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PubMed1989

RFrAP: a computer program for analysis of complex HLA RFLPs. Assignment of restriction fragments to haplotypes by segregation analysis.

The availability of HLA class II cDNA probes has led to the development of a powerful method for the discrimination of genetic variation in this region of the major histocompatibility complex. There are problems with this approach which reduce its usefulness, including the hybridization of a probe with multiple restriction fragments (RFs) from the same locus or of two different cDNA probes with the same RF (cross-hybridizing). These problems may now be largely overcome by the relatively simple computer program presented here, which allows the entry, storage, and editing of phenotype data. It includes utilities for the automatic assignment of bands to haplotypes and also statistical functions to determine several types of correlations. The outputs are presented in a format familiar to HLA serologists and immunogeneticists. In addition, the data is stored in a manner that allows the user to easily prepare "ad hoc" figures and tables that illustrate the more complex relationships among bands and between them and other variables.

Computers↗
PubMed1996

New segregation analysis of panic disorder.

We performed simple segregation analyses of panic disorder using 126 families of probands with DSM-III-R panic disorder who were ascertained for a family study of anxiety disorders at an anxiety disorders research clinic. We present parameter estimates for dominant, recessive, and arbitrary single major locus models without sex effects, as well as for a nongenetic transmission model, and compare these models to each other and to models obtained by other investigators. We rejected the nongenetic transmission model when comparing it to the recessive model. Consistent with some previous reports, we find comparable support for dominant and recessive models, and in both cases estimate nonzero phenocopy rates. The effect of restricting the analysis to families of probands without any lifetime history of comorbid major depression (MDD) was also examined. No notable differences in parameter estimates were found in that subsample, although the power of that analysis was low. Consistency between the findings in our sample and in another independently collected sample suggests the possibility of pooling such samples in the future in order to achieve the necessary power for more complex analyses.

Adult↗
PubMed1989

Human BF*F-subtypes: segregation analysis with inclusion of MHC haplotypes.

The segregation of factor B(BF)F subtypes was analyzed in conjunction with other MHC markers in 15 families with 89 offspring. Informative data for BF F subtypes were obtained from 11 families, 6 of them with known recombinant individuals for the HLA-B/DR/GLO region. The subtypes did not contribute further to the localization of the cross-overs, but followed the known segregation of conventional BF allotypes. In 2 families of one kinship, the recognition of heterozygous BF*FAFB individuals could be established following the inclusion of three generations. The rarer of the two BF F subtype alleles, BF*FA, is positively associated with the HLA haplotypes BW62, CW3, C4A*3 and A29, CWX, B44, C4A*3, B*1, DR7. BF F subtypes are regarded as a very useful additional tool for studies of MHC organization and disease association.

Alleles↗
PubMedDate not supplied

Detection of fragile X non-penetrant males by DNA marker analysis.

Segregation analysis of the fragile-X [fra(X)] syndrome uncovered an unexpected 20% excess of normal males among sibships by Sherman et al. (Sherman SL, Morton NE, Jacobs PA, Turner G [1984]. Ann Hum Genet 48:21-37; Sherman SL, Jacobs PA, Morton NE, Froster-Iskenius U, Howard-Peebles PN, Neilsen KB, Partington MW, Sutherland GR, Turner G, Watson M [1985]: Hum Genet 63:289-299). This result predicts that about 17% (1/6) of normal sons of carrier fra(X) females will be non-penetrant. A way to test this prediction is by DNA markers. We analyzed DNA samples from 100 families with a set of flanking DNA markers linked to the fra(X) locus. Ten of 51 (19.6%) normal brothers, doubly informative and non-recombinant for flanking DNA markers, were found to be non-penetrant males. This result closely confirms the predictions of the segregation analysis indicating that about 1/6 of normal brothers are non-penetrant carrier males. The use of DNA markers to identify non-penetrant brothers and grandfathers can help to clarify the inheritance of the fra(X) mutation and be of considerable clinical usefulness. Using DNA markers, it was possible to study grandparental transmission in 71 of the families. In 39 families, DNA analysis confirmed the apparent pattern of inheritance. In 18 families, the grandparents had a single daughter with affected children. Of these, a new mutation at the time of their daughters' conception was possible in 15 and quite likely in 3. In 14 families with 2 or more daughters with affected fra(X) offspring, the grandparents had no affected sons or other relatives known to be positive for fra(X).(ABSTRACT TRUNCATED AT 250 WORDS)

DNA↗
PubMed1991

Informativeness of twin-nuclear family and nuclear family designs for segregation analysis.

