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PubMed1991

Rapid genetic analysis of families with polycystic kidney disease 1 by means of a microsatellite marker.

Presymptomatic diagnosis of polycystic kidney disease 1 (PKD1) is possible by genetic linkage analysis with markers from both sides of the disease locus. The existing proximal markers are not informative in many families, so such analysis is difficult and time-consuming. We sought more useful length polymorphisms on the proximal side of the locus among simple sequence repeats (microsatellites). We identified two microsatellite polymorphisms that lie closer to the PKD1 locus than any previously described highly variable marker. One, SM7, is especially informative; we have found fourteen alleles and the observed heterozygosity in caucasians is 62.7%. Genetic linkage analysis in PKD1 families suggests that both of the markers lie proximal to the disease gene, closer than existing flanking markers. These polymorphisms can be simply assayed by polymerase chain reaction amplification of the variable regions, which generates DNA fragments that can be separated on non-denaturing acrylamide gels and directly examined after gel staining. This rapid, inexpensive, and non-radioactive method of linkage analysis allows the complete study of DNA samples within 8 h.

Alleles↗
PubMed1999

Patterning during organogenesis: genetic analysis of cardiac chamber formation.

A classical genetic approach, in which mutagenized organisms are screened for phenotypes of interest, is appealing for the analysis of developmental processes. Here, we describe the advantages of zebrafish genetics for the study of heart development. As an example of the utility of this strategy, we discuss its potential to illuminate the molecular mechanisms of cardiac chamber formation. The signals that specify ventricular and atrial lineages and the differentiation pathways that produce distinct chambers are poorly understood. Recently identified zebrafish mutations that disrupt ventricular or atrial development promise to reveal genes essential for these processes.

Animals↗
PubMed1986

Cancer family syndrome. Genetic analysis of 22 Finnish kindreds.

The genetic properties and the frequency of cancer family syndrome (CFS) were evaluated on the basis of 22 kindreds identified in Finland by investigating the family histories of young patients with colorectal carcinoma. These families had 196 members with malignancies: 120 colorectal (61%), 30 undefined intraabdominal (15%), 20 endometrial (10%), 7 gastric (4%), 5 biliary tract (3%) adenocarcinomas, and 14 (7%) other cancers. The present CFS patients represented 0.4% of all colorectal cancers diagnosed in Finland during 1961-1980, and the estimated minimum frequency of CFS was 4-4.7 X 10(-5) (1 in 25,100-21,400). An autosomal dominant pattern of genetic transmission for colorectal cancer was demonstrated through two to four generations, but the trait was also transferred by mothers with uterine carcinoma. The highest incidence of colorectal carcinoma occurred between 40 and 49 yr of age (15% per decade), and the cumulative risk in the descendants increased to 50% at 69 yr. The penetrance of CFS was 0.5-0.9. The analysis suggest that heredity is more significant in the etiology of colorectal cancer than has been previously believed. Identification of CFS seems to provide a good opportunity for screening the descendants of affected patients for colorectal cancer.

Adolescent↗
PubMed2005

Structural, functional, and genetic analysis of sorangicin inhibition of bacterial RNA polymerase.

A combined structural, functional, and genetic approach was used to investigate inhibition of bacterial RNA polymerase (RNAP) by sorangicin (Sor), a macrolide polyether antibiotic. Sor lacks chemical and structural similarity to the ansamycin rifampicin (Rif), an RNAP inhibitor widely used to treat tuberculosis. Nevertheless, structural analysis revealed Sor binds in the same RNAP beta subunit pocket as Rif, with almost complete overlap of RNAP binding determinants, and functional analysis revealed that both antibiotics inhibit transcription by directly blocking the path of the elongating transcript at a length of 2-3 nucleotides. Genetic analysis indicates that Rif binding is extremely sensitive to mutations expected to change the shape of the antibiotic binding pocket, while Sor is not. We suggest that conformational flexibility of Sor, in contrast to the rigid conformation of Rif, allows Sor to adapt to changes in the binding pocket. This has important implications for drug design against rapidly mutating targets.

Aminoglycosides↗
PubMed1993

Cell immortalization as a key, rate-limiting event in malignant transformation: approaches toward a molecular genetic analysis.

