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At least 1,297 records · Page 72Linked to original sources
PubMed1999

Multipoint genetic mapping of quantitative trait loci with dominant markers in outbred populations.

We present a multipoint algorithm for mapping quantitative trait loci (QTLs) using dominant markers. The algorithm is designed for outbred populations and is particularly suited for large families. The algorithm works with either codominant or dominant markers, either of which may be interspersed within the same linkage map. Concurrently, the algorithm also partitions dominance variance at the QTL. Computer simulations show that with large families, QTL mapping with dominant markers can be almost as powerful as with bi-allelic, codominant markers. Yet despite this, other situations show a large standard deviation in the estimate of the QTL position, thus making QTL mapping with dominant markers in outbred populations a useful detection tool, albeit limited in its resolution.

Algorithms↗
PubMed2006

Mapping genetic modulators of amyloid plaque deposition in TgCRND8 transgenic mice.

Alzheimer's disease (AD) is a complex disorder for which various in vivo models exist. The TgCRND8 mouse, transgenic for the human amyloid precursor protein, is an aggressive early onset model of brain amyloid deposition. Preliminary studies revealed that when the transgene is expressed on an A/J genetic background, these mice not only survive longer but also deposit less parenchymal amyloid-beta (Abeta) peptides as compared to those on a C57BL/6 background. We performed a genome-wide study of an F2 intercross between TgCRND8 on an A/J background and C57BL/6 mice, to identify genetic modulators of amyloid accumulation and deposition. We identified four highly significant QTLs that together account for 55% of the phenotypic variance in the number of plaques (Thioflavin S). QTLs were found on the distal part of chromosome 4 with an LOD score of 8.1 at D4Mit251, on chromosome 11 with an LOD score of 5.5 at D11Mit242, on chromosome 9 with an LOD score of 5.0 at D9Mit336 and on the proximal part of chromosome 8 with an LOD score of 4.5 at D8Mit223. A/J alleles at these loci are protective and all decreased the amount of Abeta deposition. Interestingly, the QTL on chromosome 11 is also significantly linked to the levels of brain Abeta(42) and Abeta(40). Although these QTLs do not control the levels of plasmatic Abeta, other regions on chromosomes 1 and 6 show significant linkage. Further characterization of these QTL regions may lead to the identification of genes involved in the pathogenesis of AD.

Amyloid beta-Peptides↗
PubMed1993

Genetic mapping of bfmA mutation causing fatty acid deficiency in Bacillus subtilis.

Bacillus subtilis strain 626, defective in the bfmA gene, is a derivative derivatives of B. subtilis strain 168 and requires branched short-chain carboxylic acids for growth. Branched-chain 2-keto acid decarboxylase activity and fatty acid synthesis in B. subtilis strain 626 were 14 and 7%, respectively, of their levels in strain 626-2R, a spontaneously reverted strain. These results indicate that the bfmA mutation is in either the branched-chain 2-keto acid decarboxylase gene itself or its controlling gene. Thus, primer synthesis from the 2-keto acid substrate in strain 626 is defective, causing a deficiency in fatty acid synthesis. A bfmA mutation was transferred to a suitable genetic background and analysed. The bfmA strain, CAC1, was competent and motile, and required 50 microM CaCl2 or 5 microM FeCl3 for growth on glucose minimal agar plates. The bfmA gene was mapped between glyC (320 degrees) and ctrA (325 degrees) and estimated to be at 320 degrees by protoplast fusion and PBS1 phage transduction.

Bacillus subtilis↗
PubMed2000

Genetic mapping and tailored antihypertensive therapy.

