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PubMed1988

[The genetics of breast cancer, population and familial research and segregation analysis].

The data on clinico-genealogy studies of 1046 probands with breast cancer and their relatives are presented. The nature of inheritance corresponded to the Mendelian model. As to other families, there is no strong evidence for the monogene model both with complete and incomplete penetrance of mutant homo- and heterozygotes. Penetrance of homozygotes was 7.9-30.5%, this being 2.0-7.3% for heterozygotes. The conclusion is drawn that it is necessary to consider the regularities of inheritance of breast cancer in the light of the multifactorial model.

Adult↗
PubMed1978

Efficiency and robustness of pedigree segregation analysis.

Different pedigree structures and likelihoods are examined to determine their efficiency for parameter estimation under one-locus models. For the cases simulated, family size has little effect; estimates based on unconditional likelihoods are generally more efficient than those based on conditional likelihoods. The proposed method of pedigree analysis under a one-locus model is found to be robust in the analysis of nuclear families: skewness of the data and polygenic inheritance will not lead to the spurious detection of major loci unless they occur simultaneously, and together with a moderate amount of environmental correlation among sibs.

Gene Frequency↗
PubMed1977

Extrachromosomal inheritance in Schizosaccharomyces pombe. III. Isolation and characterization of paromomycin-resistant mutants.

In the antimycin--resistant mutant anar-8 of the fission yeast Schizosaccharomyces pombe (Sch.p.) spontaneous mutants were isolated showing high resistance to the aminoglycoside antibiotic paromomycin. All mutants were resistant to the structurally related antibiotic neomycin. Tetrad analysis, mitotic segregation analysis, and mitotic haploidization revealed extrachromosomal, very likely mitochondrial inheritance. In contrast to the rapid segregation of mitochondrial markers in zygotic clones of Saccharomyces cerevisiae (S.c.) the heteroplasmic state of diploids proved to persist for at least 50 generations after zygote formation. Stationary cultures of the paromomycin-resistant mutants parr-106 and parr-112 contain up to 6% respiratory-deficient mutants, but no reversion to paromomycin-sensitivity was observed among 1700-1800 colonies tested. The ability of mutant anar-8 to produce spontaneously respiratory-deficient mutants could be separated from the antimycin-resistant phenotype of anar-8.

Ascomycota↗
PubMed1988

Family resemblance for serum uric acid in a Jerusalem sample of families.

Familial aggregation of serum uric acid was studied in a sample of families examined in the Jerusalem Lipid Research Clinic. We first examined homogeneity of familial correlations across the major origin groups in the Israeli population sample. In general correlations were homogeneous across origin groups, except for spouse pairs. Pooled correlations among biological relatives across the origin groups were all statistically significant. Spouse correlation upon adjustment for concomitant variables was moderately positive (r = 0.115), yet significantly different from zero. Genetic and cultural determinants of uric acid were estimated utilizing a path model with 10 parameters to be estimated from a total of 16 correlations. Under a reduced model, genetic heritability (h2) was estimated to be 0.47 +/- 0.05 and cultural heritability (c2) was 0.11 +/- 0.03. However, our data gave suggestive evidence that cultural heritability was higher in parents (c2 = 0.28) than in children (c2 = 0.10). Commingling analysis and segregation analysis were also performed, and our findings imply that in the Israeli population there is no evidence for a major gene for high uric acid levels segregating in families.

Adult↗
PubMed1990

Evidence for a major gene in familial anencephaly.

A 21-year-old white woman sought counseling after the birth of two consecutive anencephalic male fetuses with complete rachischisis and discordant renal dysplasia. The presence of parental consanguinity prompted reconsideration of recessive inheritance. The segregation ratio from 23 additional consanguineous cases was compared with that observed in 294 presumably nonconsanguineous families previously reported. Using classical segregation analysis, the segregation ratios in the non-sporadic cases were consistent with a major autosomal recessive locus in both populations.

Abortion, Spontaneous↗
PubMed1989

Familial analysis of bipolar affective disorder using logistic models.

