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PubMed1986

Transcriptional regulation of the mitochondrial genome of yeast Saccharomyces cerevisiae.

The relative rates of transcription of several classes of the mitochondrial genes of the yeast Saccharomyces cerevisiae have been determined. The rates were measured by pulse labeling whole yeast with [32P]O4, isolating the total RNA, hybridization to single-stranded M13 DNA probes containing segments of the gene of interest, digestion with RNase A or T1, and separation of the protected fragment by gel electrophoresis. This analysis indicated that, among the genes analyzed, transcriptional promoters varied in strength by 20-fold while the rates of transcription varied by more than 50-fold. The strengths of the promoters of the genes were ordered: tRNAMetf greater than tRNAPhe greater than 14 S rRNA greater than 21 S rRNA greater than tRNAGlu greater than Oli-1 much greater than tRNACys. In addition, transcription rates were measured within polygenic transcription units. This analysis indicated that there was transcriptional attenuation within all the polygenic transcription units with the greatest attenuation factor being as much as 17-fold, occurring after the tRNAGlu and tRNAMetf genes. This analysis indicated that regulation of the rates of transcription in the yeast mitochondrial genome occurs by two distinct mechanisms, modulation of the rate of transcriptional initiation and attenuation of transcriptional elongation.

Base Sequence↗
PubMed1978

Current research in neuro-epidemiology. Some main trends.

Recent epidemiological research has contributed to the understanding of the nature of common neurological disorders like multiple sclerosis, Parkinsonism, and amyotrophic lateral sclerosis. Viral etiology constitutes the most probable environmental factor in multiple sclerosis, but host-related genetic factors are also involved and determine susceptibility. In disorders like Parkinsonism, amyotrophic lateral sclerosis, and epilepsy, heredity seems to play a more important role than earlier believed, and segregation analyses indicate polygenic inheritance patterns. The subacute spongiform encephalopathies fit into a similar concept, and here the hunt for infectious agents has succeeded. Polygenic traits and dominantly inherited disorders seem to aggregate in genetic isolates, as shown through studies from different parts of the world. The reason for this is not quite clear, but selection through assortative matings or other mechanisms may be operating in these populations.

Adolescent↗
PubMedDate not supplied

[Genome organization in eukaryotes].

The review discussed problems of genome organization in the chromosomes of eukaryotes based on the data of genetical and molecular-biological studies. Particular attention is paid to the peculiarities of organization of genetic material in Drosophila. The main (euchromatic) part of the genome is considered as the totality of separate functional units (chromomere, gene loci), which have in the average a higher excess of DNA compared to the sized of the structural gene. The possible ways of internal organization of these units and the role of different types of DNA sequences in their function are discussed. The features of organization and function of the heterochromatic regions of chromosomes consisting of simple sequences of satellite DNA and tandemly repeated genes (polygenes), that code for general cellular functions (similar to the ribosomal genes) are considered. The instability of the number and even the sites of localization of polygenes in the chromosome, which can be determined by the peculiarities of their functions during differentiation of somatic cells is notes.

Animals↗
PubMed1979

Multifactorial genetic models for quantitative traits in humans.

Quantitative traits measured in human families can be analyzed to partition the total population variance into genetic and environmental components, or to elucidate the genetic mechanism involved. We review the estimation of variance components directly from human pedigree data, or in the form of path coefficients from correlations between pairs of relatives. To elucidate genetic mechanisms, a mixed model that allows for segregation at a major locus, a polygenic effect and a sibling environmental correlation is described for nuclear families. In each case appropriate likelihoods are derived as a basis, using numerical maximum likelihood methods, for parameter estimation and hypothesis testing. A general model is then described that allows for several familial sources of environmental variation, assortative mating, and both major gene and polygenic effects; and an algorithm for calculating the likelihood of a pedigree under this model is indicated. Finally, some of the remaining problems in this area of biometric analysis are pointed out.

Genetic Variation↗
PubMedDate not supplied

The genetics of viral infection pathology.