Recent advances using somatic cell genetic approaches have provided a convincing body of evidence that the senescence of mammalian cells in culture is controlled by a small group of genes, one or more of which are functionally deleted in the process of immortalization. Microcell-mediated mono-chromosomal transfer methods should permit precise mapping of these genes to specific chromosomal regions. Cloning of senescence genes, using either conventional 'positional cloning' techniques or retroviral insertion mutagenesis, is now a realistic possibility. The leap in our understanding of the molecular genetic events driving the alternative cellular states of limited proliferative capacity and immortality, which such advances should precipitate, will finally permit the question of the role of cell immortalization in cancer to be addressed, and may open the door to the design of new modes of cancer therapy. In addition, the precise mechanism underlying the wide difference in transformability between human and rodent cells, which should also emerge from these investigations, is likely to make a significant contribution towards resolving the key issue of the relevance of rodent tumour induction assays in assessing the potential carcinogenicity of environmental chemicals.

Animals↗
PubMed1994

Genetic analysis of alpha 2-adrenergic receptors and blood pressure using Dahl salt-sensitive rats.

OBJECTIVE: To evaluate the role of alpha 2-adrenergic receptors in genetic hypertension by cosegregation analysis using Dahl rats. DESIGN: Inbred Dahl salt-sensitive (SS/Jr) rats were crossed with inbred Dahl salt-resistant (SR/Jr) rats; also, SS/Jr rats were crossed with several control strains, and large F2 populations were subsequently produced from each cross. All F2 populations were raised on a high-salt diet. The rats were genotyped, where possible, at the loci for three different subtypes of alpha 2-adrenergic receptors designated as classes I, II and III. The blood pressures of the rats classified by genotype at each alpha 2-adrenergic receptor subtype locus were compared using analysis of variance. METHODS: Genomic clones of three classes of alpha 2-adrenergic receptors were isolated from genomic lambda-phage libraries of SS/Jr or SR/Jr rat strains, or both, by screening with complementary DNA for human alpha 2-adrenergic receptors. Fragments of the rat genomic clones obtained were used for genotyping by restriction fragment length polymorphism. Also, cloned genomic DNA flanking the alpha 2-adrenergic receptors and containing microsatellites was sequenced; genotyping at informative microsatellite markers was performed using the polymerase chain reaction. Two of the three classes of rat alpha 2-adrenergic receptors were localized to rat chromosomes by linkage analysis or using a panel of mouse-rat hybrid somatic cell lines. RESULTS: Rat alpha 2-adrenergic receptor classes I and III genes were assigned to rat chromosomes 14 and 3, respectively. These correspond to alpha 2-adrenergic receptor genes on human chromosomes 4 and 2, respectively. Extensive cosegregation analysis, involving five alleles in six segregating populations for class I alpha 2-adrenergic receptors, yielded no evidence of an effect of these loci on blood pressure. Classes II and III alpha 2-adrenergic receptors could each be tested in only one population and there was no evidence for an effect of either receptor gene on genetic differences in blood pressure. The dopamine-1B receptor was closely linked to the class I alpha 2-adrenergic receptor on rat chromosome 14. Thus, the negative cosegregation of the class I receptor with blood pressure applies equally to the dopamine-1B receptor. CONCLUSIONS: Genetic analysis in segregating populations involving crosses of inbred Dahl salt-sensitive rats with five other strains provides no evidence for a genetic effect of class I alpha 2-adrenergic receptors, or of the dopamine-1B receptor, on blood pressure. Classes II and III alpha 2-adrenergic receptors also failed to cosegregate with blood pressure but, because only limited testing was possible with the classes II and III receptors, this negative result is not definitive.

Animals↗
PubMed2005

Quantitative genetic analysis of the metabolic syndrome in Hispanic children.

Childhood obesity is associated with a constellation of metabolic derangements including glucose intolerance, hypertension, and dyslipidemia, referred to as metabolic syndrome. The purpose of this study was to investigate genetic and environmental factors contributing to the metabolic syndrome in Hispanic children. Metabolic syndrome, defined as having three or more metabolic risk components, was determined in 1030 Hispanic children, ages 4-19 y, from 319 families enrolled in the VIVA LA FAMILIA study. Anthropometry, body composition by dual energy x-ray absorptiometry, clinical signs, and serum biochemistries were measured using standard techniques. Risk factor analysis and quantitative genetic analysis were performed. Of the overweight children, 20%, or 28% if abnormal liver function is included in the definition, presented with the metabolic syndrome. Odds ratios for the metabolic syndrome were significantly increased by body mass index z-score and fasting serum insulin; independent effects of sex, age, puberty, and body composition were not seen. Heritabilities +/- SE for waist circumference, triglycerides (TG), HDL, systolic blood pressure (SBP), glucose, and alanine aminotransferase (ALT) were highly significant. Pleiotropy (a common set of genes affecting two traits) detected between SBP and waist circumference, SBP and glucose, HDL and waist circumference, ALT and waist circumference, and TG and ALT may underlie the clustering of the components of the metabolic syndrome. Significant heritabilities and pleiotropy seen for the components of the metabolic syndrome indicate a strong genetic contribution to the metabolic syndrome in overweight Hispanic children.