Data on bipolar affective disorder in 187 pedigrees from the Collaborative Depression Study were analyzed using logistic models that have been extended to incorporate age of onset information. Logistic regression analysis and segregation analysis revealed evidence for complex familial effects on this disorder.

Age Factors↗
PubMed1990

Transmission of a psychometric indicator for liability to schizophrenia in normal families.

The genetic analysis of schizophrenia would be facilitated by identification of a heritable correlate of liability. Deviance on an index of Minnesota Multiphasic Personality Inventory (MMPI) signs is associated with the disease phenotype; the familial aggregation and mode of transmission of this continuous psychometric indicator have yet to be established. In this paper, we examine the indicator through commingling analysis and segregation analysis with both the mixed and unified models on 65 nuclear families containing 211 normal individuals. Evidence for a high degree of familiality is found. Analysis of untransformed data under a conditional likelihood provides evidence for Mendelian transmission of a major gene with commingling of two distributions. The frequency of the "high index score" allele is 0.15, with the gene accounting for 31% of the total population variance; such a locus would be relevant to the study of psychopathology as 28% of the population would carry at least one deviant allele. When power-transformed scores are used to eliminate skewness, there is evidence for one distribution and it is not possible to distinguish single gene from multifactorial (polygenic or cultural) inheritance. While our findings regarding mode of transmission must be interpreted cautiously and confirmation of a single locus requires further study, demonstration of familiality warrants continued investigation of the index as an indicator of liability for schizophrenia.

Adolescent↗
PubMed1979

Congenital glaucoma: genetic models.

Modes of inheritance of congenital glaucoma have been studied. Two methods of analysis, complex segregation analysis and frequency of congenital glaucoma in second- and third-degree relatives, did not permit one to retain a unitary mode of inheritance ofthis malformation. Genetic heterogeneity of congenital glaucoma is proposed. Recurrence risks and guidelines for genetic counseling in specified situations are given.

Adult↗
PubMed1992

Molecular cloning of a gene (cfp) encoding the cytoplasmic filament protein P59Nc and its genetic relationship to the snowflake locus of Neurospora crassa.

P59Nc is a 59-kD polypeptide associated with 8-10-nm diameter cellular filaments in normal Neurospora crassa strains. Abnormally sized and shaped bundles of these structures are present in N. crassa strains carrying mutations at the locus sn (snowflake). By using molecular cloning and restriction fragment length polymorphism (RFLP) segregation analysis strategies we show here that sn is not the genetic locus of P59Nc. Several P59Nc cDNAs were cloned from a N. crassa lambda GT11 library after immunoscreening with specific polyclonal anti-P59Nc antibodies. Additional longer cDNAs were obtained from a N. crassa cDNA-lambda ZAP library. When used as probes in Southern blots of total DNA from wild-type strains, multicent-2 (a multiple mutant strain), and snowflake mutants, the P59Nc cDNAs revealed comparable patterns of hybridizing bands for all of the restriction enzymes tested. Analysis of segregation of BclI and ClaI RFLPs, detected in the genomic region of the P59Nc gene (locus cfp: cellular filament polypeptide), among a set of strains designed for RFLP mapping, or among selected progeny of crosses involving a snowflake parent, respectively, indicate that (i) there is in N. crassa a single cfp locus positioned on the right arm of linkage group VII between the locus for and the proximal breakpoint of the translocation T(VII----I)5936; (ii) the sn mutations in the centromere region of chromosome I do not represent translocations of cfp; and (iii) the snowflake mutants possesses a normal copy of the P59Nc gene on their chromosomes VII.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1987

Centromeric proteins recognized by CREST sera and meiotic chromosome segregation.

