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At least 1,189 records · Page 66Linked to original sources
PubMed1988

Reactivity of Ly-2+ T cells against 2,4,6-trinitrophenyl (TNP)-modified syngeneic stimulator cells: specificity, frequency of interleukin 2-producing Ly-2+ helper T cells and clonal segregation from Ly-2+ cytotoxic T lymphocytes.

The in vitro reactivity of purified murine Ly-2+ and L3T4+ T cells towards 2,4,6-trinitrophenyl (TNP)-modified syngeneic stimulator cells was analyzed. Both T cell subpopulations autonomously proliferated and produced interleukin 2. In either the Ly-2+ or L3T4+ T cell subset the frequencies of TNP-specific interleukin 2 (IL 2)-producing T lymphocyte precursors (IL 2 TL-p) were equally high (f = 1/400-1/1000). Clonally developing IL 2 TL of either T cell subset showed an exquisite antigen (TNP) specificity as shown by the split culture approach. TNP-specific Ly-2+ IL-2 TL used class I MHC (H-2Kk) gene products as major histocompatibility complex (MHC) restriction elements, while L3T4+ IL 2 TL proved to be class II MHC (H-2I-AkI-Ek) restricted. Clonal segregation analyses revealed that the majority of clonally developing TNP-reactive Ly-2+ TL segregated into either IL 2 TL-p or cytotoxic T lymphocyte presursors, i.e. both functions appear to be mutually exclusive. Less than 10% of the responding Ly-2+ T cells seemed to be bifunctional. These findings provide compelling evidence for the L3T4+ T cell-independent, autonomous reactivity of Ly-2+ T cells in MHC-restricted antigen-specific responses and suggest T-T cell interactions within the functional heterogenous Ly-2+ T cell population.

Animals↗
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↗
PubMed1986

Segregation analysis of hereditary nonpolyposis colorectal cancer.

Segregation analysis of eleven families comprising 2762 individuals indicated compatibility of the data with segregation of a major autosomal dominant gene for hereditary nonpolyposis colorectal cancer. It was estimated that between 71% and 79% of the gene carriers were susceptible and had age of onset that was normally distributed with mean about 47 and standard deviation about 10 years. There was a low frequency of sporadic cases at the older ages, a little less than four percent of nongene carriers being affected by age 80. No significant differences were found between the families exhibiting endometrial cancer (cancer family syndrome) and those not exhibiting endometrial cancer (hereditary site-specific nonpolyposis colonic cancer).

Adult↗
PubMed1986

Complex segregation analysis of low levels of plasma high-density lipoprotein cholesterol in a sample of nuclear families in Jerusalem.

Low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased risk of coronary heart disease (CHD). Therefore, assessment of the mode of inheritance of HDL-C is of importance. HDL-C concentrations in 3,074 nuclear families in the multiethnic Jerusalem Lipid Research Center study population were analyzed for possible involvement of major genes in determination of low levels of this trait. Complex segregation analysis under the mixed model of inheritance (major gene and multifactorial components) was performed on transformed HDL-C concentrations after adjustment for age, sex, and environmental measures. Evidence for segregation of a recessive major gene for depressed HDL-C, with an allele frequency of q = 0.06, in addition to multifactorial transmission (H = 0.45) was found in these families. Estimates from the mixed model were homogeneous across the different ethnic groups. When the substantial multifactorial background was excluded from the model, we found evidence for an additive (codominant) Mendelian gene (d = 0.48), which demonstrates the necessity of using the mixed model. Our previous results were inconclusive with respect to the involvement of a major gene in determination of high levels of HDL-C. However, we tentatively postulate an uncommon recessive gene for low levels of HDL-C in the Israeli population in addition to polygenic and environmental determinants.

Adolescent↗
PubMed1987

Genetic etiology of gastric carcinoma: II. Segregation analysis of gastric pH, nitrate, and nitrite.

A study of gastric pH, nitrate, and nitrite in 110 families collected as part of a cohort from the Narino region of Colombia is presented. All three traits are familial and have a significant linearly increasing age trend. Gastric pH has a clear bimodal distribution but does not show Mendelian segregation. The nitrate distribution is slightly skewed, but generational heterogeneity explains the data best. Gastric nitrite is also biomodal with a clear break at concentration 1.08 micrograms/ml, and 74% of the observations at zero concentration; it shows a recessive Mendelian segregation with significant residual spouse correlation. This model also fits the data best when nitrite is dichotomized into detected (measurable) and undetected values. The estimated frequency of the recessive allele is .57, so that an estimated 32% of the population sampled are recessives. Recessives whose spouses have measurable nitrite have an estimated penetrance of 99.3% at age 30 years, whereas those whose spouses have zero or undetected nitrite have a penetrance of only 8.8% at age 30 years. It appears that gastric nitrite, and, from our previous study of these families, chronic atrophic gastritis are important biologic markers for the early identification of persons predisposed to gastric cancer.

