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In addition to the 100% homologous pseudoautosom al regions, the X and Y chrom osom es share several regions of lesser hom ology located outside the two PARs (Cooke et aL, 1984) (Figs 1.2 and 1.3). These X-Y hom ologous regions could be the result of duplications and translocations betw een the sex chromosomes that took place at different times in evolution, or they may be remnants of their ancient progenitors, the proto-X and proto- Y (Sargent et aL, 1996; Lahn and Page, 1999).

Information about the extent of X-Y hom ology em erged as the map of the Y chrom osom e was established. This process involved mapping deletions from patients with sex chrom osom e rearrangem ents (A ffara et aL,

1986, 1987; Vollrath et aL, 1992) and assembling Y AC contigs of cloned Y chrom osom e DNA (Foote et aL, 1992). This enabled the determ ination o f the order and organisation of the X-Y homologous sequences on the Y chrom osom e. These maps, together with maps of the hum an

pseudoautosom al regions (Brown, 1988; Kvaloy et aL, 1994), have indicated that of the 8 -10Mb where the X-Y chromosomes share sequence, only

around 3Mb correspond to the pseudoautosom al regions, whereas the rest com prise other regions of X-Y hom ology (Fig 1.3).

Com parative studies in different prim ate species give a view of the evolution of these X-Y homologous regions. These studies have

dem onstrated that some of the sequences within the hum an X-Y

hom ologous blocks are strictly X-linked in some prim ate species. This finding suggests that the origin of the hom ologous sequences is the result o f duplication and transfer of one copy from the X to the Y after the divergence of certain prim ate species (Lambson et aL, 1992). Other hum an X-Y regions appear to be X and Y -linked in some primates, and appear at similar

chrom osom al locations, although some have clearly been rearranged. For exam ple a single contiguous segment of hum an Xq21, is hom ologous to two

X 11.32 11.2 11.1 11.1 11.21 11.22 11.23 12

Yql2

RPS4Y ,ZFY PRKY AMELY ARSEP ARSDP DFFRY DRY UTY TB4Y KALP STSP V.XGPY 'SMCY EIFAIY 22.3 22.2 22.1 21.3 21.2 21.1 11.4 11.3 11.2 11.1 11 12 13 21.1 22.2 22.3 22.1 23 24 25 26 27 28 f"XG ARSD ARSE PRKX STS L K A L l AMELX ZFX DFFRX DBX E lF A l .UTX RPS4X TB4X

Figure 1.3 X-Y homologous genes and their locations; hatched sections indicate the X-Y homologous regions. For the rest, the key is the same as for Fig 1.1

non-contiguous segments on Yp. Com parative studies show that this alm ost certainly arose as a single transposition event of 4M b segm ent from the X to the Y chrom osom e associated with an inversion (Schwartz et al., 1998). This event occurred after the divergence of the hum an species from the chim panzees.

A num ber of genes have been identified w ithin the X-Y hom ologous regions (Fig 1.3, Table 1.2). These genes share sim ilar features with those located within the PARs (Table 1.1). They are usually found as single genes or small clusters including pseudogenes, they escape X -inactivation, and are ubiquitously expressed in many tissues. The degree of identity o f the X-Y hom ologues at the nucleotide level varies between 80-95% (Lahn and Page,

1999). These genes are widely distributed throughout the Y chrom osom e, however, their X-linked homologues are mainly concentrated tow ard the distal end of the short arm with the exception of RPS4X that maps to Xq (Fig 1.3) (Vogt et aL, 1997). The X-linked hom ologues of these genes are all functional, whereas in some cases their Y-linked hom ologues are

pseudogenes (Table 1.2). This loss of function has occurred presum ably as a result of continual rearrangem ents of the Y chrom osom e and accum ulation of m utations due to lack of extensive recom bination. In com pensation for the degradation of the Y-linked genes, their X -hom ologues have acquired increased levels of expression. It is predicted that these genes will becom e subject to X -inactivation in order to balance and restore normal expression levels in both males and females (Jegalian and Page, 1998).

