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PubMed2002

Is normal tension glaucoma actually an unrecognized hereditary optic neuropathy? New evidence from genetic analysis.

Normal tension glaucoma and dominant optic atrophy share many overlapping clinical features, and differentiating between these two diseases is often difficult. The gene responsible for dominant optic atrophy is the OPA1 gene located on chromosome 3. This gene encodes for a protein product that is involved in mitochondrial metabolic function. Recent genetic linkage analysis of patients with normal tension glaucoma has shown an association with polymorphisms of the OPA1 gene. This association suggests that normal tension glaucoma may actually be a hereditary optic neuropathy with a pathophysiology based in mitochondrial dysfunction.

Disease Progression↗
PubMed2002

Fusion genetic analysis of jasmonate-signalling mutants in Arabidopsis.

Jasmonates induce plant-defence responses and act to regulate defence-related genes including positive feedback of the lipoxygenase 2 (LOX2) gene involved in jasmonate synthesis. To identify jasmonate-signalling mutants, we used a fusion genetic strategy in which the firefly luciferase (FLUC) and Escherichia coli beta-glucuronidase (GUS) reporters were expressed under control of the jasmonate-responsive LOX2 promoter. Spatial and temporal patterns of reporter expression were determined initially, and revealed that JA-responsive expression from the LOX2 promoter required de novo protein synthesis. Reporter activity was also induced by the protein kinase inhibitor staurosporine and antagonized by the protein phosphatase inhibitor okadaic acid. FLUC bio-imaging, RNA gel-blot analysis and progeny analyses identified three recessive mutants that underexpress the FLUC reporter, designated jue1, 2 and 3, as well as two recessive mutants, designated joe1 and 2, that overexpress the reporter. Genetic analysis indicated that reporter overexpression in the joe mutants requires COI. joe1 responded to MeJA with increased anthocyanin accumulation, while joe2 responded with decreased root growth inhibition. In addition, reporter induction and endogenous LOX2 expression by staurosporine was absent in joe2.

Arabidopsis↗
PubMed1991

Substrain comparison of genetically hypertensive rats using DNA fingerprinting, and genetic analysis of blood pressure in the inbred rats.

Using DNA fingerprinting, genetic heterogeneity or homogeneity was studied between substrains of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats maintained in Japan. Using human myoglobin minisatellite 33.15 as a probe, we did not detect any inter- or intra-substrain genetic heterogeneities in HinfI digests of SHR or WKY rat DNA. However, analysis of Sau3AI digests of rat DNA using mouse C-6 gene as a probe revealed intra-substrain heterogeneity of 1-2 DNA bands in one of the WKY rat substrains. In the other substrains of SHR and WKY rats, there existed no intra-substrain heterogeneities, but several inter-substrain heterogeneities were observed in both SHR and WKY rats. In another experiment using the inbred substrains of SHR and WKY rats which have been confirmed as genetically homogeneous, we produced F1 and F2 rats, and biometrically analyzed their systolic blood pressure. The results suggested that there may be 1-4 dominant antihypertensinogenic genes with high heritability of 0.6-0.7.

Animals↗
PubMed1994

Genetic analysis of Rough sheath1 developmental mutants of maize.

Maize Rough sheath1 (Rs1) mutants are dominant and cause a proliferation of sheath-like tissue at the base of the blade and throughout the ligular region. They also cause ligule displacement, a chaotic pattern of vasculature and abnormal cellular structure of vascular bundles. The affected region of Rs1-O leaves displays genetic and morphological attributes of both sheath and auricle, suggesting an overlap of these genetic programs. The rs1 locus maps approximately 26 map units distal to opaque2 (o2) on chromosome 7S, defining a new distal-most locus on the genetic map. Three mutant alleles, Rs1-O, Rs1-1025 and Rs1-Z, all display similar phenotypes. The mutations are completely dominant and the Rs1-O phenotype is not affected by dosage of the chromosome arm carrying the rs1+ allele, indicating that these alleles are neomorphic. Analysis of genetic mosaics showed that the Rs1-O phenotype is non-cell-autonomous, suggesting that intercellular signals convey the phenotype. Rs1 mutant phenotypes are affected by modifiers present in particular genetic backgrounds. An enhancer of Rs1-O was identified; segregation data imply a single recessive gene, ers1. Rs1 mutants were also found to enhance the expression of unlinked rs2 and Rs4 mutants, suggesting that these mutations affect similar developmental processes. We discuss the phenotypic and genetic similarities between Rs1 and Knotted 1 (Kn1) mutants that led to the identification of rs1 as a kn1-like homeobox gene (unpublished data).