The genetic diversity of viruses and the genetic constitution (polygenic configuration) of susceptible organisms participate together in the determination of a virus disease and of its clinical forms. Genes of sensitivity to viral infection, genes of nonspecific defense (encoding for interferons, complement factors), immune response regulating genes and immunoglobulin genes would form the background of an intrinsic polygenic group involved in viral infection pathology.

Alleles↗
PubMed1984

Ascertainment and goodness of fit of variance component models for pedigree data.

The multivariate normal parameterization of the polygenic model (Lange et al., 1976) provides a great deal of flexibility for analyzing quantitative data on pedigrees. The likelihood approach employed ensures statistical efficiency and allows for hypothesis testing using the likelihood ratio criterion. The parameterization also facilitates ascertainment correction and goodness-of-fit testing (Spence et al., 1977; Ott, 1979; Hopper and Mathews, 1982; Boehnke, 1983). We reviewed these results and then described a simulation study undertaken to determine their utility when applied to data. Pedigree data were generated under polygenic and mixed models and sampled either randomly or via probands. We found that the variance components of the model were accurately estimated for random sampling, but less so for ascertained data analyzed by conditioning on probands. Goodness-of-fit tests employing test statistics corresponding to individual phenotypes and entire pedigrees were conservative, but pedigree tests did demonstrate reasonable power to reject a variety of mixed model alternatives. In addition, we found that the pedigree test statistics could be used to enrich a sample of pedigrees for those pedigrees segregating at a major locus, providing an objective criterion for choosing pedigrees to be included in a linkage analysis.

Chromosome Mapping↗
PubMed1983

Errors of inference in the detection of major gene effects on psychological test scores.

Computer simulation methods were employed to generate abilities of 10 sets of 250 nuclear families, each comprising a pair of randomly mated parents and two children. It was assumed that the distribution of abilities in the population was normal and caused entirely by additive polygenic effects. A simulated psychological test was administered to each sample to generate test scores for each subject. A different test, consisting of 40 items of varying difficulty and discriminating power, was used in each sample. The "mixed model," specifying a single major gene with polygenic and environmental background variation, was tested for each data set. Likelihood ratios were computed to test for the contribution of a major locus and its conformity to Mendelian segregation. Only one out of 10 samples was consistent with pure multifactorial inheritance. Of the remaining nine samples, four showed non-Mendelian segregation and five were consistent with current statistical criteria for establishing the contribution of a major gene to variation in psychological test scores. This high frequency of false conclusions suggests that the naïve application of such methods to behavioral data is often likely to be misleading. Raw test scores alone are not sufficient to test the mixed model. The development of tractable models for behavioral traits requires the responses of subjects to individual items.

Adult↗
PubMed1984

An evaluation of three statistics of structured exploratory data analysis.

The power of structured exploratory data analysis (SEDA) to discriminate among major genic, polygenic, and nongenetic determination of phenotypes was investigated using computer simulation. Three classes of SEDA indices (the major gene index, the offspring between parents function, and the midparent-child correlation coefficient) were evaluated. These three statistics, in combination, were reasonably sensitive in detecting the presence of a major locus and in discriminating between phenotypes with genetic effects and those with no genetic component. However, they were unable to discriminate between major genic and polygenically determined phenotypic models.

Chromosome Mapping↗
PubMed1984

Structured exploratory data analysis: an evaluation of the use of three SEDA statistics in assessing mode of inheritance.

Several SEDA statistics are described and three of them (the Midparent-Child Correlation Coefficient, the Major Gene Index, and the Offspring Between Parents Function) are evaluated with respect to their ability to distinguish monogenic, polygenic and sporadic effects on quantitative traits. The MPCC, MGI, and OBP, used in combination, are sensitive but not specific in identifying monogenic inheritance. In our tests, traits determined by a simple type of polygenic inheritance were almost invariably classified as monogenic. Sporadic traits, on the other hand, were correctly identified in 84 percent of cases. The concurrent use of these SEDA statistics and two sibship variance tests yielded some improvement whenever the two procedures agreed (which happened about 50 percent of the time). These results suggest that under some circumstances, SEDA can be a valuable adjunct to other methods of genetic analysis. SEDA methodology also appears promising as an aid in understanding the contribution of various nongenetic factors to quantitative traits.

