The mouse X chromosome is enriched for sex-biased genes not subject to selection by meiotic sex chromosome inactivation

Sex chromosomes are subject to sex-specific selective evolutionary forces. One model predicts that genes with sex-biased expression should be enriched on the X chromosome. In agreement with Rice's hypothesis, spermatogonial genes are over-represented on the X chromosome of mice and sex- and reproduction-related genes are over-represented on the human X chromosome. Male-biased genes are under-represented on the X chromosome in worms and flies, however. Here we show that mouse spermatogenesis genes are relatively under-represented on the X chromosome and female-biased genes are enriched on it. We used Spo11(-/-) mice blocked in spermatogenesis early in meiosis to evaluate the temporal pattern of gene expression in sperm development. Genes expressed before the Spo11 block are enriched on the X chromosome, whereas those expressed later in spermatogenesis are depleted. Inactivation of the X chromosome in male meiosis may be a universal driving force for X-chromosome demasculinization.     

The mouse X chromosome is enriched for multicopy testis genes showing postmeiotic expression

According to the prevailing view, mammalian X chromosomes are enriched in spermatogenesis genes expressed before meiosis and deficient in spermatogenesis genes expressed after meiosis. The paucity of postmeiotic genes on the X chromosome has been interpreted as a consequence of meiotic sex chromosome inactivation (MSCI)--the complete silencing of genes on the XY bivalent at meiotic prophase. Recent studies have concluded that MSCI-initiated silencing persists beyond meiosis and that most genes on the X chromosome remain repressed in round spermatids. Here, we report that 33 multicopy gene families, representing approximately 273 mouse X-linked genes, are expressed in the testis and that this expression is predominantly in postmeiotic cells. RNA FISH and microarray analysis show that the maintenance of X chromosome postmeiotic repression is incomplete. Furthermore, X-linked multicopy genes exhibit a similar degree of expression as autosomal genes. Thus, not only is the mouse X chromosome enriched for spermatogenesis genes functioning before meiosis, but in addition, approximately 18% of mouse X-linked genes are expressed in postmeiotic cells.     

Dosage compensation of the active X chromosome in mammals

Monosomy of the X chromosome owing to divergence between the sex chromosomes leads to dosage compensation mechanisms to restore balanced expression between the X and the autosomes. In Drosophila melanogaster, upregulation of the male X leads to dosage compensation. It has been hypothesized that mammals likewise upregulate their active X chromosome. Together with X inactivation, this mechanism would maintain balanced expression between the X chromosome and autosomes and between the sexes. Here, we show that doubling of the global expression level of the X chromosome leads to dosage compensation in somatic tissues from several mammalian species. X-linked genes are highly expressed in brain tissues, consistent with a role in cognitive functions. Furthermore, the X chromosome is expressed but not upregulated in spermatids and secondary oocytes, preserving balanced expression of the genome in these haploid cells. Upon fertilization, upregulation of the active X must occur to achieve the observed dosage compensation in early embryos.     

Telomere-associated chromosome fragmentation: applications in genome manipulation and analysis.

Telomere-associated chromosome fragmentation (TACF) is a new approach for chromosome mapping based on the non-targeted introduction of cloned telomeres into mammalian cells. TACF has been used to generate a panel of somatic cell hybrids with nested terminal deletions of the long arm of the human X chromosome, extending from Xq26 to the centromere. This panel has been characterized using a series of X chromosome loci. Recovery of the end clones by plasmid rescue produces a telomeric marker for each cell line and partial sequencing will allow the generation of sequence tagged sites (STSs). TACF provides a powerful and widely applicable method for genome analysis, a general way of manipulating mammalian chromosomes and a first step towards constructing artificial mammalian chromosomes.     

The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant syndrome of unknown aetiology characterized by lifelong elevation in serum calcium concentration and low urinary calcium excretion. These features suggest that the causal gene is important for maintenance of extracellular calcium homeostasis by the parathyroid gland and kidney. To identify the chromosomal location of FHH gene(s), we clinically evaluated 114 individuals in four unrelated affected families and performed linkage analyses. The disease gene mapped to the long arm of chromosome 3 in each family (combined maximum multipoint lod score = 20.67). We suggest that this is the predominant FHH locus and anticipate that identification of the FHH gene will improve our understanding of the molecular basis for physiologic and pathologic regulation of calcium.     

The new date, new format, new goals and new sponsor of the Archon Genomics X PRIZE competition

The Archon Genomics X PRIZE presented by MEDCO is a $10 million prize for whole human genome sequencing that will test 100 samples and establish a defined method for determining quality and cost per genome. The contest will entail a head-to-head competition starting on 3 January 2013. The $10 million grand prize will be awarded to the first team to meet all the quality standards. If there is no grand prize winner, lesser awards will be made for single achievements in the three categories of accuracy, completeness and haplotype phasing. Similar to the open comment period offered earlier this year for the validation protocol, the X PRIZE Foundation seeks commentary from the scientific community on the revised competition format and judging criteria prior to publishing final rules as part of a master agreement with competing teams next year. The official validation protocol will make the competition judging transparent and fair using multiple standard techniques and robust bioinformatics. With sponsorship from Medco Health Solutions (MEDCO), the 100 samples will be derived from genomes of appropriately consented centenarian subjects. At the conclusion of the contest, the data from the redundantly sequenced genomes will be deposited into a scientific database and provide a heretofore unrealized depth of sequence data based on multiple technologies. The sample set and the bioinformatic pipeline will also be made available to the scientific community.