Analysis of the peptides recognized by CREST sera was carried out in different mouse tissues and cells, including spermatozoa. In all cases, a polypeptide of Mr = 18,000 was recognized by the sera and occasionally two other proteins of Mr = 80,000 and Mr = 140,000 were observed after immunoblotting of nuclear proteins. In both early and late spermatids, centromeric staining was observed after incubation and immunofluorescence with CREST sera. After detergent treatment, it was even possible to detect centromeric staining in mature spermatozoa. In spermatid cells, the immunofluorescent pattern presented a binomial distribution of the number of fluorescent spots, with a mean value around half of the haploid number of chromosomes. Since this pattern is the result of chromosome segregation after meiosis II, our data suggest that this centromeric peptide is not directly implicated in the chromosome segregation process. On the other hand, the distribution of spots after immunofluorescence suggests a different organization of centromeric components in meiosis I and meiosis II.

Animals↗
PubMed1989

Equivalence of the mixed and regressive models for genetic analysis. I. Continuous traits.

The mixed model of segregation analysis specifies major gene effects and partitions the residual variance into polygenic and environmental components. The model explains familial correlations essentially in terms of genetic causation. The regressive model, on the other hand, is constructed by successively conditioning on ancestral phenotypes and major genes. Familial patterns of dependence are described in terms of correlations without necessarily introducing a particular scheme of causal relationship. These two approaches are compared both theoretically and numerically through computer simulations for the case of continuous traits on nuclear families. The class D regressive model, which is characterized by equal sib-sib correlations, is mathematically and numerically equivalent to the mixed model. The simpler class A regressive model, which is also characterized by equal sib-sib correlations determined in this case by the common parentage, provides good estimates of the mixed model parameters: major gene parameters and residual polygenic heritability, derived from the parent-offspring correlation. However, in the absence of a major gene, the restriction imposed by the class A model on the sibling correlation can affect the conclusions of segregation analysis: False inference of a major gene was observed in two out of ten replicates. Our simulations also indicate that the mixed model allowing for different heritabilities in adults and children leads to correct estimates of the major gene parameters and residual familial correlations (parent-offspring and sib-sib) as specified by the class A model. For all the models studied, major gene effects, when present, are correctly detected and estimated.

Adult↗
PubMed1991

Analysis of the patterns of inheritance of splenomegaly and serum IgM levels in the Watut of Papua New Guinea.

Hyperreactive malarious splenomegaly (HMS) reflects abnormal immune responses to malarial infection. The central question is whether HMS results from unusual patterns of malarial infection or from immune incompetence in the host. Family distributions of two features of the syndrome, splenomegaly and excessively high IgM levels, have been examined in a Papau New Guinea population in which HMS is exceptionally common. Segregation analysis of spleen grade shows that a major sex-linked gene controls hyperresponsiveness to malaria. This finding is supported by additional segregation analysis, which shows that an autosomal locus cannot account for a significant proportion of variation in spleen grade, and by path analysis, which rejects a model that assumes that parents contribute equally to the child's genotype. The sex-linked gene contributing to HMS was not mediated through sex linkage of a major gene for IgM concentrations, as shown by segregation analysis. It has yet to be determined whether this pattern of inheritance also applies to HMS occurring sporadically in other less severely affected populations. The applicability of these findings to the general variability in "normal" IgM responses to malaria also remains to be established.

Adult↗
PubMed1986

The effects of a known family-size distribution on the estimation of genetic parameters.

We consider the question: In a segregation analysis, can knowledge of the family-size distribution (FSD) in the population from which a sample is drawn improve the estimators of genetic parameters? In other words, should one incorporate the population FSD into a segregation analysis if one knows it? If so, then under what circumstances? And how much improvement may result? We examine the variance and bias of the maximum likelihood estimators both asymptotically and in finite samples. We consider Poisson and geometric FSDs, as well as a simple two-valued FSD in which all families in the population have either one or two children. We limit our study to a simple genetic model with truncate selection. We find that if the FSD is completely specified, then the asymptotic variance of the estimator may be reduced by as much as 5%-10%, especially when the FSD is heavily skewed toward small families. Results in small samples are less clear-cut. For some of the simple two-valued FSDs, the variance of the estimator in small samples of one- and two-child families may actually be increased slightly when the FSD is included in the analysis. If one knows only the statistical form of the FSD, but not its parameter, then the estimator is improved only minutely. Our study also underlines the fact that results derived from asymptotic maximum likelihood theory do not necessarily hold in small samples. We conclude that in most practical applications it is not worth incorporating the FSD into a segregation analysis. However, this practice may be justified under special circumstances where the FSD is completely specified, without error, and the population consists overwhelmingly of small families.