Female↗
PubMed1981

Estimation of environmental and genetic components of quantitative traits with application to serum cholesterol levels.

A mixed model of environmental, polygenic, and major locus effects is developed, allowing for environmental correlations between first-degree relatives and spouses. Maximum-likelihood techniques are used to determine the relative contributions of each of these effects to a quantitative trait. Inclusion of a nuclear family in the sample is assumed to depend on the value of the quantitative trait of one member of the family, so conditional distributions are used. Application of the method to serum cholesterol data from the general population shows that the addition of a polygenic effect to a model that assumes only an environmental effect makes a significant improvement. A completely dominant single gene is also found to be influencing serum cholesterol levels. Although cholesterol levels have been adjusted for a range of factors, such as age, sex, weight/height, and marital status, environmental factors still account for about half the variability in the residual values.

Adult↗
PubMed1978

Multifactorial inheritance with cultural transmission and assortative mating. I. Description and basic properties of the unitary models.

A general linear model of familial resemblance is described which allows for cultural transmission from parent to offspring, polygenic inheritance, phenotypic assortative mating, common environment, maternal and paternal effects, and threshold effects. Three special cases are described in detail which are particularly useful when data are only available about a few classes of relatives reared in intact families. The cultural model, the polygenic model, and the pseudopolygenic model share the common feature that all factors which are transmitted from parent to offspring may be represented by one parameter without any loss of information. We introduce a new model, termed the unitary model, which includes these models and is appropriate when combined genetic and cultural transmission is present and when data are available only for individuals reared in intact nuclear families. The basic properties of these models are explored using path analysis and computer simulation, including description of the relationship between parameters under random and assortative mating, rate of approach to equilibrium, and constraints on the magnitude of the parameters. General formulae for familial resemblance in extended pedigrees are given for any ancestor or descendant of either vertical or collateral relatives. Estimation procedures are described and a FORTRAN program TAU, available upon request, is used to provide maximum likelihood estimates of the parameters from reported correlations. A powerful test for detecting the presence of cultural transmission is suggested and applied to simulated data and to data sets reported by others for human stature, for which cultural transmission is suggested. In addition, it is shown that there is no need to postulate dominance to account for available data about height.

Environment↗
PubMed1995

Familial hypercholesterolemia: molecular, biochemical, and clinical characterization of a French-Canadian pediatric population.

BACKGROUND: Familial hypercholesterolemia (FH) is a dominantly-inherited disorder attributable to a defect in the low-density lipoprotein (LDL) receptor gene. Five mutations at this locus have been identified in French-Canadians. In children, it may be difficult to clinically distinguish FH from other forms of polygenic or monogenic hyperlipidemia. Therefore, our objectives were to define the molecular basis of our subjects' hypercholesterolemia, to characterize their biochemical phenotype in relation to the underlying molecular defect, and to assess their response to chronic dietary therapy. METHODS: We studied 88 unrelated French-Canadian children with a persistent increase in LDL cholesterol and a parental history of hyperlipidemia. Baseline and end-of-diet lipid and apolipoprotein levels were measured. Mutational analysis at the LDL receptor gene locus was performed. RESULTS: Heterozygosity for the common French-Canadian LDL receptor gene > 10-kb deletion was found in 57% of subjects (group 1), 14% carried one of the other four previously characterized LDL receptor gene mutations (group 2), and none of the five molecular defects tested was detected in 29% (group 3). Total cholesterol, LDL cholesterol, and apolipoprotein B baseline levels were similar among these three groups but significantly higher than in control subjects. However, there was wide interindividual variability even among those carrying the same mutation. Significantly lower baseline levels of high-density lipoprotein cholesterol and apolipoprotein A1 were found in group 1 compared with group 3 and the controls. The response to diet was similar among the three groups with an average reduction in the mean level of total cholesterol of 4.4%. CONCLUSIONS: The frequency of proven FH heterozygotes (71%) was remarkable in the pediatric population studied. Our data suggest that, in children, a persistent primary increase in LDL cholesterol associated with a parental history of hyperlipidemia is a good predictor of an underlying monogenic disorder as opposed to a polygenic disorder, at least in French-Canadians. Only molecular analysis allowed us to unequivocally define the cause of our patients' hypercholesterolemia. Most children with familial hyperlipidemia did not reach desirable plasma lipid levels solely under diet therapy.