Crosses, Genetic↗
PubMed1997

Preimplantation diagnosis of single gene disorders by two-step oocyte genetic analysis using first and second polar body.

Previous work on preimplantation genetic diagnosis (PGD) of single gene disorders by the first polar body (IPB) analysis has demonstrated that the genotype of a considerable number of embryos resulting from heterozygous oocytes cannot be predicted without testing their second PB (IIPB). To overcome this limitation we introduce a two-step DNA analysis of oocytes using both IPB and IIPB to identify hemizygous mutation-free oocytes following the second meiotic division. In the application of the approach to PGD of cystic fibrosis (CF) Delta F-508 mutation, sickle cell disease, and hemophilia B, 80 oocytes were studied by both PBs, resulting in the identification and transfer of 32 homozygous normal embryos. A follow-up genotyping of 52 embryos, resulting from oocytes tested by both IPB and IIPB demonstrated the accuracy of the predicted genotypes. In addition to a nested PCR analysis of the mutant genes in PBs and resulting embryos, simultaneous amplification of different polymorphic markers was performed, demonstrating the reliability of the two-step polar body analysis of oocytes.

Alleles↗
PubMed1999

Malignant fibrous histiocytoma of the pancreas: a case report with genetic analysis.

BACKGROUND: Malignant fibrous histiocytoma (MFH) is the most common type of soft tissue sarcoma in adults; it occurs frequently in the extremities, the trunk, or retroperitoneal tissues. MFH rarely is detected in digestive organs, such as the liver or stomach. METHODS: The authors report a patient with MFH of the pancreas who was treated with surgery alone. The tumor was studied for genetic alterations in the p53, p16ink4a, and DPC4 tumor suppressor genes as well as the K-ras oncogene by immunohistochemistry, single strand conformation variant (SSCV) analysis, and direct DNA sequencing. RESULTS: The authors believe that this is the 13th report of primary pancreatic MFH in the world literature and the first genetic analysis of this rare tumor. The patient is alive with no evidence of recurrence 34 months after surgery. Immunohistochemistry revealed no abnormal accumulation of the p53 protein and normal nuclear p16 expression. Mutation analysis of the p53, p16, DPC4, and K-ras genes showed only a polymorphism at codon 72 of the p53 gene and no mutations in any of the genes. CONCLUSIONS: Genotypically, MFH of the pancreas is clearly different from other malignant pancreatic tumors, which further supports the hypothesis that this tumor is a rare but distinct entity.

Aged↗
PubMed1988

Genetical analysis of intrapopulational variation in olfactory response in Drosophila melanogaster.

Genetical study of olfactory response to ethyl alcohol (8 per cent) has been carried out on inbred lines extracted from a natural population using biometrical and chromosome analyses. A full diallel analysis was made in seven endogamic lines (3 high, 3 low and 1 intermediate in response values). Our results show a highly significant (P less than 0.001) additive component of variance and a less significant (P less than 0.05) directional dominance component suggesting overdominance and some endogamic depression. No significant maternal or reciprocal components of variation appear in our population. Two chromosome substitution assays among 3 inbred lines of extreme olfactory response add up information to the results of diallel analysis. The differences in response are due to chromosome III with an additive effect highly significant (P less than 0.001) in both studies. The other major chromosomes do not show any effect themselves but some interactions with chromosome III are significant. They can explain the directional dominance that we find in the diallel study. Analysed olfactory variation in response to ethanol can be considered as unspecific in relation to various chemical compounds.

Alleles↗
PubMed1991

Genetic analysis of yeast iso-1-cytochrome c structural requirements: suppression of Gly6 replacements by an Asn52----Ile replacement.

