[HLA and leprosy III. Segregation analysis of HLA haplotypes in multicase families of leprosy].
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Disease Susceptibility↗
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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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Induced segregation in interspecific hybrids of Aspergillus nidulans and Aspergillus rugulosus obtained by protoplast fusion.
Interspecific hybrids produced by polyethylene glycol induced fusion of protoplasts from auxotrophic mutants of Aspergillus nidulans and Aspergillus rugulosus were grown in the presence of the recombinogens benomyl and chloral hydrate to stimulate segregation. The A. nidulans parental strains used had a known genetic marker in each linkage group. Hybrids grown on complete medium containing benomyl yielded more segregants. Analysis of the segregants showed that the distribution of A. nidulans linkage groups was random. No specific linkage group appeared in all the segregants. The two parents are closely related taxonomically and the findings from these experiments suggest that a high degree of chromosomal homology may exist between them.
Aspergillus↗
Epidemiology and genetics of primary congenital glaucoma in Slovakia. Description of a form of primary congenital glaucoma in gypsies with autosomal-recessive inheritance and complete penetrance.
This study includes all registered cases of PCG in the whole of Slovakia since 1950. Whenever possible the diagnosis was confirmed and a genealogical investigation was made. The patients were assigned to one of two groups depending on their ethnic origin - Gypsy or non-Gypsy. There were 118 Gypsy patients from 45 families (later reduced to 41 families) and 87 non-Gypsy patients from 81 families. Results from the Gypsy population can be summarised as follows: (1) Exceptionally high prevalence (1/2,120) and incidence (1/1,250) of PCG. (2) Sex ratio of 1:1. (3) High probability of autosomal-recessive inheritance based on results of segregation analysis (a priori method of Finney and Weinberg proband method). (4) Results of segregation analysis point to complete gene penetrance. (5) There was bilateral occurrence in all Gypsies. (6) The disease could already be diagnosed at birth in 82% of the patients. This shows that in the majority of cases the disease begins prenatally. (7) Clinical investigations indicated a more severe course and worse prognosis than in non-Gypsies. (8) The disease was familial in 85% of the PCG patients, i.e. only 15% of the cases were the only one in the family. (9) The proportion of kinship marriages among the parents of patients was 45%. (10) Values of 2.8% for the gene frequency and 5.4% for heterozygote frequency were established. (11) Relative reproductive fitness was estimated to be 0.26. (12) Selection coefficient was 0.74. (13) Inbreeding coefficient of patients from kinship marriages was 0.0203, for all patients together 0.0091. (14) The high incidence of the glaucoma gene can best be explained by genetic drift (founder effect). (15) Special measures to ensure early diagnosis and treatment would be justified on these grounds. The characteristics of PCG in the non-Gypsy population are comparable to those in published reports. (a) The prevalence (1/51,000) and the incidence (1/22,200) in the non-Gypsy population of Slovakia are slightly higher than, but still comparable to, those in the literature. (b) The sex ratio was significantly shifted towards the male side, being 1.55:1 (60.9% males). (c) The most common age at diagnosis was 6 months. The distribution of the ages at diagnosis is in accordance with that in the literature. (d) Bilateral PCG was present in 73% of the patients, corresponding to findings in other populations. (e) The proportion familial: sporadic (12:88) was similar to data in recent publications. (f) Kinship marriages were found in the parents of 5.9% of the patients.(ABSTRACT TRUNCATED AT 400 WORDS)
Age Factors↗
Whole exome sequencing identifies three novel variants and establishes the molecular diagnosis of ATP6V0A4-related distal renal tubular acidosis in a lebanese infant.