Adult↗
PubMed1987

Linkage and segregation analyses of apolipoproteins A1 and B, and lipoprotein cholesterol levels in a large pedigree with excess coronary heart disease: the Bogalusa Heart Study.

Robust methods were employed, using data from a single large pedigree, to screen serum apolipoprotein A1 and B levels, serum lipoprotein cholesterol levels, and ratios of serum lipoprotein cholesterol fractions to apolipoprotein A1 and B levels for genetic linkage to 31 polymorphic markers. Segregation analyses were performed for each of the apolipoprotein and lipoprotein cholesterol fractions to obtain estimates for use in applying likelihood methods of linkage analysis. Trait-marker combinations for which linkages were suggested from the robust methods were then reexamined for linkage using the likelihood (lod score) method. Results from the segregation analyses were consistent with major gene determination of apo B and HDL-C levels, the HDL-C to apo A1 ratio, the LDL-C to apo B ratio, and a measure of relative content of cholesterol in HDL-C and LDL-C. Linkage between haptoglobin and the HDL-C/apo A1 ratio was suggested, with a lod score of 1.72 at theta = 0.05.

Apolipoprotein A-I↗
PubMed1988

Possible heterogeneity in the segregation pattern of breast cancer in families with bilateral breast cancer.

We investigated the segregation pattern of breast cancer in families with bilateral breast cancer, classifying families with respect to menopausal status (premenopausal versus postmenopausal) and the interval between diagnosis of the two primary tumors in the probands. Probands were "synchronous" if both primaries were diagnosed within 1 year; "asynchronous" if the interval was at least 2 years. Results for four complex segregation analyses are here presented; the findings support heterogeneity in the transmission of breast cancer. In the asynchronous premenopausal-cases-only analysis, a dominant Mendelian gene can explain the breast cancer pattern. A recessive gene is sufficient to describe the breast cancer distribution in the synchronous premenopausal-cases-only analysis. The synchronous all-cases and the asynchronous all-cases analyses add postmenopausal cases of breast cancer to the premenopausal ones, considering any case to be affected. In the asynchronous all-cases analysis, neither the single-locus model nor the mixed model (that is, a major locus plus other factors, genetic and/or cultural) without generation differences in heritability can be rejected by the unrestricted mixed model with generation differences in heritability. For the synchronous all-cases analysis, a mixed model with generation differences in heritability is necessary to explain the breast cancer transmission. Potential sources of error and possible interpretations are discussed.

Breast Neoplasms↗
PubMed1989

Complex segregation analysis for a three-allele locus: experience from an analysis of acid phosphatase activity.

A complex segregation analysis of acid phosphatase activity in 50 British families showed that the essential features of the acid phosphatase polymorphism, i.e., a major gene with three alleles, is retrieved by using the biallelic mixed model. The estimates of gene frequency and displacement obtained from segregation analysis were in agreement with those obtained from electrophoretic studies. In addition, there was evidence for a multifactorial component.

Acid Phosphatase↗
PubMed1989

Segregation analysis of quantitative traits in nuclear families: comparison of three program packages.

Segregation analysis frequently is used to test for the presence of major gene effects and to estimate the various genetic and environmental components contributing to diseases. Recent advances in both theoretical models and computational algorithms have provided a number of new programs for performing segregation analyses. We compared two newer programs: REGC (part of the package "SAGE") and FISHER/MENDEL with an older established program (PAP) to determine relative accuracy in recovering parameter values and asymptotic standard errors, ability to discriminate between alternative transmission models, and execution speeds. Each program was applied to a set of computer simulations of a quantitative trait generated under a variety of genetic models. The results of these comparisons indicated that all the programs provided very similar parameter estimates, but that they differed in their abilities to identify the correct mode of transmission. In our simulations, PAP more often led to the selection of the correct transmission model, whereas REGC frequently indicated the presence of a major gene in simulations of purely polygenic transmission. Relative speeds for the programs differed, and their rank ordering varied with the complexity of the model being fitted. Although REGC was the fastest program for fitting a major gene or mixed model, it was by far the slowest program for estimating parameters in a sporadic or polygenic model.

Computer Simulation↗
PubMed1991

Multivariate segregation analysis using the mixed model.