A tailored or individualized antihypertensive therapy represents the new frontier for the treatment of essential hypertension and its organ complications. Indeed, individual variation in the efficacy and tolerability of antihypertensive drugs in human essential hypertension is currently experienced by all physicians and is linked to the genetic heterogeneity of this multifactorial disease. Different approaches have been pursued in the attempt to correlate specific responsiveness to the therapy with phenotypic traits of the patients, but with poor results. More recently, the genetic approach to the study of the mechanisms underlying hypertension has led to the identification of some quantitative trait loci or genes that influence blood pressure both in animal models and in patients. But the relevance of these polymorphisms for defining and classifying patients in terms of therapy responsiveness must be analyzed in a more complex context that takes into account the crucial aspects of environmental influences, stage of disease, previous treatments, efficacy, tolerance, and duration of the treatment. Only a few examples of a pharmacogenomic approach to hypertension therapy are now available. In particular, the association of different variants of ACE, angiotensinogen, and G-protein genes with the blood pressure response to drugs interfering with RAS or beta-adrenergic receptor has been studied. However, the results of these studies cannot be considered conclusive, since not all the criteria have been fully applied for proper assessment of an association between genetic polymorphism and drug response. Our group has identified a polymorphism of the genes coding for the cytoskeletal protein, adducin, which is associated with both rat and human hypertension, sodium sensitivity, and the antihypertensive effects of diuretics. A modification of the renal Na-KATPase leading to an increase of tubular sodium reabsorption seems to be the most likely underlying mechanism. A new antihypertensive compound has been developed that can correct the abnormality of the renal Na-KATPase and the blood pressure increase associated with adducin polymorphism in the rat. At present, the antihypertensive activity of this compound is under evaluation in patients with different adducin genotypes.

Animals↗
PubMed2000

Genetic mapping of the human C5a receptor. Identification of transmembrane amino acids critical for receptor function.

Many hormones and sensory stimuli signal through a superfamily of seven transmembrane-spanning receptors to activate heterotrimeric G proteins. How the seven transmembrane segments of the receptors (a molecular architecture of bundled alpha-helices conserved from yeast to man) work as "on/off" switches remains unknown. Previously, we used random saturation mutagenesis coupled with a genetic selection in yeast to determine the relative importance of amino acids in four of the seven transmembrane segments of the human C5a receptor (Baranski, T. J., Herzmark, P., Lichtarge, O., Gerber, B. O., Trueheart, J., Meng, E. C., Iiri, T., Sheikh, S. P., and Bourne, H. R. (1999) J. Biol. Chem. 274, 15757-15765). In this study, we evaluate helices I, II, and IV, thereby furnishing a complete mutational map of the seven transmembrane helices of the human C5a receptor. Our analysis identified 19 amino acid positions resistant to non-conservative substitutions. When combined with the 25 essential residues previously identified in helices III and V-VII, they delineate two distinct components of the receptor switch: a ligand-binding surface at or near the extracellular surface of the helix bundle and a core cluster in the cytoplasmic half of the bundle. In addition, we found critical amino acids in the first and second helices that are predicted to face the lipid membrane. These residues form an extended surface that might mediate interactions with lipids and other membrane proteins or function as an oligomerization domain with other receptors.

Amino Acid Sequence↗
PubMed1995

Genetic mapping of F13A to BTA23 by sperm typing: difference in recombination rate between bulls in the DYA-PRL interval.

Our objective was to extend the linkage and comparative maps of BTA23 by determining whether the structural gene for the A subunit of blood coagulation factor XIII (F13A) is linked to BoLA-DYA, a centromeric marker, or the distally located gene encoding prolactin (PRL). Bovine F13A was mapped relative to DYA and PRL in an experiment that examined segregation of alleles in 176 sperm. Genotyping was performed by PCR-RFLP for all loci, following amplification of the haploid genome by primer extension preamplification. F13A was found to be linked to PRL (theta = 0.314 +/- 0.038). The most likely order is DYA-PRL-F13A (odds > 10(4):1). This result demonstrates conservation of synteny between BTA23 and most of HSA6p. Surprisingly, theta DYA-PRL was 0.310 +/- 0.039, 83.4% greater (P < 0.02) than we found for another bull (Van Eijk et al., Mamm. Genome 4: 113, 1993). The difference in recombination rate in the DYA-PRL interval provides further evidence for an unusual recombination hot spot between the bovine Mhc class IIa and class IIb subregions and suggests that bull-specific maps may be necessary for marker-assisted selection.

Animals↗
PubMed1997

Physical and genetic map of the chromosome of Dichelobacter nodosus strain A198.

A physical map of the chromosome of Dichelobacter nodosus strain A198 was constructed using the restriction endonucleases EagI and StuI. Mapping data indicated the presence of a single, circular chromosome of 1.54 Mb. The three rRNA operons and the virulence related locus (vrl) were precisely positioned at the junctions of EagI and StuI fragments, and their transcriptional orientations were also determined. Other D. nodosus genes were assigned to specific EagI and StuI fragments. Analysis of the resultant map revealed that the putative virulence genes were not clustered on the chromosome which suggests that the D. nodosus virulence determinants have been acquired gradually and that virulence in D. nodosus is an evolving trait.