BACKGROUND: Distal renal tubular acidosis (dRTA) is a rare inherited disorder characterized by impaired urinary acidification, leading to metabolic acidosis, hypokalemia, nephrocalcinosis, and growth impairment. Pathogenic variants in ATP6V0A4 are among the most common genetic causes of autosomal recessive dRTA. METHODS AND RESULTS: We report a Lebanese infant presenting with failure to thrive, recurrent vomiting, severe hyperchloremic metabolic acidosis, hypokalemia, and bilateral nephrocalcinosis, in whom whole-exome sequencing (WES) was performed to establish the molecular diagnosis and perform a comprehensive genomic evaluation. WES identified three novel variants, including a novel homozygous likely pathogenic ATP6V0A4 variant, consistent with the patient's phenotype. Two additional novel variants in TTN and CEP290 were also detected. Family segregation analysis confirmed the inheritance pattern of all three variants and refined the interpretation of the additional genomic findings. The patient showed sustained clinical and biochemical improvement to alkali therapy, with normalization of biochemical abnormalities and improvement in growth during follow-up. CONCLUSIONS: This report expands the molecular spectrum of ATP6V0A4-related dRTA and illustrates the clinical utility of comprehensive WES combined with segregation analysis for accurate molecular diagnosis, variant interpretation, genetic counseling, and the evaluation of additional genomic findings in rare inherited disorders.
Humans↗
Major gene effect for insulin levels in familial NIDDM pedigrees.
Insulin resistance and hyperinsulinemia are familial traits that may precede and predict the onset of non-insulin-dependent diabetes mellitus (NIDDM). In some populations, the distribution of fasting insulin levels and measures of in vivo insulin action suggest the effects of a single major gene. We previously noted hyperinsulinemia among unaffected members of 16 large white pedigrees ascertained through two or more NIDDM siblings. To examine the hypothesis that insulin levels are determined by a single major genetic locus, we used segregation analysis to examine fasting insulin levels in 206 family members and 65 spouses who had normal glucose tolerance tests by World Health Organization criteria. Segregation analysis supported a major locus determining fasting insulin levels and segregating as an autosomal recessive allele with a frequency of 0.25. Thus, homozygotes represented 6.25% of the population, and homozygosity for the hyperinsulinemia allele elevated the mean fasting insulin level from 70.3 to 211.1 pM (11.7-35.2 microU/ml). The analysis apportioned the variance in fasting insulin as 33.1% due to the major autosomal locus, 11.4% due to polygenic inheritance, and 55.5% due to unmeasured effects. Homozygotes for the recessive allele had higher 1-h insulin levels than all others (911.7 vs. 427.2 pM [152.0 vs. 71.2 microU/ml]). We also found evidence for a major locus determining 1-h-stimulated insulin levels, with codominant inheritance as the most likely pattern in inheritance. The causal relationship between these findings and NIDDM has not been determined, and segregation of direct measures of insulin action remains to be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels.
The hypothesis of a genetic control of plasma angiotensin I-converting enzyme (ACE) level has been suggested both by segregation analysis and by the identification of an insertion/deletion (I/D) polymorphism of the ACE gene, a polymorphism contributing much to the variability of ACE level. To elucidate whether the I/D polymorphism was directly involved in the genetic regulation, plasma ACE activity and genotype for the I/D polymorphism were both measured in a sample of 98 healthy nuclear families. The pattern of familial correlations of ACE level was compatible with a zero correlation between spouses and equal parent-offspring and sib-sib correlations (.24 +/- .04). A segregation analysis indicated that this familial resemblance could be entirely explained by the transmission of a codominant major gene. The I/D polymorphism was associated with marked differences of ACE levels, although these differences were less pronounced than those observed in the segregation analysis. After adjustment for the polymorphism effects, the residual heritability (.280 +/- .096) was significant. Finally, a combined segregation and linkage analysis provided evidence that the major-gene effect was due to a variant of the ACE gene, in strong linkage disequilibrium with the I/D polymorphism. The marker allele I appeared always associated with the major-gene allele s characterized by lower ACE levels. The frequency of allele I was .431 +/- .025, and that of major allele s was .557 +/- .041. The major gene had codominant effects equal to 1.3 residual SDs and accounted for 44% of the total variability of ACE level, as compared with 28% for the I/D polymorphism.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