Most major genes involved in the etiology of complex diseases are likely to have pleiotropic effects on a number of intervening quantitative traits. Methods of segregation analysis that incorporate the additional information from such multiple traits will exhibit greater power for detecting the effects of major genes and allow explicit tests of major locus pleiotropy hypotheses. In this study, we present a new method for multivariate segregation analysis that utilizes a multivariate generalization of Hasstedt's [1982] technique for calculating approximate mixed model likelihoods on pedigrees. The method is based on a simplification of the multivariate conditional likelihood via a transformation that simultaneously orthogonalizes the residual additive genetic and environmental covariance matrices. This transformation allows the multivariate conditional likelihood to be factored into the product of independent univariate conditional likelihoods. Resulting computations are relatively fast, making it feasible to analyze multiple traits in extended pedigrees. We demonstrate our method with a bivariate analysis of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apo AI) serum levels in 585 pedigreed baboons.

Apolipoprotein A-I↗
PubMed1991

Genetics of total serum IgE levels: a regressive model approach to segregation analysis.

The genetics of basal total serum IgE levels was investigated in 278 individuals from 42 randomly ascertained nuclear families. The data were analyzed using the regressive model approach to segregation analysis with age, sex, and a measure of skin test responsiveness as covariates in the Class D models. The best fitting model was that of recessive inheritance of high IgE levels with a gene frequency of 0.99 for the "high" allele. Only 3 families showed evidence for segregation of the rare "low" allele, and, if extended further, these families could be useful for molecular genetic linkage studies. These results suggest that there may be a rare allele for very low total serum IgE levels that can be detected even after a measurement of allergic responsiveness (skin test results) is considered as a covariate. Therefore, this major gene for IgE levels appears independent of any similar locus controlling atopy.

Adolescent↗
PubMed1992

Sensitivity of transmission probabilities to paternity exclusion in segregation analysis.

Paternity exclusions are known to be common in Western countries and are yet neglected in segregation analysis because it is almost impossible to check it systematically on a large family sample. We had the opportunity of observing the sensitivity of segregation analysis parameters to a paternity exclusion in analyzing 34 families for a simple Mendelian trait, the acetylator phenotype. We found that only one family, with proven paternity exclusion, was responsible for a strong rejection of Mendelian transmission probabilities (P much much less than 0.001).

Acetyltransferases↗
PubMed1993

A form of sensorineural deafness is determined by a mitochondrial and an autosomal locus: evidence from pedigree segregation analysis.

We have previously reported a large Israeli-Arab pedigree with sensorineural deafness possibly determined simultaneously by two loci--one mitochondrial, and one autosomal recessive. This was analyzed by extending classic segregation analysis methods to the many nuclear families derived from the maternal line pedigree. Here we expand this pedigree and extend our analysis by using the regressive models for segregation analysis on the entire pedigree. The corresponding REGD computer program was utilized and the marrying-in males' and paternal line members' affection statuses were assigned as unknown to accommodate the exclusive maternal transmission pattern. For the autosomal locus, a simple autosomal recessive (q = 0.52) model with a nearly complete penetrance (0.93) was found to be the best-fitting model. Equally importantly, we were also able to use the power of the regressive models to test the hypothesis of mitochondrial heteroplasmy as an alternative for the proposed autosomal locus. We found no evidence for the heteroplasmy hypothesis as an explanation for the incomplete maternal transmission of deafness in this pedigree. Thus, even if the mitochondrial mutation occurred in a heteroplasmic distribution in the family members, this could not explain the familial aggregation in this pedigree, and an autosomal recessive locus is still required. These results provide further support for the concept that the sensorineural deafness occurring in this large Israeli-Arab pedigree results from simultaneous involvement of two genes at two different loci, one mitochondrial and likely homoplasmic, and the other autosomal and recessive.

Computer Simulation↗
PubMed1993

Genetic segregation analysis of red blood cell (RBC) histamine N-methyltransferase (HNMT) activity.

Methylation is an important pathway in the biotransformation of many drugs, neurotransmitters, and xenobiotic compounds. Histamine N-methyltransferase (HNMT) catalyzes the N tau-methylation of histamine and structurally related compounds. Measurement of HNMT activity in the RBC makes it possible to access variation in the enzyme activity that may reflect differences in less accessible tissues such as brain. Previously reported high family correlations for RBC HNMT activity suggested that genetic inheritance plays a major role in the regulation of variation in this enzyme. In the present study we completed complex segregation analyses of RBC HNMT activity of 241 individuals in 51 nuclear families that were randomly ascertained through children in the Rochester, Minnesota public school system in order to characterize the mode of inheritance of this important enzyme. We found evidence for major gene influence on the regulation of RBC HNMT activity. Both transformed and untransformed data support the presence of Mendelian major gene segregation, but the gene frequency differences do not indicate a direct correspondence between genotypes inferred from the two sets of analyses. Analyses of the skewed untransformed data indicated the presence of a relatively rare (Q = 0.121) additive major gene for high activity, with the three overlapping genotype distributions representing 77, 21, and 2% of individuals. Analyses of the normalized transformed data indicated the presence of a common (Q = 0.71) additive major gene for high activity, with the three overlapping genotype distributions accounting for 9, 41, and 50% of individuals. The analyses of transformed data give the best fit as well as the most parsimonious Mendelian major gene model.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Segregation analysis of human red blood cell thiopurine methyltransferase activity.

Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine (6-MP). Inherited differences in the activity of this enzyme are related to individual differences in the therapeutic efficacy and toxicity of 6-MP and other thiopurine drugs. Variation of TPMT activity in the red blood cell (RBC) has been found to reflect activity differences in less accessible tissues. Previously reported qualitative analyses of inheritance of RBC TPMT in families suggested that a major gene plays a role in the regulation of activity of this enzyme. In the present study we completed complex segregation analyses of RBC TPMT activity of 213 individuals in 49 families that were randomly ascertained through children in the Rochester, MN, public school system. We found clear evidence of a major gene effect on RBC TPMT activity. Both transformed and untransformed data supported the segregation of a Mendelian major gene with frequency of 0.94 for the allele conferring high enzyme activity. The genotype distributions of individuals who were homozygous for the low activity allele, heterozygous, and homozygous for the high activity allele accounted for approximately 0.3%, 11.2%, and 88.5%, respectively, of the individuals in the sample. This major locus accounted for 66% of the total variance in untransformed RBC TPMT activity. Although there were significant residual family correlations among probable high activity homozygotes, there was insufficient power to detect additional major locus or polygenic inheritance effects on the residual variance.

Adolescent↗
PubMed1995

General purpose model and a computer program for combined segregation and path analysis (SEGPATH): automatically creating computer programs from symbolic language model specifications.

A general purpose model and a flexible computer program, called SEGPATH, have been developed to assist in the creation and implementation of a variety of genetic epidemiological models. SEGPATH is a computer program which can be used to generate programs to implement linear models for pedigree data, based upon a flexible, model-specification syntax. SEGPATH models can perform segregation analysis, path analysis, or combined segregation and path analysis using any user-specified path model and can be structured to analyze any number of multivariate phenotypes, environmental indices, and/or measured covariate fixed effects (including measured genotypes). Population heterogeneity models, repeated-measures models, longitudinal models, auto-regressive models, developmental models, and gene-by-environment interaction models can all be created under SEGPATH. Pedigree structures can be defined to be arbitrarily complex, and the data analyzed with programs generated by SEGPATH can have any missing value structure, with entire individuals missing, or missing on one or more measurements. Corrections for ascertainment can be done on a vector of phenotypes and/or other measures. Because the model specification syntax is general, SEGPATH can also be used in non-genetic applications where there is a hierarchical structure, such as longitudinal, repeated-measures, time series, or nested models. A variety of applications are demonstrated.

Genetics, Population↗
PubMed1995

The influence of response bias on segregation and linkage analysis.

Response bias in epidemiologic studies can occur if affected individuals are more (or less) likely to participate in a survey than their unaffected counterparts. To examine the effect of response bias in the context of a family study, we conducted segregation and linkage analysis in all 1,000 individuals in the Problem 2 data set, and in two different 65% samples: one sample consisting of 648 randomly selected individuals, and the other sample nonrandomly constructed so that individuals with high levels of Q1 were oversampled. In this simulation the ability to detect major genes for Q1-Q4 in segregation analysis and to link these putative major genes to genetic markers in linkage analysis was not markedly different between the 65% random and the 65% enriched samples.

Alleles↗
PubMed2001

Gibbs sampling-based segregation analysis of asthma-associated quantitative traits in a population-based sample of nuclear families.

Asthma is a common, complex human disease. Elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts, and increased airway responsiveness are physiological traits that are characteristic of asthma. Few studies have investigated major gene effects for these traits in a population-based sample. Further, it is not known if any putative major genes may be common to two or more of these traits. We investigated the existence and nature of major genes modulating asthma-associated quantitative traits in an Australian population-based sample of 210 Caucasian nuclear families. The sharing of these major genes was also investigated. Segregation analysis was based upon a Markov Chain Monte Carlo (Gibbs sampling) approach as implemented in the program BUGS v0.6. All models included adjustment for age, height, tobacco smoke exposure, and gender. The segregation of total IgE levels, blood eosinophil counts, and dose-response slope (DRS) of methacholine challenge were all consistent with major loci at which a recessive allele acted to increase or decrease the phenotype. The respective estimated frequencies of the recessive alleles were 68% (total IgE), 10% (blood eosinophil count), and 27% (DRS). Extensive modelling suggested that the major loci controlling total serum IgE levels, blood eosinophil counts, and airway responsiveness represent different genes. These data provide evidence, for the first time, of the existence of at least 3 distinct genetic pathways involving major gene effects on physiological traits closely associated with asthma. These results have implications for gene discovery programs.

Adolescent↗