Chromosome Mapping↗
PubMed2001

Candidate disease resistance genes in sunflower cloned using conserved nucleotide-binding site motifs: genetic mapping and linkage to the downy mildew resistance gene Pl1.

Disease resistance gene candidates (RGCs) belonging to the nucleotide-binding site (NBS) superfamily have been cloned from numerous crop plants using highly conserved DNA sequence motifs. The aims of this research were to (i) isolate genomic DNA clones for RGCs in cultivated sunflower (Helianthus annuus L.) and (ii) map RGC markers and Pl1, a gene for resistance to downy mildew (Plasmopara halstedii (Farl.) Berl. & de Toni) race 1. Degenerate oligonucleotide primers targeted to conserved NBS DNA sequence motifs were used to amplify RGC fragments from sunflower genomic DNA. PCR products were cloned, sequenced, and assigned to 11 groups. RFLP analyses mapped six RGC loci to three linkage groups. One of the RGCs (Ha-4W2) was linked to Pl1, a downy mildew resistance gene. A cleaved amplified polymorphic sequence (CAPS) marker was developed for Ha-4W2 using gene-specific oligonucleotide primers. Downy mildew susceptible lines (HA89 and HA372) lacked a 276-bp Tsp5091 restriction fragment that was present in downy mildew resistant lines (HA370, 335, 336, 337, 338, and 339). HA370 x HA372 F2 progeny were genotyped for the Ha-4W2 CAPS marker and phenotyped for resistance to downy mildew race 1. The CAPS marker was linked to but did not completely cosegregate with Pl1 on linkage group 8. Ha-4W2 was found to comprise a gene family with at least five members. Although genetic markers for Ha-4W2 have utility for marker-assisted selection, the RGC detected by the CAPS marker has been ruled out as a candidate gene for Pl1. Three of the RGC probes were monomorphic between HA370 and HA372 and still need to be mapped and screened for linkage to disease resistance loci.

Base Sequence↗
PubMed1995

The genetic mapping and gene structure of mouse paraoxonase/arylesterase.

The physiological role of mammalian paraoxonase/arylesterase is unknown. However, paraoxonase is an HDL-associated protein, and recent studies indicate that it may have anti-atherogenic functions. We describe the chromosomal localization and structure of the mouse paraoxonase gene (Pon1) to establish Pon1 as a candidate gene for genetically determined traits or pathological states in the mouse. The coding portion of Pon1 extends over approximately 25-26 kb and consists of nine exons and eight introns. We also present nucleotide sequences from the 5'-flanking region of Pon1 containing numerous consensus sequences for DNA binding proteins. Haplotype analysis of 94 N2 progeny from an interspecific cross indicates that Pon1 is localized on proximal mouse chromosome 6 near D6Mit86. This assignment excludes Pon1 as a candidate for the atherosclerosis susceptibility genes Ath1, Ath2, and Ath3. However, Pon1 is a promising candidate for the remaining unmapped Ath genes.

Amino Acid Sequence↗
PubMed2003

Genetic mapping studies of familial juvenile hyperuricemic nephropathy on chromosome 16p11-p13.

Familial juvenile hyperuricemic nephropathy (FJHN), which is inherited as an autosomal dominant disorder, is characterized by hyperuricemia, a low fractional renal excretion of urate, and chronic renal failure that is associated with interstitial fibrosis. Studies in 4 families (3 European and 1 Japanese) have mapped the gene causing autosomal dominant FJHN to chromosome 16p11-p13. To refine this location we have pursued linkage studies in 7 European families with autosomal dominant FJHN and used 11 chromosome 16p11-p13 polymorphic loci whose order has been established as 16pter-D16S3069-D16S3060-D16S3041-D16S3036-D16S3046-[D16S403,D16S417]-D16S420-D16S3113-D16S401-D16S3133-16cen. Cosegregation between these polymorphic loci and FJHN was observed in 5 of the families, and linkage was established between FJHN and 6 loci (peak LOD score, 5.32 with D16S417, at 0% recombination), with the most likely location of FJHN being within a 22-centimorgan interval flanked centromerically by D16S401 and telomerically by D16S3069. Furthermore, FJHN in 2 families was found not to be linked to chromosome 16p11-p13, thereby demonstrating genetic heterogeneity. Thus, 5 additional families with FJHN showing linkage to chromosome 16p11-p13 loci have been identified, and genetic heterogeneity has been demonstrated in more than 25% of FJHN families. These results will facilitate the characterization of this gene regulating urate metabolism.