Adolescent↗
PubMedDate not supplied

Genetic analysis of a cross-pollinated species, Secale cereale L., for the character with polymorphic genetic basis.

Theoretical basis and an algorithm of calculations for frequencies of genes and genotypes in the population of species with obligate cross-pollination under assessment for the character of polymorphic genetic basis are proposed. Use of four rye populations and the F1 and F2 from their crossings allows to determine genetic control of beta-amylase spectrum through identification of two genes, establishment of the allele number in each gene, and showing the linkage between beta-Amy-1 and the gene for self-incompatibility S2.

Alleles↗
PubMed1995

Autosomal dominant, familial spastic paraplegia, type I: clinical and genetic analysis of a large North American family.

"Familial spastic paraplegia" (FSP) refers to clinically and genetically diverse syndromes characterized by insidiously progressive lower extremity spasticity. We evaluated 126 members of a large kindred, including 31 affected subjects, in which FSP was transmitted as a stereotyped, autosomal dominant disorder that showed complete genetic penetrance. Affected subjects developed insidiously progressive gait disturbance between ages 12 and thirty-five. Neurologic examination revealed hyperreflexia and spasticity in the lower extremities, weakness of hip flexion and ankle dorsiflexion, extensor plantar response, diminished vibratory sense in the feet, and pes cavus. Using genetic linkage analysis, we excluded the FSP1 locus on chromosome 14q11.2 as the disease locus in this family. We present the clinical and genetic features of FSP type I, including the age-adjusted risk of developing the disorder in this family.

Adolescent↗
PubMed1989

Diallel genetic analysis of the elements of paradise fish's (Macropodus opercularis L.) behavior in familiar and novel situations.

Elements of the paradise fish's ethogram were recorded in 1 familiar and 3 different unfamiliar situations and the inheritance of these behavioral elements was investigated employing a five times replicated diallel cross between 3 inbred strains. A generalized Hayman Analysis of Variance and a Variance Covariance Analysis were performed to estimate genetic effects and parameters, such as, additive genetic variance, different sorts of dominance variance, reciprocal effects, direction and degree of dominance, ratio between the frequency of dominant and of recessive alleles, minimum number of effective factors and heritabilities, etc. Knowing the genetic architecture, we make inferences about the possible evolutionary past of the behavioral elements and explain why selection might favor certain types of paradise fish's behavior in particular circumstances. In several cases a possibility of "monogenic" inheritance emerged. We explain this finding and conclude that in a cross experiment where the inheritance of phenotypical units are investigated by employing only a few genetically different strains this result may be expected.

Alleles↗
PubMed2005

Linkage disequilibrium mapping via cladistic analysis of phase-unknown genotypes and inferred haplotypes in the Genetic Analysis Workshop 14 simulated data.

We recently described a method for linkage disequilibrium (LD) mapping, using cladistic analysis of phased single-nucleotide polymorphism (SNP) haplotypes in a logistic regression framework. However, haplotypes are often not available and cannot be deduced with certainty from the unphased genotypes. One possible two-stage approach is to infer the phase of multilocus genotype data and analyze the resulting haplotypes as if known. Here, haplotypes are inferred using the expectation-maximization (EM) algorithm and the best-guess phase assignment for each individual analyzed. However, inferring haplotypes from phase-unknown data is prone to error and this should be taken into account in the subsequent analysis. An alternative approach is to analyze the phase-unknown multilocus genotypes themselves. Here we present a generalization of the method for phase-known haplotype data to the case of unphased SNP genotypes. Our approach is designed for high-density SNP data, so we opted to analyze the simulated dataset. The marker spacing in the initial screen was too large for our method to be effective, so we used the answers provided to request further data in regions around the disease loci and in null regions. Power to detect the disease loci, accuracy in localizing the true site of the locus, and false-positive error rates are reported for the inferred-haplotype and unphased genotype methods. For this data, analyzing inferred haplotypes outperforms analysis of genotypes. As expected, our results suggest that when there is little or no LD between a disease locus and the flanking region, there will be no chance of detecting it unless the disease variant itself is genotyped.

