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PubMed1990

Evidence of a rare gene for low systolic blood pressure in the Framingham Heart Study.

A major risk factor for coronary heart disease in both men and women is elevated systolic blood pressure (SBP). We performed segregation analysis on age, sex-adjusted, and transformed systolic blood pressure data on 1,141 families from the Framingham cohort-offspring study using the segregation analysis program POINTER. The results of hypothesis testing revealed: (1) these data are consistent with familial transmission; (2) there is evidence for the transmission of a rare, major gene for low SBP with a gene frequency of q = 0.02; and (3) most of the transmissible component to SBP can be attributed to the polygenic background with H = 0.31.

Adult↗
PubMed2004

Complex segregation and linkage analysis of familial gout in Taiwanese aborigines.

OBJECTIVE: The prevalence of gout and hyperuricemia in Taiwanese aborigines is remarkably high. Although previous studies have failed to find evidence of a major gene responsible for gout, the disease is thought to involve genetic predisposition. We sought to determine whether genetic factors for familial gout exist among Taiwanese aborigines, and, if so, their chromosomal location. METHODS: We first performed complex segregation analysis. The study sample comprised 945 relatives distributed in 64 pedigrees; among them, 261 affected members (including probands) were found. In all of the aboriginal probands with gout, the disease was diagnosed and confirmed by rheumatologists. Blood specimens were then collected from 127 individuals living in one community that was used in the segregation analysis (from 25 pedigrees, 36 nuclear families, and 112 full sibpairs), and sibpair linkage analysis and a combined transmission disequilibrium test (TDT) method were used to test the genetic components. RESULTS: In segregation analysis, after adjusting for sex and age, an autosomal-arbitrary major gene model was found to fit the data best, with disease allelic frequency of 0.31 and susceptibility of 0.92. In sibpair analysis, there was a clustering of many flanking markers showing significant linkage, including D1S498 (regression coefficient -0.52), D1S2635 (regression coefficient -0.47), and D1S196 (regression coefficient -0.51), in the 1q21 region of chromosome 1 (all P < 0.005). Results of the combined TDT showed that the marker D1S484 was significantly associated (had linkage) with allele 1 and was transmitted more frequently than other markers to the affected offspring (P < 0.005). CONCLUSION: Results of this study provide evidence of a genetic basis for familial gout in the aboriginal Taiwanese population and suggest that a susceptibility locus may be located in the 1q21 region of chromosome 1.

Adult↗
PubMed1993

Polymorphic 2-hydroxylation of desipramine. A population and family study.

We have studied desipramine hydroxylation capacity, determined as the metabolic ratio of desipramine to 2-hydroxydesipramine in the urine after a single oral dose of 10 mg of desipramine, in 340 Swedish Caucasians, including the members of 45 two-generation families. Desipramine metabolic ratios were bimodally distributed among 237 unrelated subjects and 8% were poor metabolizers. There was a strong correlation between the metabolic ratios for desipramine and debrisoquine in 337 subjects phenotyped with both drugs and there was no dissociation between their capacities to hydroxylate desipramine and debrisoquine. Complex segregation analysis in the 45 families gave evidence for a major locus with incomplete recessivity (d = 0.14) controlling the 2-hydroxylation of desipramine. Similar results were obtained in segregation analysis for debrisoquine. There was evidence for linkage between the CYP2D6 gene and the gene regulating the hydroxylation of desipramine and debrisoquine. This study has provided unequivocal evidence that the capacity to 2-hydroxylate desipramine is polymorphic and under similar genetic control to the hydroxylation of debrisoquine.

Adolescent↗
PubMed1995

Segregation and linkage analysis of the complex trait Q1.

Segregation and linkage analysis of GAW9 Problem 2 quantitative trait 1 (Q1) was performed. Eight segregation models comprising all possible combinations of the environmental factor (EF), quantitative trait 2 (Q2), and quantitative trait 3 (Q3) as covariates were considered. Seven of the eight segregation models showed strong evidence for a major gene, the other model was marginal. When all genotypes are known, some evidence for linkage (lod > 2) was found to all three of the markers that affect Q1. Furthermore, four of the eight models each showed some linkage (lod > 2) to two of the three markers that affect Q1 with no false positives. Each of these segregation analysis major genes is a hybrid combination of the true multiple loci that affect Q1.

Alleles↗
PubMed1999

Detection of quantitative trait loci associated with alcohol-dependence: use of model-free sib-pair method and combined segregation-linkage analysis based on regressive models.