Gly6 (vertebrate numbering system) is an evolutionarily invariant amino acid located in an electron-dense region of cytochrome c. Serine, cysteine, and aspartic acid replacements of Gly6 abolished yeast iso-1-cytochrome c function, presumably by destabilizing the mature forms of the altered proteins (1). Here we report that genetic reversion analysis of these mutants has uncovered a single base-pair substitution, encoding an Asn52----Ile replacement, that suppresses all three position 6 defects, as well as a Gly6....Gly29----Ser6....Ser29 double replacement. In each case the suppressor restored at least partial function to the altered iso-1-cytochromes c, with the Sera6....Ile52 protein being nearly indistinguishable from the normal protein. The suppressor also affected otherwise normal iso-1-cytochrome c, enhancing the in vivo amount of the protein by about 20%. While this work was in progress, Das et al. (1989, Proc. Natl. Acad. Sci. USA 86, 496-499) uncovered Ile52 as a suppressor of single Gly29 and His33 replacements in iso-1-cytochrome c. The ability of Ile52 to suppress amino acid replacements at three different sites, and its effect in isolation from the primary mutations, defines Ile52 as a global suppressor of specific iso-1-cytochrome c structural defects. These data suggest that position 52 plays a critical role in the folding and/or stability of iso-1-cytochrome c.

Base Sequence↗
PubMed2004

Genetic analysis of cold-tolerance of photosynthesis in maize.

The genetic basis of cold-tolerance was investigated by analyzing the quantitative trait loci (QTL) of an F2:3 population derived from a cross between two lines bred for contrasting cold-tolerance using chlorophyll fluorescence as a selection tool. Chlorophyll fluorescence parameters, CO2 exchange rate, leaf greenness, shoot dry matter and shoot nitrogen content were determined in plants grown under controlled conditions at 25/22 degrees C or 15/13 degrees C (day/night). The analysis revealed the presence of 18 and 19 QTLs (LOD > 3.5) significantly involved in the variation of nine target traits in plants grown at 25/22 degrees C and 15/13 degrees C, respectively. Only four QTLs were clearly identified in both temperatures regimes for the same traits, demonstrating that the genetic control of the performance of the photosynthetic apparatus differed, depending on the temperature regime. A major QTL for the cold-tolerance of photosynthesis was identified on chromosome 6. This QTL alone explained 37.4 of the phenotypic variance in the chronic photoinhibition at low temperature and was significantly involved in the expression of six other traits, including the rate of carbon fixation and shoot dry matter accumulation, indicating that the tolerance to photoinhibition is a key factor in the tolerance of maize to low growth temperature. An additional QTL on chromosomes 2 corresponded to a QTL identified previously in another population, suggesting some common genetic basis of the cold-tolerance of photosynthesis in different maize germplasms.

Adaptation, Physiological↗
PubMed1996

Do animal models have a place in the genetic analysis of quantitative human behavioural traits?

It seems that the genetic basis of common psychiatric diseases such as schizophrenia and manic-depressive psychosis is amenable to the genetic mapping strategies that have been successful in other complex disorders such as diabetes. The next challenge is the genetic dissection of quantitative behavioural traits such as mood, personality and intelligence. Quantitative traits pose new problems for gene cloning experiments. We argue that one way forward is by using animal models. One of the features of quantitative traits is that the DNA sequence variants which are responsible for them are unlikely to be immediately recognizable. In contrast to many qualitative traits where a discrete phenotypic difference is often the consequence of an inactivating mutation, the allelic variation responsible for quantitative traits probably has a more subtle basis. This distinction means that strategies to clone the genetic basis of quantitative behavioural traits will have to rely on functional assays of alleles thought to be important in determining the phenotype. We suggest that an efficient strategy for detecting sequences that give rise to quantitative behavioural traits can be devised in the mouse. The importance and utility of the mouse for quantitative trait analysis make it worthwhile to investigate mouse models of human behaviour; these advantages outweigh the difficulties that arise in attempts to validate the animal models. As an example we review the evidence that validates rodent emotionality as an animal model for susceptibility to human anxiety. We show that there is good evidence that rodent emotionality is a central nervous system state with a genetic basis, and that there are neuropharmacological and neuroanatomical parallels with human anxiety. Furthermore, our own work has shown that the genetic basis of the trait is relatively simple, and that the task of characterizing it at a molecular level is feasible. We expect that future experiments will show us how genetic variation gives rise to quantitative behavioural traits.

Animals↗
PubMed1978

A herpes simplex virus 1 integration site in the mouse genome defined by somatic cell genetic analysis.

