The pseudoautosomal regions, SHOX and disease

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The pseudoautosomal regions represent blocks of sequence identity between the mammalian sex chromosomes. In humans, they reside at the ends of the X and Y chromosomes and encompass roughly 2.7 Mb (PAR1) and 0.33 Mb (PAR2). As a major asset of recently available sequence data, our view of their structural characteristics could be refined considerably. While PAR2 resembles the overall sequence composition of the X chromosome and exhibits only slightly elevated recombination rates, PAR1 is characterized by a significantly higher GC content and a completely different repeat structure. In addition, it exhibits one of the highest recombination frequencies throughout the entire human genome and, probably as a consequence of its structural features, displays a significantly faster rate of evolution. It therefore represents an exceptional model to explore the correlation between meiotic recombination and evolutionary forces such as gene mutation and conversion. At least twenty-nine genes lie within the human pseudoautosomal regions, and these genes exhibit ‘autosomal’ rather than sex-specific inheritance. All genes within PAR1 escape X inactivation and are therefore candidates for the etiology of haploinsufficiency disorders including Turner syndrome (45,X). However, the only known disease gene within the pseudoautosomal regions is the SHORT STATURE HOMEBOX (SHOX) gene, functional loss of which is causally related to various short stature conditions and disturbed bone development. Recent analyses have furthermore revealed that the phosphorylation-sensitive function of SHOX is directly involved in chondrocyte differentiation and maturation.

Introduction

Nowadays, it is well accepted that the mammalian sex chromosomes originated from a pair of autosomes that ultimately evolved into the X and Y chromosomes [1]. This development was accompanied by the appearance of pseudoautosomal regions as an indirect consequence of the evolution of XY sex-determination in three mammalian groups, the Prototheria, Metatheria and Eutheria. Evolution of the sex chromosomes, particularly the progressive decay of the Y chromosome after its acquisition of SRY (SEX-DETERMINING REGION Y) as the male-determining gene, has led to a unique genetic diversity of formerly homologous autosomes, owing to the establishment of a recombination barrier [1•, 2]. Meiotic chromosome-pairing, however, necessitated the conservation on both chromosomes of specific regions that share sufficient homology to enable chromosome alignment during male meiosis, and this task is accomplished by the pseudoautosomal regions [3]. As autosomal additions that have undergone substantial rearrangements and degradation, these regions represent short genomic stretches of sequence homology between the modern sex chromosomes. In humans, they represent about 2% of the X- and 5% of the Y-chromosomal sequence. PAR1 (pseudoautosomal region 1) is necessary for homologous X–Y chromosome-pairing during male meiosis and, as with autosomes, undergoes one crossover event during this process [4, 5, 6]. Consequently, a loss of PAR1 is associated with male sterility [7]. Although PAR2 is not implicated in mediating male meiosis and recombines at a rate of only 2%, this still represents a sixfold higher recombination frequency when compared with the average of the remainder of the X chromosome [8]. The pseudoautosomal boundaries thus separate highly recombining regions from a non-recombining region on the Y and a moderately recombining region on the X chromosome.

Whereas the human PAR1 is homologous to the pseudoautosomal regions of several species, including great apes and Old World monkeys, the PAR2 sequence has a much shorter evolutionary history and is specific to humans [9, 10]. Rodents seem to have lost the distal 9 Mb portion of the short arm of the X chromosome, and instead have a different, considerably shorter PAR1, which in Mus musculus spans only 720 kb [11]. In summary, these attributes emphasize the extraordinary evolutionary forces imposed on the pseudoautosomal regions and explain their exceptional status within the genome. To date, only one pseudoautosomal gene, SHOX (SHORT STATURE HOMEOBOX), has been associated clearly with disease.

This review focuses on the structural features of the pseudoautosomal regions, and their particular genetic properties, and summarizes the latest findings on the functional properties of the SHOX gene.

Section snippets

Structural highlights of the pseudoautosomal regions

Although the sequences of the entire PAR2 region and 99.3% of the euchromatic sequence of the X chromosome have been determined, only roughly 80% of the PAR1 sequence is available to date [12••]. This discrepancy is caused by the presence of seven gaps in PAR1, with an estimated combined size of 600 kb that cannot be filled with existing genomic clones. Consequently, the anticipated size of 2.7 Mb predicted for PAR1 still has to be considered a rough estimate. PAR1, very differently from PAR2 [10

Genes within the pseudoautosomal regions

With at least 29 genes (24 in PAR1 and 5 in PAR2) the pseudoautosomal regions display a higher gene-content (∼10 genes per Mb in PAR1 and ∼15 genes per Mb in PAR2) than the remainder of the X (∼7 genes per Mb [12••]) or the Y chromosome (∼3 genes per Mb [19••]). In addition, it is conceivable that further genes might reside within the seven gaps of the PAR1 sequence. For example, on the basis of the conserved gene order between chicken chromosome 1 and the human PAR1 sequence, the ortholog of

Diseases linked to the pseudoautosomal regions

To date, only three clinical conditions have been described to demonstrate a clear genotype–phenotype correlation to the pseudoautosomal regions. All three phenotypes, namely isolated short stature, Leri-Weill and Langer syndromes (see Glossary), share reduced body-height as the indicative feature, whereas Leri-Weill and Langer syndrome patients exhibit additional and characteristic bone malformations. Interestingly, these variable phenotypes are all caused by the functional loss of a single

The SHOX gene and its functions

SHOX is a member of the paired-related homeobox family, highly conserved among species as diverse as humans, chicken and fish. In contrast to other family members, SHOX is absent from all investigated rodent species. SHOX comprises seven exons and encodes two differentially spliced mRNAs, SHOXa and SHOXb (Figure 2) [32, 33]. Although its functional loss was originally correlated with ‘idiopathic’ (or isolated) short stature, subsequent linkage and mutation analyses have also established a

Conclusions

Recent advances made by comparative sequence analyses, SNP-typing and large-scale haplotype mapping have added valuable information to our knowledge on the pseudoautosomal regions of the mammalian sex chromosomes. Clearly, with approximately one-fifth of PAR1 still unknown, completion of the sequencing is an important goal for the near future. Comparative re-sequencing analyses will furthermore clarify that the paucity of SNPs available for PAR1 and PAR2 present in the HapMap database is an

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Mark Ross and Chris Tyler-Smith for comments on the manuscript. Owing to space constraints we apologize to colleagues whose work was not mentioned. The authors are supported by the Deutsche Forschungsgemeinschaft.

Glossary

HapMap project
The HapMap Project is a multi-country effort to identify and catalog genetic similarities and differences among human beings. Public and private organizations from six countries are participating in this project, and the accumulated information generated by the project is made publicly available.
Isolated short stature
In contrast to short stature syndromes, in which variable somatic features occur in addition to reduced body-height, isolated short stature refers to clinical

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