IBD sharing around the PPARG locus is not increased in dizygotic twins or their mothers

Busjahn et al reported finding linkage between PPARG (3p25) and being a dizygotic (DZ) twin. We differentiate, as do the authors, between the conception of DZ twins, and being the viable result of such a conception.     

Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice

We targeted the locus encoding the cyclin-dependent kinase 2 (CDK2) by homologous recombination in mouse embryonic stem (ES) cells. Embryonic fibroblasts lacking CDK2 proliferate normally and become immortal after continuous passage in culture. Elimination of a conditional Cdk2 allele in immortal cells does not have a significant effect on proliferation. Cdk2-/- mice are viable and survive for up to two years, indicating that CDK2 is also dispensable for proliferation and survival of most cell types. But CDK2 is essential for completion of prophase I during meiotic cell division in male and female germ cells, an unforeseen role for this cell cycle kinase.     

Insulin gene region-encoded susceptibility to type 1 diabetes is not restricted to HLA-DR4-positive individuals.

Type 1 or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease of the insulin-producing pancreatic beta-cells which is determined by both genetic and environmental factors. The major histocompatibility complex and the insulin gene region (INS) on human chromosomes 6p and 11p, respectively, contain susceptibility genes. Using a mostly French data set, evidence for linkage of INS to IDDM was recently obtained but only in male meioses (suggesting involvement of maternal imprinting) and only in HLA-DR4-positive diabetics. In contrast, we find evidence for linkage in both male and female meioses and that the effect of the susceptibility gene(s) in the INS region is not dependent on the presence of HLA-DR4.     

The SNRPN promoter is not required for genomic imprinting of the Prader-Willi/Angelman domain in mice.

In mice and humans, the locus encoding the gene for small nuclear ribonucleoprotein N (SNRPN/Snrpn), as well as other loci in the region are subject to genomic imprinting. The SNRPN promoter is embedded in a maternally methylated CpG island, is expressed only from the paternal chromosome and lies within an imprinting center that is required for switching to and/or maintenance of the paternal epigenotype. We show here that a 0.9-kb deletion of exon 1 of mouse Snrpn did not disrupt imprinting or elicit any obvious phenotype, although it did allow the detection of previously unknown upstream exons. In contrast, a larger, overlapping 4.8-kb deletion caused a partial or mosaic imprinting defect and perinatal lethality when paternally inherited.     

FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity

Naturally occurring variation in gene copy number is increasingly recognized as a heritable source of susceptibility to genetically complex diseases. Here we report strong association between FCGR3B copy number and risk of systemic lupus erythematosus (P = 2.7 x 10(-8)), microscopic polyangiitis (P = 2.9 x 10(-4)) and Wegener's granulomatosis in two independent cohorts from the UK (P = 3 x 10(-3)) and France (P = 1.1 x 10(-4)). We did not observe this association in the organ-specific Graves' disease or Addison's disease. Our findings suggest that low FCGR3B copy number, and in particular complete FCGR3B deficiency, has a key role in the development of systemic autoimmunity.     

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.     

PTPRC (CD45) is not associated with the development of multiple sclerosis in U.S. patients

A C-->G nucleotide transition in exon 4 of PTPRC (encoding protein-tyrosine phosphatase receptor-type C, also known as CD45) was recently reported to be genetically associated with the development of multiple sclerosis (MS). We performed an extensive evaluation of this polymorphism using large family-based and case-control comparisons. Overall, we observed no evidence of genetic association between the PTPRC polymorphism and MS susceptibility or disease course.     

On not reinventing the wheel

An alphabet soup of organizations and initiatives across the world are concerned with identifying, collecting and evaluating disease-causing human gene variants and using them to diagnose and treat rare diseases. Despite increasing standardization of nomenclature and technology, our efforts still need coordination to produce a pipeline leading from discovery to delivery.