Adolescent↗
PubMed1975

Analysis of family resemblance. IV. Operational characteristics of segregation analysis.

In simulated data, segregation analysis of quantitative traits was found to be powerful for resolving a major locus from polygenic and cultural inheritance. It is reasonably robust against a variety of deviations from the model if and only if a major locus, polygenic heritability, and environment common to sibs are simultaneously included in the model, and heterogeneity tests among mating types are performed. Most of the information in quantitative data about a major locus is lost when reduced to affection status.

Environment↗
PubMed1994

Robust variance-components approach for assessing genetic linkage in pedigrees.

To assess evidence for genetic linkage from pedigrees, I developed a limited variance-components approach. In this method, variability among trait observations from individuals within pedigrees is expressed in terms of fixed effects from covariates and effects due to an unobservable trait-affecting major locus, random polygenic effects, and residual nongenetic variance. The effect attributable to a locus linked to a marker is a function of the additive and dominance components of variance of the locus, the recombination fraction, and the proportion of genes identical by descent at the marker locus for each pair of sibs. For unlinked loci, the polygenic variance component depends only on the relationship between the relative pair. Parameters can be estimated by either maximum-likelihood methods or quasi-likelihood methods. The forms of quasi-likelihood estimators are provided. Hypothesis tests derived from the maximum-likelihood approach are constructed by appeal to asymptotic theory. A simulation study showed that the size of likelihood-ratio tests was appropriate but that the monogenic component of variance was generally underestimated by the likelihood approach.

Family↗
PubMed1993

Lovastatin enhances hepatic uptake of low density lipoprotein in humans.

A noninvasive method for visualizing the uptake of low density lipoprotein (LDL) was used to investigate the effect of hypolipidemic drugs on LDL uptake by the human liver in vivo. Fourteen hypercholesterolemic patients (six with familial hypercholesterolemia and eight with common hypercholesterolemia) were studied. Autologous LDL particles were isolated and divided into two aliquots; one was labeled with 99mTC and the other with 131I, and both preparations were reinjected simultaneously. The labeled LDL was visualized 24 h later by scanning the thorax and abdomen with a gamma camera, and the liver/heart ratio was calculated as an estimate of the hepatic uptake of LDL. The results of 99mTC-labeled LDL scintigraphy were compared with conventional determinations of the fractional catabolic rate (FCR) for 131I-labeled LDL. The latter correlated best with the liver/heart ratio (r = 0.80, P < 0.001). Lovastatin treatment increased the liver/heart ratio (15%, P < 0.01) in the patients with polygenic hypercholesterolemia and the FCR for LDL in both groups (22%, P < 0.05, for those with familial hypercholesterolemia and 37%, P < 0.01 for those with polygenic hypercholesterolemia). Scanning of the liver using the 99mTC-labeled LDL method provides a noninvasive method for visualizing the hepatic uptake of LDL in vivo in humans. This study also provides direct proof that lovastatin, a drug that enhances LDL receptor activity in the liver, also increases the hepatic uptake of LDL in humans.

Adult↗
PubMed1993

Statistical genetic approaches to human adaptability.