Family Characteristics↗
PubMed1992

A genetic model for control of hypertriglyceridemia and apolipoprotein B levels in the Johns Hopkins colony of St. Thomas Hospital rabbits.

The St. Thomas Hospital (STH) rabbit has been previously shown to have a Mendelian form of hypertriglyceridemia, accompanied by accelerated atherosclerosis, and these animals may serve as a useful model for human dyslipoproteinemia syndromes. Here we describe the establishment of a new colony of these STH animals, and present genetic analysis of triglyceride (TG) and apolipoprotein B (apoB) levels. Segregation analysis of TG in 39 STH animals and 24 controls gave evidence of Mendelian segregation for an allele leading to both elevated TG levels and increased variability in these levels. Predicted means from the most parsimonious model for the Johns Hopkins STH colony were quite similar to that seen in the original London colony, and this model accounted for 80% of the variation in TG seen in the sample. This hypertriglyceridemia locus indirectly influenced the mean apoB levels in these rabbits, and segregation analysis of mean apoB levels suggested a second locus controlling apoB levels. Analysis of residual apoB levels (adjusted for predicted effects of the hypertriglyceridemia locus) revealed clearer evidence for a second locus controlling mean apoB levels in this colony. Arguments for two distinct genetic mechanisms operating in these STH animals are presented.

Animals↗
PubMed1989

Familial susceptibility to breast cancer: a complex inheritance.

The main results of segregation analysis aimed at identifying a major genetic factor involved in susceptibility to breast cancer are reviewed. They show that the existence of a single major gene is not sufficient to explain the distribution of the disease observed in the families concerned and suggest that the genetic inheritance involved is heterogeneous and complex. Heterogeneity has been explored in various studies according to epidemiological criteria. From these analyses, genetically homogeneous subgroups emerged (for instance families with breast cancer only or with affected males). The study of such homogeneous subgroups might help to better locate the susceptibility gene(s) on the chromosome map by analysis of genetic linkage using different markers. The results of segregation analysis depend on how epidemiological factors are taken into account. It is of major importance that epidemiological data on the proband (i.e., the individual prompting selection of a family) as well as on the members of his/her family are taken into consideration to improve understanding of the complexity of breast cancer transmission.

Breast Neoplasms↗
PubMed1988

Natural selection with nuclear and cytoplasmic transmission. III. Joint analysis of segregation and mtDNA in Drosophila melanogaster.

Despite the widespread use of mitochondrial DNA by evolutionary geneticists, relatively little effort has been spent assessing the magnitude of forces maintaining mtDNA sequence diversity. In this study the influence of cytoplasmic variation on viability in Drosophila was examined by analysis of second chromosome segregation. A factorial experiment with balancer chromosomes permitted the effects of cytoplasma and reciprocal crosses to be individually distinguished. The first test used six lines of diverse geographic origin, testing the segregation of all six second chromosomes in all six cytoplasms. The second and third tests were also factorial designs, but used flies from one population in central Pennsylvania. The fourth test was a large chain cross, using 28 lines from the same Pennsylvania population. Only the first test detected a significant nuclear-cytoplasmic effect. Restriction site variation in the mtDNA of all of these lines was assayed by Southern blotting, and statistical tests were performed in an effort to detect an influence of mtDNA type on fitness components. Posterior linear contrasts revealed an effect of mtDNA on segregation only among lines of diverse geographic origin. Within a population, no such influence was detected, even though the experiment was sufficiently large to have revealed statistical significance of a 0.5% segregation difference with a 57% probability.

Animals↗