Two linkage methods were used to detect loci underlying neurophysiological measures associated with alcohol dependence 1) the Haseman-Elston (H-E) sib pair method for genome-wide search, and 2) the combined segregation-linkage (CSL), based on regressive models, to confirm positive linkages found by the genome screening. Among 14 linkage results that were significant at the 0.5% level using H-E, the CSL method leads to similar p-values in only three cases but to higher p-values in all others. Investigation of these discrepancies shows that assumptions (normality and homoscedasticity of the error term) of H-E least-squares regression method are not verified. A robust estimator of slope parameters without assuming any distribution function for the linear model error terms increases the p-values and reduces the difference between H-E and CSL results. Alternatively, the CSL approach may lack power when multiple genes with small effects are involved.

Alcoholism↗
PubMed1996

Genetic analysis of serum alanine transaminase activity in normal and hepatitis C virus-infected chimpanzees: an application of research-oriented genetic management.

The hepatic enzyme alanine transaminase (ALT) is a diagnostic marker for liver damage but has a considerable degree of normal variation. We used complex segregation analysis to determine whether evidence exists for major genic determination of normal ALT values in an important animal model, the chimpanzee (Pan troglodytes). Normal ALT values were available for 212 chimpanzees. Available genealogical data allowed assignment of 165 animals to a total of 19 pedigrees; 47 animals were treated as independent. A major gene explaining 60% of the phenotypic variance in normal alanine transaminase (ALT) activity was detected by complex segregation analysis. The allele for high ALT activity had a frequency of 0.20. Polygenes accounted for an additional 20% of the variation. The observation that 80% of the total phenotypic variance is attributable to genetic factors has important implications for studies that use ALT activity in assessments. Genetic analysis of change in ALT activity after inoculation with hepatitis C virus (HCV) in a subset of animals indicated that approximately 30% of the variation in response may also be attributable to genetic factors and that the estimated major locus genotypes differ in their responses. This suggests that genetic components can exert substantial influences on experimental parameters in hepatitis research.

Alanine Transaminase↗
PubMed2002

Detection of putative functional angiotensinogen (AGT) gene variants controlling plasma AGT levels by combined segregation-linkage analysis.

Previous studies have suggested that angiotensinogen (AGT) gene variants are associated with increased plasma AGT levels, and may also contribute towards the inherited component of predisposition to essential hypertension in humans. To explore the potential functionality of several AGT polymorphisms and estimate their effects, together with other sources of familial correlations, on plasma AGT, we undertook a large study involving 545 healthy French volunteers in 130 nuclear families that include 285 offspring. Plasma AGT levels were measured in all participants, and bi-allelic AGT variants were analysed as candidate functional variants at three sites in the 5'-flanking region (C-532T, A-20C, G-6A), two sites in exon 2 (M235T, T174M) and two newly identified variant sites in the untranslated sequence of exon 5 and the 3'-flanking region (C+2054A, C+2127T) of the gene. Analysis with the class D regressive model showed significant effects influencing plasma AGT levels of all AGT polymorphisms tested, with the exception of T174M. The most significant result was found at C-532T (P=0.000001), which accounts for 4.3% of total plasma AGT variability in parents and 5.5% in offspring, with substantial residual familial correlations. Maximum likelihood estimates of haplotype frequencies and tests of linkage disequilibrium between each AGT polymorphism and a putative QTL are in agreement with a complete confounding of C-532T with the QTL, when taking into account sex and generation specific effects of the QTL. However, further combined segregation-linkage analyses showed significant evidence for additional effects of G-6A, M235T and C+2054A polymorphisms after accounting for C-532T, which supports a complex model with at least two functional variants within the AGT gene controlling AGT levels.

Analysis of Variance↗
PubMed1996

Single-parent segregant pools for allocation of markers to a specified chromosomal region in outcrossing species.

Bulked co-segregant analysis is a method of rapidly allocating unmapped genetic markers to a specific chromosomal region. Although originally developed for utilization in populations derived from crosses between fully inbred lines, it has been proposed that co-segregant pools could also serve the same purpose in outbreeding populations, if individuals from only a single large family are pooled. Large, fully mapped, single-sire backcross and half-sib families are presently available as part of the international chicken and bovine reference family panels respectively. In this study, power and tests of significance for single-parent co-segregant analysis are derived for full-sib, single-parent back-cross and single-parent half-sib families, as a function of proportion of recombination between index marker and linked marker, pro-portion of single-parent alleles among the mates, number of individuals in each segregant pool and technical error variance. Power was found to be greater than 0.80 for many reasonable parameter combinations. The method is illustrated using microsatellite markers and a large single-sire bovine family, part of the international bovine reference family panel.