Chromosome Mapping↗
PubMed1997

Genetic analysis of a quantitative trait in a mouse model of polycystic kidney disease.

The development of a variety of powerful tools for genome analysis has facilitated the ability to genetically map loci which contribute to the variation of a quantitative trait. However, the fact that these traits are often determined as a result of complex genetic interactions has made their analysis considerably more difficult then the molecular characterization of qualitative traits that are monogenic in origin. We have described the use of a novel method of chromosomal exclusion to map the recessive mutation juvenile cystic kidney (jck) to mouse chromosome 11 using an intercross between (C57BL/6J x DBA/2J) F1 jck/+ mice. The severity of polycystic kidney disease (PKD) in the intercross progeny, which could be quantitated as a function of kidney size, was significantly more variable than that found in the parental C57BL/6J strain, suggesting that a modifier locus or loci introduced from DBA/2J affects expression of jck. Two regions (one from DBA/2J on chromosome 10 and a second from C57BL/6J on chromosome 1) were found to be associated with inheritance of a more severe PKD phenotype. The finding of a highly significant association of inheritance of a C57BL/6J-related locus with disease severity was unexpected since the PKD phenotype in this inbred background is mild. This result suggests that inheritance in the affected F2 mice of loci from the two different parental backgrounds results in the more severe phenotype, presumably as a consequence of a direct or indirect interaction between their protein products. This type of effect, which is an example of genetic epistasis, will make the molecular characterization of loci that contribute to complex traits markedly more difficult than the analysis of monogenic disorders.

Animals↗
PubMed1993

The origins of individual differences in memory among the elderly: a behavior genetic analysis.

The purpose of this investigation was to apply behavior genetic methods to investigate individual differences in memory performance. Memory and various cognitive and lifestyle variables were obtained from 93 monozygotic twin pairs and 67 dizygotic twin pairs aged 60-88 years as part of the Minnesota Twin Study of Adult Development and Aging. Univariate analysis, used to determine the relative influence of genetic and environmental factors on 4 measures of memory (word recall, immediate and delayed text recall, and figure memory), suggested that 55% of the variance in memory performance could be attributed to genetic factors. Bivariate analysis was used to determine the specific variables that mediate the genetic and environmental influences on memory. Results suggested that the relationship between memory and cognitive variables was genetic in nature, whereas the nature of the relationship between memory and lifestyle variables was environmental.

Aged↗
PubMed1985

Genetic analysis of field trials of sex-linked translocation strains for genetic control of the Australian sheep blowfly Lucilia cuprina (Wiedemann).

The results of progeny tests of males and females captured during two field trials of sex-linked translocation strains for genetic control of L. cuprina are presented. Males released as mature larvae survived to adulthood and mated with field females. However, the levels of genetic death introduced into the population were insufficient to suppress the native population. This was due partly to seasonal ineffectiveness of the release method, and partly to poor performance of the released males. On average, the mating competitiveness of the released males was only one-third that of field males, whereas their field-reared, translocation-bearing sons were fully competitive with native males.

Animals↗
PubMed2001

FISH analysis of replication and transcription of chromosome X loci: new approach for genetic analysis of Rett syndrome.

Differential replication staining using the 5-bromo-2'-deoxyuridine+Hoechst 33258 technique has been carried out on a series of 28 girls with Rett syndrome (RTT). The results indicated that regions Xq23 and Xq28 of inactive chromosome X could contain early replicating and, therefore, transcriptionally active loci in RTT. Interphase fluorescence in situ hybridization studies of replication timing, using chromosome X-specific genomic DNA probes, was applied to determine the loci with altered replication and transcription in RTT. Randomly selected P1 artificial chromosome (PAC) clones for Xp, Xcen and Xq were used. Two PAC clones from Xq28 (anonymous clone 24.23.0 and 671D9, containing MeCP2 locus) probably escape inactivation in late replicating chromosome X in some RTT patients. Therefore, region Xq28 could contain the genes escaping X inactivation and with expression from the human active and inactive X chromosomes. These results support the hypothesis proposing the disturbances in dosage compensation effect due to aberrant activation of genes in inactive chromosome X in RTT (bi-allelic expression instead of mono-allelic). Our results indicate that the normal allele of the MeCP2 gene could escape X inactivation and reduce the pathogenic effect of mutated allele in RTT.