This brief note examines the precision of segregation parameter estimates from both twin-nuclear family and conventional nuclear family designs. The program MENDEL was used to derive expected frequencies of different family patterns of affectation (with fixed sibship size) under various single gene models, and then to estimate the standard errors (and information) associated with gene frequency and penetrance values at given sample sizes. As might be expected, a 2- to 5-fold increase in relative efficiency was found for the same family size if families included an MZ twin pair among their offspring. The methods used allow convenient calculation of expected informativeness of a given study design.

Epidemiologic Methods↗
PubMed1990

Restriction fragment length polymorphism segregation analysis of the Li locus in Trifolium repens L.

The Li locus in white clover controls the presence of cyanogenic beta-glucosidase (linamarase) activity in leaf tissue, such that plants homozygous for the 'null' allele (li) have no linamarase activity in this tissue. The isolation of a cDNA clone from linamarase mRNA is described. The cDNA clone is used to further characterise alleles of the Li locus. Northern blot analysis shows that plants homozygous for the 'null' allele (li li) produce very reduced levels of mRNA which hybridises to the cDNA. Heterozygous plants (Li li), which have intermediate levels of enzyme activity, produce intermediate levels of mRNA. Southern blot analysis of Hind III digested genomic DNA shows that the white clover genome contains three genes with homology to the linamarase cDNA and that at least two of these genes segregate independently. Analysis of the cosegregation of linamarase activity and the presence of genomic restriction fragments identifies the genomic sequence specifying linamarase structure and indicates either a structural or cis acting control function of the Li locus.

Alleles↗
PubMed1986

Linkage arrangement in the vitellogenin gene family of Xenopus laevis as revealed by gene segregation analysis.

Using restriction fragment length polymorphism (RFLP) we have analyzed the segregation of alleles of the different vitellogenin genes of Xenopus laevis. The results demonstrate that the four genes whose expression is controlled by oestrogen, form two linkage groups. The genes A1, A2 and B1 are linked genetically whereas the fourth gene, the gene B2, segregates independently. The possible origin of this unexpected arrangement is discussed.

Alleles↗
PubMed1993

Segregation analysis of fat mass and other body composition measures derived from underwater weighing.

Segregation patterns of three body composition measures which were derived from underwater weighing were evaluated in a random sample of 176 French-Canadian families. Two of the variables can be considered as primary partitions of weight (fat mass [FM] and fat-free mass [FFM]), while the remaining variable (percent body fat [%BF]) is a derived index combining the measures of both fat and fat-free weight. This study represents the first report investigating major gene effects for these measures. Segregation analyses revealed that a major locus hypothesis could not be rejected for two of the three phenotypes. The single exception was FFM, for which nearly 60% of the variance was accounted for by a non-Mendelian major effect, which may reflect environmentally based commingling or may be in part a function of gene-environment interactions or correlations. In contrast to the results for FFM, the results for each of FM and %BF were similar and suggested a major locus which accounted for 45% of the variance, with an additional 22%-26% due to a multifactorial component. Given the similarity of the major gene characteristics for these two phenotypes, the possibility that the same gene underlies both measures warrants investigation. A reasonable hypothesis is to consider genes that may influence nutrient partitioning, as the family of candidate genes to receive the major attention.

Adipose Tissue↗
PubMedDate not supplied

Segregation analysis of a-b ridge count in human palms.

Frequency distribution and segregation analyses have been performed on a-b ridge counts from 422 families. The results support the hypothesis of two commingled distributions of the trait, high-value distributions being 5.4% in females and 2.4% in males of the whole population. Segregation analyses point out evidence for simultaneously a multi-factorial inheritance (h = 0.72) and a major effect (P = 0.01). However, by testing different hypotheses on transmission laws for the major effect, we cannot decide between Mendelian transmission and no transmission. Hypothesis of an accident occurring in the developmental process of the a-b count has to be investigated further.