Child↗
PubMed2000

Genetic mapping of a mouse modifier gene that can prevent ALS onset.

Mutations in the cytoplasmic Cu/Zn superoxide dismutase (SOD1) gene on human chromosome 21q22.1 cause 10-20% of familial amyotrophic lateral sclerosis (ALS) cases. The expression of the ALS phenotype in mice carrying the murine G86R SOD1 mutation is highly dependent upon the mouse genetic background. This is similar to the phenotypic variation observed in ALS patients containing identical SOD1 mutations. In the FVB/N background, mice expressing mG86R SOD1 develop an ALS phenotype at approximately 100 days. However, when these mice were bred into a mixed background of C57Bl6/129Sv, the onset of the ALS phenotype was delayed (143 days to >2 years). Using 129 polymorphic autosomal markers in a whole genome scan, we have identified a major genetic modifier locus with a maximum lod score of 5.07 on mouse chromosome 13 between D13mit36 and D13mit76. This 5- to 8-cM interval contains the spinal muscular atrophy (SMA)-associated gene Smn (survival motor neuron) and seven copies of Naip (neuronal apoptosis inhibitory protein), suggesting a potential link between SMA and ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1996

Molecular cloning of a highly conserved mouse and human integral membrane protein (Itm1) and genetic mapping to mouse chromosome 9.

We have isolated and characterized a novel cDNA coding for a highly hydrophobic protein (B5) from a fetal mouse mandibular condyle cDNA library. The full-length mouse B5 cDNA is 3095 nucleotides long and contains a potential open reading frame coding for a protein of 705 amino acids with a calculated molecular weight of 80.5 kDa. The B5 mRNA is differentially polyadenylated, with the most abundant transcript having a length of 2.7 kb. The human homolog of B5 was isolated from a cDNA testis library. The predicted amino acid sequence of the human B5 is 98.5% identical to that of mouse. The most striking feature of the B5 protein is the presence of numerous (10-14) potential transmembrane domains, characteristic of an integral membrane protein. Similarity searches in public databanks reveal that B5 is 58% similar to the T12A2.2 gene of Caenorhabditis elegans and 60% similar to the STT3 gene of Saccharomyces cerevisiae. Furthermore, the report of an EST sequence (Accession No. Z13858) related to the human B5, but identical to the STT3 gene, indicates that B5 belongs to a larger gene family coding for novel putative transmembrane proteins. This family exhibits a remarkable degree of conservation in different species. The gene for B5, designated Itm1 (Integral membrane protein 1), is located on mouse chromosome 9.

Animals↗
PubMed1981

Idiotypic analysis of anti-GAT antibodies. IX. Genetic mapping of the Gte idiotypic marker within the Igh-V locus.

The gene controlling the expression of the murine Gte idiotype marker was mapped within the Igh-V gene complex. This idiotypic marker was identified in B6, C.B-20 and A/J and C.AL-20 anti-GAT antisera, but either was not detectable or was present in very low quantities in the anti-GAT antisera obtained from BALB/c, BAB-14, SM/J, NZW, and NZB mice. The data are consistent with the interpretation that the latter 5 strains do not process Igh-Gte genes and the Igh haplotypes of these strains represent examples of crossing over within the Igh complex. Furthermore, the expression of the Gte idiotype(s) is not influenced by the Lyt-3 linked genes that control the kappa light chain polymorphism. Segregation analysis with 52 recombinant inbred strains confirmed the close linkage of Igh-Gte idiotype with Igh-1b locus. The recombination frequency between these loci was calculated to be 1 +/- 0.7 percent. Furthermore, by using B X D recombinant inbred strains, the Igh-Gte gene was mapped within the Igh-V region gene closely linked to the Igh-Np, Igh-Nbp, and Igh-BgI genes.

Animals↗