A candidate prostate cancer susceptibility gene at chromosome 17p.

It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).

Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23.

Coronary heart disease (CHD) accounts for half of the 1 million deaths annually ascribed to cardiovascular disease and for almost all of the 1.5 million acute myocardial infarctions. Within families affected by early and apparently heritable CHD, dyslipidemias have a much higher prevalence than in the general population; 20%-30% of early familial CHD has been ascribed to primary hypoalphalipoproteinemia (low HDL-C). This study assesses the evidence for linkage of low HDL-C to chromosomal region 11q23 in 105 large Utah pedigrees ascertained with closely related clusters of early CHD and expanded on the basis of dyslipidemia. Linkage analysis was performed by use of 22 STRP markers in a 55-cM region of chromosome 11. Two-point analysis based on a general, dominant-phenotype model yielded LODs of 2.9 for full pedigrees and 3.5 for 167 four-generation split pedigrees. To define a localization region, model optimization was performed using the heterogeneity, multipoint LOD score (mpHLOD). This linkage defines a region on 11q23.3 that is approximately 10 cM distal to-and apparently distinct from-the ApoAI/CIII/AIV gene cluster and thus represents a putative novel localization for the low HDL-C phenotype.

Multilocus quantitative trait analysis using the multipoint identity-by-descent method.

The multipoint identity-by-descent method (MIM) was extended to test for evidence of quantitative trait loci in two independent genetic regions. This method is a fast and feasible implementation of a multiple-marker, two-region linkage analysis for quantitative traits. It tests for significant evidence of quantitative trait loci (QTL) in neither, one or both genetic regions tested, and could be extended to an arbitrary number of independent genetic regions. A two-stage analysis was used for the nuclear family data from GAW10. Initially, an analysis of the genomic search was carried out using single-region MIM, with sets of six adjacent markers. Chromosomal regions that showed some evidence of linkage were identified and used in a two-region MIM analysis.

A high resolution CEPH crossover mapping panel and integrated map of chromosome 11.

High resolution (0.1 cM) CEPH crossover mapping panels were constructed for chromosome 11. These panels will facilitate a transition from top-down physical and genetic mapping strategies to integrated breakpoint mapping strategies. Novel methods, which differ from other methods in overcoming the limitations of incomplete heterozygosity and variable marker density, were developed for creating the panels and integrated maps. This made it possible to identify and sublocalize the majority of crossovers in 61 families. The panels were used to map 139 microsatellite markers. A semi-integrated map and a fully-integrated map were constructed by combining these data with data from CEPH 7.1 and then integrating data from the radiation hybrid (RH) map. Genetic lengths estimated from the mapping panels were similar to the estimates obtained when all recombinant and non-recombinant offspring were included (189.4 cM in females and 126.1 cM in males), indicating that genetic distances are stable at this high marker density. The maps have a cM density of 0.62. The distance between ordered markers is 1.39-2.92 cM depending on the criterion for order and the extent of map integration. The 2D maps provide the resolution and flexibility needed to enhance current applications such as positional cloning and mapping complex disorders; while the mapping panels will greatly improve the resolution, reliability and efficiency of future genetic mapping.

A 2D crossover-based map of the human X chromosome as a model for map integration.

We have constructed a two-dimensional map of 243 markers on the X chromosome. The average distance between markers ordered by two recombinants is 5.4 centiMorgans (cM), which is reduced to 3.2 cM using a less stringent criterion of one recombinant. Map resolution is enhanced by replacing the usual reference marker format with a 2D format, and the two-recombinant rule is more conservative than the lod 3.0 criterion for order. Taken together, crossover mapping and the 2D format produces maps with greater reliability and higher resolution than maps constructed using currently accepted standards. This first high-density crossover-based map of an entire human chromosome provides a model for integrating physical and genetic maps.

Attraction by repellents: an error in sensory information processing by bacterial mutants.

Normal Escherichia coli bacteria are repelled by acetate, benzoate, and indole and attracted by alpha-aminoisobutyrate. We have isolated mutants that are attracted to acetate, benzoate, and indole and may be repelled by alpha-aminoisobutyrate. These reversed-taxis mutants are defective in a central processing component: a set of methylated proteins known as MCP 1. The mechanism of reversal of taxis is discussed.

Role of methionine in bacterial chemotaxis: requirement for tumbling and involvement in information processing.

Chemotactic responses are mediated by modulation of the frequency of tumbling. Studies with methionine auxotrophs of wild-type Escherichia coli and four mutants which tumble continuously show that methionine or one of its metabolites is involved in the tumbling process. Following removal of methionine, the wild type and two mutants, after various periods of time, became unable to tumble. The presence of constant levels of chemical attractants considerably shortened these periods in the three strains and eliminated tumbling in another mutant. This effect of attractants considerably shortened these periods in the three strains and eliminated tumbling in another mutant. This effect of attractants implies that methionine or some derivative of methionine is also involved in transducing chemical stimuli to bacterial responses.

Methylation of a membrane protein involved in bacterial chemotaxis.

A protein methylation reaction involved in chemotaxis of Escherichia coli has been identified. The involvement of this reaction in chemotaxis in indicated by four lines of evidence. (a) The methylation reaction is altered in several classes of generally nonchemotactic mutants and is coreverted with the chemotaxis defects. (b) The methylation level of the protein is affected by chemotactic stimuli. (c) The transferred methyl group is derived from methionine and is labile, in accord with the known fact that chemotaxis requires a continuous supply of methionine. (d) Methylation is abnormal in various mutants having defective or missing flagella.