Alleles↗
PubMed1984

Segregation analyses of stuttering.

Although stuttering is known to be a familial disorder, no clear evidence regarding precise mode of transmission has arisen from previous research. In this report segregation analysis is applied to data on 386 stuttering probands and their first-degree relatives in an effort to discriminate among possible genetic models for the transmission of stuttering. Two different segregation analysis programs, PAP and POINTER, gave comparable results with respect to both hypothesis testing and parameter estimation. Specifically, the transmission of stuttering observed in these families cannot be adequately explained by a Mendelian major locus. The hypothesis of no polygenic component in the transmission of stuttering can, however, be rejected. Existence in these data of potential heterogeneity and possible violations of assumptions concerning ascertainment are considered in interpreting the results.

Adolescent↗
PubMed2003

A fluorescent method for detecting low-grade 11patUPD mosaicism in Beckwith-Wiedemann syndrome.

The quantitative evaluation of mosaicism for uniparental disomy (UPD) involving a restricted chromosomal region requires the availability of a sensitive and reproducible method that is capable of detecting even a small percentage of disomic cells and avoiding false positive and false negative results. The occurrence of UPD is usually monitored by means of the parent-proband segregation analysis of microsatellites mapping to the target region. We here describe the quantitative blood cell evaluation of segmental mosaic UPD11, a marker of Beckwith-Wiedemann syndrome, by means of the segregation analysis of 11p15 microsatellites using both radioactive and fluorescence-based techniques. As the greater amplification efficiency of the shorter allele in heterozygous subjects may bias the correct evaluation of disomy, the mean short/long allele ratio was established at three loci of each of 30 normal heterozygous subjects, as well as the peak As/Al area in the presence of 50% of each allele. The interval was defined using a 5% level of significance. The results show that the fluorescence-based technique is superior to radioactivity in detecting the subtle allelic imbalances present in low-grade mosaicism conditions.

Alleles↗
PubMed2005

Soybean phytophthora resistance gene Rps8 maps closely to the Rps3 region.

Root and stem rot is one of the major diseases of soybean. It is caused by the oomycete pathogen Phytophthora sojae. A series of resistance genes (Rps) have been providing soybean with reasonable protection against this pathogen. Among these genes, Rps8, which confers resistance to most P. sojae isolates, recently has been mapped. However, the most closely linked molecular marker was mapped at about 10 cM from Rps8. In this investigation, we attempted to develop a high-density genetic map of the Rps8 region and identify closely linked SSR markers for marker-assisted selection of this invaluable gene. Bulk segregant analysis was conducted for the identification of SSR markers that are tightly linked to Rps8. Polymorphic SSR markers selected from the Rps8 region failed to show cosegregation with Phytophthora resistance. Subsequently, bulk segregant analysis of the whole soybean genome and mapping experiments revealed that the Rps8 gene maps closely to the disease resistance gene-rich Rps3 region.

Breeding↗
PubMed2001

Segregation patterns and heteroplasmy prevalence in Leber's hereditary optic neuropathy.

PURPOSE: To investigate the segregation pattern of the mitochondrial DNA mutation at nucleotide position 3460 responsible for Leber's hereditary optic neuropathy (LHON) and to determine the prevalence of heteroplasmy for the three primary LHON mutations at positions 11778, 3460, and 14484. METHODS: Segregation analysis was performed in a cross-sectional study by determining the level of heteroplasmy in blood leukocytes of 23 LHON patients and unaffected carriers from four unrelated families. One family comprising two affected and three unaffected carriers was followed over 5.5 years for a longitudinal segregation analysis of heteroplasmy. The percentage of mutant mtDNA was determined using a novel procedure of fluorescence-based primer extension and restriction fragment length polymorphism analysis. The prevalence of heteroplasmy was assessed by determining the number of genealogically unrelated LHON pedigrees with heteroplasmic maternal family members from the LHON patient records of the Department of Ophthalmology, University of Tübingen, Germany. RESULTS: The authors observed a marked variability in the degree of heteroplasmy levels within each pedigree and a tendency toward a higher mutant allele frequency in offspring generations. Disease expression was correlated with higher levels of mutant mtDNA molecules. Longitudinal analysis revealed no statistically significant decrease in the heteroplasmy level in the family studied but a reduction of 11% and 12% in one affected and one unaffected individual, respectively. In 167 genealogically unrelated LHON families the prevalence of heteroplasmy was 5.6%, 40%, and 36.4% for the 11778, 3460, and 14484 LHON mutations, respectively. CONCLUSIONS: Cross-sectional studies of heteroplasmy for the 3460 LHON mutation suggest that the genotype shifts toward a higher mutational load in offspring generations. Long-term decrease in the blood mutant load in single cases indicates negative selection of the mutant allele in the hematopoietic cell system. The prevalence of heteroplasmy varies significantly between the different primary LHON mutations, suggesting genotypical differences in disease expression.

