the corresponding region is only 3.38 Mb on the Y chromosome (Figure 05).
• Only 54 of the 1098 genes annotated on the X chromosome have functional homologues on the Y chromosome. Direct evidence is obtained for 24 genes in PAR1. Another five annotated genes reside in PAR2. Outside the XY-recombining regions of the X chromosome, there are 25 genes that have functional homologues on the Y chromosome. Fifteen of these are within the XAR, and a further three genes are shared by the X and Y copies of the XTR. The seven other XY gene pairs are believed to have descended from the proto-sex chromosomes. It is estimated that approximately 15 protein-coding genes on the Y chromosome have no detectable X chromosome homologue.