Transfection experiments with HSV 1 in which one uses herpes simplex virus (HSV) thymidine kinase (TK) as a selectable prototrophic marker yield two classes of transformed cells: stable and unstable. In this report, we test the hypothesis that the stability phenotype can be explained by virus genome integration into a recipient cell chromosome. The method of analysis is by means of somatic cell genetics. We have isolated a series of microcell hybrids between a TK- Chinese hamster cell line and a transformed mouse cell line expressing the TK encoded by HSV 1. Several of the hybrid lines contain a single murine chromosome and express only the viral TK. Karyotypic analysis of these hybrids and of TK- derivatives generated by BrdUrd counterselection reveals that the TK+ phenotype is correlated with the presence of the terminal portion of the long arm of a specific murine chromosome. Results of extensive isozyme analyses of the hybrids and their TK- segregants fully corroborate the karyologic data. The results are consistent with the hypothesis that the viral tk gene is covalently integrated into this chromosomal region which itself does not appear to carry the endogenous murine tk locus. Other more complicated models are discussed. Our findings also show that somatic cell genetics can be used to localize viral integration sites in host chromosomes with high resolution.

Animals↗
PubMed2005

A genomic population genetics analysis of the pathogenic enterocyte effacement island in Escherichia coli: the search for the unit of selection.

Comparative genomic analysis is a powerful tool for understanding the history and organization of complete genomes. The mathematical tools of population genetics combined with genomic analysis provide a powerful approach to dissect heterogeneities in genome evolution. This study presents a hierarchical analysis of the enterocyte and effacement island (35 kb), which is found in the enteropathogenic and enterohemorrhagic strains in Escherichia coli and in Citrobacter rodentium. The locus of enterocyte and effacement in E. coli is considered to be a clonal unit inside a clonal organism and is expected to evolve as a single unit. This analysis examines the clonal assumption by determining genetic diversity, GC content, and the substitution rates at the different functional levels of (i) the complete pathogenic island, (ii) the five operons in which the island is organized, and (iii) for each of the individual 41 genes that comprise the locus. We find that there is a conserved region that is composed of genes that belong to the type III secretion system and that may be products of horizontal transfer. A more diverse region is composed of genes for secreted proteins and genes that we infer to be original components of the E. coli genome. This genetic mosaic seems to be differentially affected by selection and mutation. Our results suggest that recombination and selection may be breaking this structure so that different elements are, at best, weakly coupled in their evolution. These observations suggest that the units of selection are not the complete island, but rather, much smaller units that comprise the island.

Codon↗
PubMed1998

Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon.

We describe an extended Dutch family with a new hereditary disorder: autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon. Information was obtained on 289 family members (151 males, 138 females), of whom 198 were personally interviewed. Retinopathy was found in 20 (6.9%) of the family members, migraine in 65 (22.5%) and Raynaud's phenomenon in 50 (17.3%). A combination of all three symptoms was found in 11 subjects. In a genetic linkage analysis we firstly excluded several candidate loci. Subsequently, 75% of the autosomal genome was excluded in a genome-wide search. The following conclusions were drawn. First, genetic factors are involved in Raynaud's phenomenon. Secondly, the genetic linkage of migraine with vascular retinopathy and Raynaud's phenomenon supports a vascular aetiology of this disorder. Finding the gene for this family may help to elucidate the genetic background of migraine and of vascular disorders in general.

Adolescent↗
PubMed2005

Posterior polar cataract: genetic analysis of a large family.

Congenital cataracts are clinically and genetically heterogeneous. Loci for autosomal dominant posterior polar cataracts have been mapped to chromosomes 1p36, 11q22-q22.3, 16q22, and 20p12-q12. We investigated a large four-generation family with 20 individuals affected with congenital posterior polar cataracts. After exclusion of known loci for posterior polar cataracts, a genome-wide screen was conducted. In this family, we mapped dominant congenital posterior polar cataracts to chromosome 10q24. On haplotype analysis, we identified an 11-cM interval between loci D10S1680 and D10S467, which included the PITX3 gene. On sequencing the coding region of PITX3, we found a 17-base-pair duplication in exon 4. Although the same genotype was described in a family with ASMD and cataracts, the common phenotype of this mutation is probably posterior polar cataract; a modifier gene is presumed to cause anterior segment abnormalities in the previously described patients. The same mutation was recently identified in four families with congenital cataracts. This study provides further evidence of genetic heterogeneity of autosomal dominant posterior polar cataract.

Amino Acid Sequence↗
PubMed2003

Quantitative genetic analysis of ventral midbrain and liver iron in BXD recombinant inbred mice.