Chromosome Segregation↗
PubMed2002

Seek protein which can interact with hepatitis B virus X protein from human liver cDNA library by yeast two-hybrid system.

AIM: To seek the X associated protein (XAP) with the constructed bait vector pAS2-1X from normal human liver cDNA library. METHODS: The X region of the HBV gene was amplied by PCR and cloned into the eukaryotic expression vector pAS2-1. The reconstituted plasmid pAS2-1X was transformed into the yeast cells and the expression of X protein (pX) was confirmed by Western blot analysis. Yeast cells were cotransformed with pAS2-1X and the normal human liver cDNA library and were grown in selective SC/-trp-leu-his-ade medium, the second screen was performed with the LacZ report gene. Furthermore, segregation analysis and mating experiment were performed to eliminate the false positive and the true positive clones were selected for PCR and sequencing. RESULTS: Reconstituted plasmid pAS2-1X including the anticipated fragment of X gene was proved by auto-sequencing assay. Western blot analysis showed that reconstituted plasmid pAS2-1X expressed BD:X fusion protein in yeast cells. Of 5 x 10(6) transformed colonies screened,65 grew in the selective SC/-trp-leu-his-ade medium, 5 scored positive for beta-gal activity, and only 2 remaining clones passed through the segregation analysis and mating experiment. Sequence analysis identified that two clones contained similar cDNA fragment:GAACTTGCG. CONCLUSION: The short peptide(glutacid-leucine-alanine)is a possible required site for XAP binding to pX. Normal human liver cDNA library has difficulties in expressing the integrated XAP on yeast cells.

Base Sequence↗
PubMed2006

Podoconiosis: a tropical model for gene-environment interactions?

Podoconiosis (endemic non-filarial elephantiasis) is a geochemical disease occurring in individuals exposed to red clay soil derived from alkalic volcanic rock. It is a chronic, debilitating disorder and a considerable public health problem in at least 10 countries in tropical Africa, Central America and northern India. Only a small proportion of individuals exposed to red clay develop disease and familial clustering of cases occurs, so we tested the hypothesis that disease occurs in genetically susceptible individuals on exposure to an environmental element in soil. Using multiple statistical genetic techniques we estimated sibling recurrence risk ratio (lambda(s)) and heritability for podoconiosis, and conducted segregation analysis on 59 multigenerational affected families from Wolaitta Zone, southern Ethiopia. We estimated the lambda(s) to be 5.07. The heritability of podoconiosis was estimated to be 0.629 (SE 0.069, P=1x10(-7)). Segregation analysis showed that the most parsimonious model was that of an autosomal co-dominant major gene. Age and use of footwear were significant covariates in the final model. Host genetic factors are important determinants of susceptibility to podoconiosis. Identification of the gene(s) involved will lead to better understanding of the gene-environment interactions involved in the pathogenesis of podoconiosis and other complex multifactorial conditions.

Age of Onset↗
PubMed1992

Wiskott-Aldrich syndrome carrier detection with the hypervariable marker M27 beta.

Whole-blood cells of obligate carriers of the X-linked Wiskott-Aldrich syndrome (WAS) exhibit nonrandom inactivation of the X-chromosomes. However, because of the limited polymorphism of the probes available, the X-methylation pattern can only be determined in a restricted proportion of females. We thus analysed a large set of normal females and members of WAS families, using the recently described marker M27 beta, which detects the hyperpolymorphic locus DXS255. The probe was used to detect differences in methylation between the active and inactive X-chromosome, and the findings were compared with the pattern obtained using the well-documented probes from the 5' end of the PGK and HPRT genes. All the normal females were found to use either X-chromosome randomly, and there was complete correlation between the three probes in the populations studied. Segregation analysis performed with M27 beta and other related markers in the WAS families was fully in accordance with the X-inactivation data. The use of M27 beta, for both X-inactivation and segregation analysis of WAS kindreds, provides a basis for genetic counselling in the majority of families, including those with no surviving males.

DNA Probes↗
PubMedDate not supplied

Bone ageing: genetics versus environment.

