Sequences of three gene fragments ( flaA, flaB, and vacA) from Helicobacter pylori strains isolated from patients in Germany, Canada, and South Africa were analyzed for diversity and for linkage equilibrium by using the Homoplasy Test and compatibility matrices. Horizontal genetic exchange in H. pylori is so frequent that different loci and polymorphisms within each locus are all at linkage equilibrium. These results indicate that H. pylori is panmictic. Comparisons with sequences from Escherichia coli, Neisseria meningitidis, and Drosophila melanogaster showed that recombination in H. pylori was much more frequent than in other species. In contrast, when multiple family members infected with H. pylori were investigated, some strains were indistinguishable at all three loci. Thus, H. pylori is clonal over short time periods after natural transmission.Helicobacter pylori is genetically one of the most diverse bacterial species so far reported. It also is subject to the highest known rate of intraspecific recombination. This paper presents the evidence for these two assertions and discusses their significance. In particular, is there a causal connection between high variability and high recombination rate?Infection with H. pylori, a common human pathogen, causes chronic type B gastritis and is a prerequisite for the development of duodenal ulcers and most gastric ulcers (1). H. pylori infection is also an important risk factor for gastric malignancies such as adenocarcinoma (2) and mucosa-associated lymphoid tissue lymphoma (3). Most microbiological studies of H. pylori have concentrated on virulence factors (4) and much less is known about its population biology. DNA fingerprinting (5-7), multilocus enzyme electrophoresis (MLEE) (8) and DNA sequence analysis of the ureC͞glmM and cagA genes (9-11) have revealed an unusually high degree of genetic variability within this species, whose origin is unclear.Motility is essential for the virulence of H. pylori and is based on a flagellar apparatus with several unique features (12). The flagellar filament is composed of two flagellins, FlaA and FlaB, which are covered by a flagellar sheath and therefore thought to be shielded from antibody selection. Little has been published about the sequence variability of the flaA and flaB genes. VacA is a secreted vacuolating cytotoxin thought to be involved in ulcerogenesis (13), whose sequence variability seems to reflect mosaicism (14). During sequence analyses of the flaB gene directed to better understanding of its role in virulence, we noticed a degree of sequence variability which seemed unprecedented in the bacterial kingdom. We extended these analyses to data available in GenBank from gene fragments of the flaA and vacA genes and tested the sequence diversity of these three gene fragments among strains isolated from individuals in three different study groups. The sequence data were analyzed for evidence of recombination using a novel tool, the Homoplasy Test (15), which has been designed to test recombination in nu...

Mutations in the gene encoding the dopamine-synthetic enzyme GTP cyclohydrolase-1 (GCH1) cause DOPA-responsive dystonia (DRD). Mencacci et al. demonstrate that GCH1 variants are associated with an increased risk of Parkinson's disease in both DRD pedigrees and in patients with Parkinson's disease but without a family history of DRD.

Wegener's granulomatosis (WG) is a systemic disease with complex genetic background. It is characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract, glomerulonephritis, vasculitis and the presence of antineutrophil cytoplasmatic autoantibodies (C-ANCAs) in sera of patients. Here, we report on an extended association screen (EAS) with 202 microsatellite markers, representing apoptosis-related genes and further genes down-regulated in apoptotic neutrophils, using pooled DNA of 150 Northern German patients suffering from WG and 100 healthy Northern German controls. Six microsatellite allele patterns were found significantly associated with WG, three of which could be confirmed by individual genotyping. One marker remained significantly associated after multiple corrections. This marker representing the retinoid X receptor beta gene (RXRB, P=7.60x10(-6), distance to gene: approximately 5.3 kb) is localised in the major histocompatibility complex (MHC) region between the HLA-DPB1 and DAXX genes. HLA-DPB1 typing and fine mapping of the region with additional microsatellites and single-nucleotide polymorphisms (SNPs) revealed a strong association of WG with the significantly over-represented DPB1*0401 ( P=1.51x10(-10), OR=3.91) allele compared with the control cohort. In addition, an extended haplotype DPB1*0401/RXRB03 was identified showing an even stronger association with WG ( P=7.13x10(-17), OR=6.41). These results represent the strongest association of a genomic region with WG, suggesting a major genetic contribution in the aetiology of the disease. Thus, our data demonstrate that EAS may be a valuable alternative approach for determining genetic predisposition factors in multifactorial diseases.

No abstract

The proportion of rectal cancers and shorter time span to metachronous cancers indicates the need for a defined treatment strategy for primary rectal cancers in hereditary nonpolyposis colorectal cancer patients. Male MLH1 mutation carriers require earlier colonoscopy beginning at age 20 years. We propose regular gastric surveillance starting at age 35 years, regardless of the familial occurrence of this cancer. The association of prostate cancer with MSH2 mutations should be taken into consideration both for clinical and genetic counseling practice.