Male and female mice from 15 of the BXD/Ty recombinant inbred strain panel were examined for regional brain and liver iron content. Brain regions included medial prefrontal cortex, nucleus accumbens, caudate-putamen and ventral midbrain. Our focal tissue was the ventral midbrain, containing the ventral tegmentum and substantia nigra. This area contains the perikarya of the dopamine neurons that project to nucleus accumbens and caudate-putamen. Genetic correlations between ventral midbrain and liver iron content were not statistically significant, suggesting that peripheral and central iron regulatory systems are largely independent. Correlations between ventral midbrain iron and iron in the caudate-putamen and nucleus accumbens, but not the prefrontal cortex were moderately high and significant. Ventral midbrain and liver iron contents were subjected to quantitative trait loci analysis to identify associated chromosomal locations. This analysis revealed several suggestive loci for iron content in ventral midbrain but fewer loci for liver. Genetic correlations between ventral midbrain iron and published dopamine functional indices were significant, suggesting a link between ventral midbrain iron status and central dopamine neurobiology. This work shows the value of quantitative genetic analysis in the neurobiology of iron and in showing the close association between ventral midbrain iron and nigrostriatal/mesolimbic dopamine function.

Animals↗
PubMed1981

Fine cytogenetical analysis of the band 10A1-2 and the adjoining regions in the Drosophila melanogaster X chromosome. II. Genetical analysis.

The X chromosome region 9F12-10A7 (7 bands removed by Df(1)VL3) was saturated with lethal, semi-lethal, visible and male sterile mutations A total of 11 complementation groups were found. In the more narrow interval of Df()1)VL1 which removes 3 bands (10A1-2, 10A3, 10A4-5) 6 loci were localised. - The band 10A1-2 consists of a sereis of 5 different subunits: (i) silent DNA where no functions were found - at the distal edge of the band; (ii) and (iii) two genes: v and 1(1)BP4; (iv) silent DNA in middle of the band, (v) locus sev on the proximal edge of the band. About 70% of the band's DNA was found to be silent. - Using the set of chromosome rearrangements removing different parts of the band it was shown that these five sequences may function independently from each other.

Animals↗
PubMed1989

Genetic analysis of eight loci tightly linked to neurofibromatosis 1.

The genetic locus for neurofibromatosis 1 (NF1) has recently been mapped to the pericentromeric region of chromosome 17. We have genotyped eight previously identified RFLP probes on 50 NF1 families to determine the placement of the NF1 locus relative to the RFLP loci. Thirty-eight recombination events in the pericentromeric region were identified, eight involving crossovers between NF1 and loci on either chromosomal arm. Multipoint linkage analysis resulted in the unique placement of six loci at odds greater than 100:1 in the order of pter-A10-41-EW301-NF1-EW207-CRI-L581-CRI-L946 -qter. Owing to insufficient crossovers, three loci--D17Z1, EW206, and EW203--could not be uniquely localized. In this region female recombination rates were significantly higher than those of males. These data were part of a joint study aimed at the localization of both NF1 and tightly linked pericentromeric markers for chromosome 17.

Chromosome Mapping↗
PubMed1997

Molecular genetic analysis of familial neuroblastoma.

Neuroblastoma has several clinical and molecular genetic parallels with the other paediatric embryonal tumours, such as retinoblastoma, including a hereditary form of the disease. We hypothesised that neuroblastoma susceptibility is due to germline mutations in a tumour suppressor gene and that this predisposition gene may be involved in sporadic neuroblastoma tumorigenesis as well. We therefore aimed to localise the familial neuroblastoma predisposition gene by linkage analysis in neuroblastoma kindreds. Eighteen families segregating for neuroblastoma were ascertained for candidate locus linkage analysis. Although many of the 49 affected individuals in these families were diagnosed as infants with multifocal primary tumours, there was marked clinical heterogeneity. We originally hypothesised that familial neuroblastoma predisposition would map to the telomeric portion of chromosome band 1p36, a genomic region likely to contain a sporadic neuroblastoma suppressor gene. However, neuroblastoma predisposition did not map to any of eight polymorphic markers spanning 1p36.2-.3 in three large kindreds. In addition, there was strong evidence against linkage to two Hirschsprung disease susceptibility genes (RET and EDNRB), a condition that can cosegregate with neuroblastoma as in one of the kindreds tested here. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 neuroblastoma suppressor and two of the currently identified Hirschsprung disease susceptibility genes.

Adult↗