Bone ageing results from a complex interaction between genetic and environmental factors (such as diet, climate and physical exercise) throughout human life. According to current literature, the most popular measures of bone ageing are osseometric measurements (OSM), bone mineral density (BMD) and osseographic scores (OSS), based on descriptive criteria of bone age. Plain roentgenography allows simultaneous assessment of all three measures. Ethnic differences with regard to these bone ageing characteristics have prompted us to study to the process anew, with the aim of elucidation the nature of the genetic and environmental components involved, and the possible interaction(s) between them. Despite abundant data on ethnic differences regarding these measures, modern knowledge on the genetics of these processes has derived primarily from the family studies of BMD, which pointed to strong involvement of the familial factors on bone mass. Segregation analysis performed by us in two ethnically different samples of pedigrees revealed a significant effect of the putative major gene on BMD of both compact and cancellous bone. The major finding of our bivariate segregation analysis was that it lead to the acceptance of the hypothesis predicating a single major locus with pleiotropy to both cancellous and compact BMD, but clearly rejecting the polygenic hypotheses. Our study of cortical index (CI) provided evidence that a single potential major gene controls not only the baseline trait level, but also the age at onset of the involutive bone changes, and the rate of the CI change with age. When we examined the environmental vs genetic influences on OSS variation in 32 human populations, we found very little environmental effect on the rate of bone change (r2 = 0.107), but a substantial effect on this rate of the genetic differences between populations (r = 0.480). Clarification of the genetic basis of bone ageing could have wide-ranging applications in the prevention and treatment of bone degenerative diseases such as osteoporosis and osteoarthritis, before irreversible damage takes place. There is thus a need to target the genetic analysis of BMD and the biochemical regulating factors of bone turnover through the use of molecular genetic techniques.

Aging↗
PubMed2004

[Screening hepatitis B virus X-interactive proteins by yeast two-hybrid system].

BACKGROUND & OBJECTIVE: Hepatitis B virus-encoded X protein is a promiscuous transactivator and contributes to the development of hepatocellular carcinoma. Protein-protein interaction seems to be crucial for HBx transactivation. The aim of this study was to screen and identify the proteins which interact with hepatitis B virus (HBV) X protein by yeast two-hybrid system. METHODS: HBV X gene was amplified by polymerase chain reaction (PCR). HBV X bait plasmid, named pAS2-1-X, was constructed by yeast-two hybridization system 3 and verified by sequencing. pAS2-1-X was transformed into the yeast AH109, and X-BD fusion protein expressed in the yeast cells was confirmed by Western blot analysis. Yeast cells cotransformed with pAS2-1-X and normal human liver cDNA library were cultured in selective SC/-trp-leu-his-ade medium. The second screening was performed with beta-gal activity detection. The false positive clones were eliminated by segregation analysis and mating experiment. The real positive clones were amplified, sequenced, and analyzed with bioinformatics. RESULTS: Bait plasmid pAS2-1-X was successfully constructed. The result of Western blot analysis confirmed that pAS2-1-X correctly expressed X-BD fusion protein in the transformed yeast AH109. Ninety-seven clones grew in the selective SC/-trp-leu-his-ade medium; however, only one clone past through the beta-gal activity detection, segregation analysis, and mating experiment. The inserted cDNA fragment of positive clone showed high homology with Fis gene. CONCLUSION: Fis protein is a novel protein which can interact with X protein in vivo by yeast two-hybrid system.

Gene Library↗
PubMed2002

Interactions between genetic and reproductive factors in breast cancer risk in a population-based sample of African-American families.

Incidence of breast cancer (BC) varies among ethnic groups, with higher rates in white than in African-American women. Until now, most epidemiological and genetic studies have been carried out in white women. To investigate whether interactions between genetic and reproductive risk factors may explain part of the ethnic disparity in BC incidence, a genetic epidemiology study was conducted, between 1989 and 1994, at the Howard University Cancer Center (Washington, DC), which led to the recruitment of 245 African-American families. Segregation analysis of BC was performed by use of the class D regressive logistic model that allows for censored data to account for a variable age of onset of disease, as implemented in the REGRESS program. Segregation analysis of BC was consistent with a putative dominant gene effect (P < 0.000001) and residual sister-dependence (P < 0.0001). This putative gene was found to interact significantly with age at menarche (P = 0.048), and an interaction with a history of spontaneous abortions was suggested (P = 0.08). A late age at menarche increased BC risk in gene carriers but had a protective effect in non-gene carriers. A history of spontaneous abortions had a protective effect in gene carriers and increased BC risk in non-gene carriers. Our findings agree partially with a similar analysis of French families showing a significant gene x parity interaction and a suggestive gene x age at menarche interaction. Investigating gene x risk factor interactions in different populations may have important implications for further biological investigations and for BC risk assessment.

Abortion, Spontaneous↗