Adolescent↗
PubMed1998

Genetic analysis of extended life span in Drosophila melanogaster. I. RAPD screen for genetic divergence between selected and control lines.

Using lines selected for long life by Luckinbil and his co-workers, we screened two selected and two control lines for allelic frequency differences at 1200 randomly chosen RAPD marker loci. Twenty-three marker loci showed frequency differences in excess of 80%, and five were greater than 90%. Age-specific effects of the five most differentiated loci were estimated by collecting complete survival data in segregating backcross populations. Alleles at four of the five marker loci were associated with significant extension of life span in males, while two marker loci had significant effects in females. Eighty percent of the total selection response in males can be explained by the identified QTL's, under the assumption of additivity. The N14+ marker allele accounted for a 12-day life span extension in males, but had little effect in females. Both sex-limited and sex-shared effects were observed. Analysis of age-specific mortality rates suggests that life span extension occurs by a combination of genetic factors that moderate both the level of mortality and the rate at which mortality increases with age.

Aging↗
PubMed2003

Bimodal run distribution in a northern population of sockeye salmon (Oncorhynchus nerka): life history and genetic analysis on a temporal scale.

Life history variation and genetic differentiation were analysed in sockeye salmon in Klukshu River, Yukon Canada over 7 years (1994-2000). Sockeye salmon return to the Klukshu River in two distinct runs, with a small 'early run' in June-August, and a larger 'late run' in August-September. A maximum likelihood test for clusters indicated that the return frequency distribution was bimodal in all the years analysed. Life history differences (fork length, sex ratio, age at maturity, fresh- and saltwater residency times) were found between the early and late runs; however, inconsistent patterns suggest that environmental effects outweigh, or strongly interact with, genetic effects for the life history characters evaluated. Analysis of variation at eight microsatellite loci showed that the early and late runs are genetically differentiated in all years examined (exact test). FST estimates between runs within years were significantly greater than zero (range: 0.018-0.041) for all years except one (0.004). The genetic variance explained by early vs. late runs (2.27%) was twice the variance among years (1.16%) based on analysis of molecular variance. Our neighbour-joining tree showed early and late runs generally clustering separately, indicating higher gene flow among the early or late run fish across years relative to between-run gene flow. Two years did not fit the general clustering pattern; although the early and late runs in 1995 and 2000 were genetically differentiated, they clustered separately from the rest of the groups. We cannot offer a definitive explanation for these anomalies; however, an analysis of possible cryptic population structure in early and late runs indicated that at least a few fish strayed between the runs in each year, and the highest rate of mixing was in 1995 and 2000. Our data indicate that the runs are at least partially reproductively isolated as a result of temporal and/or spatial isolating mechanisms. Such reproductive isolation has important implications for conservation and management of the Klukshu sockeye salmon, and make them an evolutionarily interesting group because of parallels with incipient speciation.

Alleles↗
PubMed2000

[Genetic analysis on flowering and boll setting in upland cotton (Gossypium hirsutum L.). III. Genetic behavior at different developing stages].

An additive-dominant genetic model with genotype by environment interaction was employed to analyze the genetic behavior of flowering and fruiting at different development stages, with 2-year data from 4 x 4 diallel crosses. The results of variance analysis indicated that flowering and fruiting behaviors were mainly controlled by dominant effects at early period, but by additive effects later on. Compared with genetic main effects, GE interaction effects playeda minor role on the flowering and fruiting behavior. The analysis of covariance between average flower number, boll number at different development stages and total number of bolls showed that there were significant positive dominant correlation and negative or zero additive correlation before August 1st, but having the opposite results afterward. Interaction correlation existed during the whole period. It was found, by further analysis of conditional variances, that different development stages have diverse gene action intensity. The last ten days of July and the first-middle ten days of August had the highest gene action level. Time interval of investigation played a great role on exploring the law of gene action during the flowering and fruiting period; when selecting the time interval of investigation, it is necessary to contemplate the purpose of the experiment, environmental condition, investigating traits and developing period simultaneously.

Gossypium↗