Some of the X-linked copies of these genes have been associated with genetic disease in man. For example mutations in the A M ELX gene causes am elogenesis im perfecta a disorder of tooth enam el developm ent. A lthough the Y -linked copy of this gene encodes a functional protein, its level o f expression is only 10% of that of its X homologue. N evertheless, despite this low level of expression of the Y-linked gene, there are detectable

Table 1.2 Genes with X and Y homologues

Symbol Name of gene Comments X-Y homologues

locations

References

(for Y-linked homologues)

ZFY Zing-finger-Y Transcription factor with multiple zinc-finger motifs; X and Y copies

functional X p 2 2 .2 -p 2 1 .3 /Y p ll.3 autosomal homologue 9p22-9pter Page et al., 1987 Affara et al., 1989

AMELY amelogenin Development of tooth enamel; X and Y copies functional

Y p ll.2 /X p 2 2 .3 -p 2 2 .1 Lau et al., 1989 Salido et al., 1992 STSP Steroid sulfatase pseudogene Y-linked non-processed pseudogene

with functional X-linked copy

X p 2 2 .3 2 /Y q l 1.21 Yen et al., 1988

PRKY Protein kinase Y-linked protein kinase similar to catalytic subuni of cAM P dependent protein kinases; X and Y copies are functional; involved in

ectopic recombination leading to XX male X p 2 2 .3 /Y p ll.2 Pseudogene at Xq 12-13 (PRKXP2) Pseudogene at 15q26 (PRK X Pl) K \m k et al., 1995 Schiebel et al., 1997 DFFRY (also known as

Drosophila fat facets related Y-linked

two isoforms by alternative splicing; may regulate ubiquitin precursors; functional X copy, Y copy is non­

X p l 1 .4 / Y q l l .2 Jones et al., 1996

Symbol Name of gene Comments X-Y homologues locations

References

(for Y-linked homologues)

SMCY Selected mouse cDNA on Y X and Y copies functional; encode human H-Y epitope HLA-B7

X p l l . l - p l l . 2 / Y q l l . 2 Agulnik et aL, 1994

XGPY XG blood group system pseudogene Y-linked

Spans pseudoautosomal boundary of the X chr; multiple copies on Y, all

lack an ORF. There is an intron containing pseudogene (XGPY) in

Y q ll.2 1

Xpter-p22.32 / Y q ll.2 1 Ellis et a i, 1994 W eller et aL, 1995

DRY Dead Box Y Putative RNA helicase; functional X and Y copies

X p l l .3 - p l l .2 3 / Y q l l Lahn and Page, 1997

TB4Y Thymosin (34 Y isoform X homologue functions in actin sequestration; functional X and Y

copies

X q 2 1 .3 -q 2 2 /Y q ll Lahn and Page 1997

UTY Ubiquitous TPR m otif Y Functional X and Y copies; Mouse homologue encodes an H-Y antigen; contains 10 tandem tetratricopeptide

repeats (TPR);

X p l 1 . 2 / Y ql 1 Lahn and Page, 1997

RPS4Y Ribosomal protein 84 Y-linked

X and Y copies functional; encode ribosomal protein S4, implicated in

Turner syndrome

X q l 3 / Y p l l .3 Fisher et al., 1990

Symbol Name of gene Comments X-Y homologues locations

References

(for Y-linked homologues)

EIFIAY Translation initiation factor lA Y isoform

X homologue implicated in translation initiation; Y copy, unknown function

X pl 1 .2 / Y q l l .2 Lahn and Page 1997

ARSE/D Arylsulfatases E and D Y-linked truncated pseudogenes with X-linked functional copies

Xp22.3 / Yq proximal to the centromere

M eroni et al., 1996

KALP Kallman syndrome gene Y-linked pseudogene with a functional X-linked copy

X p 2 2 .3 /Y q l 1.21 Del Castillo et aL, 1992

differences in the properties of hum an enamel proteins which can be distinguished according to the sex of the individual (Fincham et aL, 1991; Salido et aL, 1992). M utations in the X-linked K A L I gene are responsible for causing Kallman syndrome (see section 1.4.3), whereas the Y-linked hom ologue appears to be a pseudogene. M utations of the X -linked ARSE and ARSD genes cause X-linked recessive chondroplasia punctata (C D P X l) and m utations in the X-linked STS gene cause X-linked ichthiosis and placental steroid sulfatase deficiency, while the Y -linked hom ologues are non-functional. Genes in the X pl 1.2-p22.1 region which shares hom ology with genes located in the short and long arms of the Y chrom osom e have also been im plicated in the determ ination of the short stature, ovarian failure, high-arched palate and autoim m une thyroid disease which are characteristic of Turner syndrome (45, XO) (Zinn et aL, 1998)

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