The genetic determinants of physiological and developmental responses to environmental stress are poorly understood. This has been primarily due to the difficulty of direct measurement of response and the lack of appropriate statistical genetic methods. Here, I present a unified statistical genetic methodology for human adaptability studies that permits evaluation of the inheritance of quantitative trait response to environmental stressors. The foundation of this approach is the mathematical relationship between genotype-environment interaction and the genetic variance of response to environmental challenge. I describe two basic methods that can be used for either discrete or continuous environments. Each method allows for major loci, residual polygenic variation, and genotype-environment interaction at both the major genic and the polygenic levels. The first method is based on multivariate segregation analysis and is appropriate for situations in which data are available for each individual in each environment. The second method is appropriate for the more common case when response to the environment cannot be observed directly. This method is based on an extension of a mixed major locus/variance component model and can be used when singly measured related individuals are observed in different environments. Three example applications using data on lipoprotein variation in pedigreed baboons are provided to show the utility of these methods.

Adaptation, Physiological↗
PubMed1993

The genetic background of individual variations of circadian-rhythm periods in healthy human adults.

As a group phenomenon, human variables exhibit a rhythm with a period (tau) equal to 24 h. However, healthy human adults may differ from one another with regard to the persistence of the 24-h periods of a set of variables' rhythms within a given individual. Such an internal desynchronization (or individual circadian dyschronism) was documented during isolation experiments without time cues, both in the present study involving 78 male shift workers and in 20 males and 19 females living in a natural setting. Circadian rhythms of sleep-wake cycles, oral temperature, grip strength of both hands, and heart rate were recorded, and power-spectra analyses of individual time series of about 15 days were used to quantify the rhythm period of each variable. The period of the sleep-wake cycle seldom differed from 24 h, while rhythm periods of the other variables exhibited a trimodal distribution (tau = 24 h, tau > 24 h, tau < 24 h). Among the temperature rhythm periods which were either < 24 h or > 24 h, none was detected between 23.2 and 24 h or between 24 and 24.8 h. Furthermore, the deviations from the 24-h period were predominantly grouped in multiples of +/- 0.8 h. Similar results were obtained when the rhythm periods of hand grip strength were analyzed (for each hand separately). In addition, the distribution of grip strength rhythm periods of the left hand exhibited a gender-related difference. These results suggested the presence of genetically controlled variability. Consequently, the distribution pattern of the periods was analyzed to elucidate its compatibility with a genetic control consisting of either a two-allele system, a multiple-allele system, or a polygenic system. The analysis resulted in structuring a model which integrates the function of a constitutive (essential) gene which produces the exact 24-h period (the Dian domain) with a set of (inducible) polygenes, the alleles of which, contribute identical time entities to the period. The time entities which affected the rhythm periods of the variables examined were in the magnitude of +/- 0.8 h. Such an assembly of genes may create periods ranging from 20 to 28 h (the Circadian domain). The model was termed by us "The Dian-Circadian Model." This model can also be used to explain the beat phenomena in biological rhythms, the presence of 7-d and 30-d periods, and interindividual differences in sensitivity of rhythm characteristics (phase shifts, synchronization, etc.) to external (and environmental) factors.

Adult↗
PubMed1996

Major-locus contributions to variability of the craniofacial feature dystopia canthorum in Waardenburg syndrome.

We used segregation analysis to investigate the genetic basis of variation in dystopia canthorum, one of the key diagnostic features of Waardenburg syndrome type 1 (WS1). We sought to determine whether the W-index, a quantitative measure of this craniofacial feature, is influenced primarily either by allelic variation in the PAX3 disease gene or other major loci, by polygenic background effects, or by all of these potential sources of genetic variation. We studied both WS1-affected individuals and their WS1-unaffected relatives. After adjustment of the W-index for WS1 disease status, segregation analyses by the regression approach indicated major-locus control of this variation, although residual parent-offspring and sib-sib correlations are consistent with additional (possibly polygenic) effects. Separate analyses of WS1-affected and WS1-unaffected individuals suggest that epistatic interactions between disease alleles at the PAX3 WS1 locus and a second major locus influence variation in dystopia canthorum. Our approach should be applicable for assessing the genetic architecture of variation associated with other genetic diseases.

Alleles↗