Dermatoglyphics↗
PubMed1999

Inclusion of risk factor covariates in a segregation analysis of a population-based sample of 426 breast cancer families.

Although many segregation analyses of breast cancer have been published, few have included risk factor covariates. Maximum likelihood segregation analyses examining age-at-onset (model 1) and susceptibility (model 2) models of breast cancer were performed on 426 four-generation families originally ascertained between 1944 and 1952 through a breast cancer proband. Cancer status and risk factor data were collected through interviews of participants or surrogates. When segregation analyses were performed on 10,791 women, without estimation of any covariates, all hypotheses under both models were rejected. Model 1, which required estimation of fewer parameters than model 2, provided a better fit to the data according to Akaike's Information Criterion. Further segregation analyses were performed under model 1 on a subset of women with complete data on education, age at first birth (nulliparous women included), and alcohol use, covariates that were found to significantly (P<0.05) improve the fit over the addition of exam age alone in logistic regression models. All three covariates improved the fit of the models, as did year of birth, but at all stages of model building, all of the hypotheses were still rejected. After the allele frequency was fixed at 0.0033, a subset of families appeared to fit a dominant model. Using this model, risk estimates were calculated based on inferred genotype, age, and covariate values. The penetrance was estimated to be 0.15, much lower than previous estimates based on families ascertained through breast cancer probands with early onset. Moreover, the estimates of penetrance were not greatly influenced by incorporation of the measured risk factors.

Adult↗
PubMed1992

Commingling and complex segregation analysis of fasting plasma glucose in the Lipid Research Clinics family study.

Commingling and segregation patterns of fasting plasma glucose (GL) were examined in family data from 5 clinics (Cincinnati, Stanford, Iowa, Minnesota, and Oklahoma) of the Lipid Research Clinics (LRC) family study. In addition to the primary question of whether there was a major gene for GL, a secondary purpose was to investigate the possibility of genetic heterogeneity among the 5 clinics. No statistical support was found for heterogeneity among clinics, either in the commingling of distributions or in the segregation patterns. For the combined clinics sample, both a major effect and a multifactorial component were significant. However, the major effect (accounting for 73% of the variance) was not found to be consistent with a major gene, as the hypothesis of Mendelian transmission was rejected. The most parsimonious model involved equal transmission probabilities, which suggests that the major effect is not transmitted from parents to offspring. Possible sources of this major non-Mendelian effect were explored. The multifactorial component accounted for 10% of the variance in GL levels, and no generational differences were noted. Although our study was unable to provide evidence in favor of a major gene effect, it should be noted that a major gene cannot be firmly refuted. For example, a variety of interactions, such as genotype-dependent age effects, could have masked the transmission probabilities.

Adolescent↗
PubMed1990

Segregation analysis of breast cancer from the cancer and steroid hormone study: histologic subtypes.

The segregation pattern of breast cancer in white families from the Cancer and Steroid Hormone Study was investigated. Families were categorized into four groups based on the histologic type of breast cancer in the probands:ductal cancer, lobular cancer, adenocarcinoma, and medullary cancer. The ductal cancer sample was further split into a premenopausal-proband and a postmenopausal-proband subset. Results for six complex segregation analyses are presented; the findings suggest heterogeneity in the transmission of breast cancer. For all analyses, there was no evidence for a multifactorial component in the mixed model, ie, a major locus plus other transmission, genetic and/or cultural. Interpretation of the medullary cancer, adenocarcinoma, and lobular cancer analyses does not permit discrimination among the major locus models. Segregation of breast cancer in the entire ductal sample was consistent with autosomal recessive transmission. In the ductal subanalyses, a recessive gene was sufficient to explain the breast cancer distribution when the proband had postmenopausal breast cancer. In contrast, when the proband had premenopausal breast cancer, the transmission model was consistent with a dominant major gene, with sporadic cases of disease.

Adenocarcinoma↗
PubMed1990

Segregation analysis of dominant osteogenesis imperfecta in Italy.

We have performed linkage analysis in seven Italian families, in which mild osteogenesis imperfecta (OI) segregated as a dominant trait, by means of six DNA restriction fragment length polymorphisms (RFLPs) of type I collagen genes. OI type I was linked to the alpha 1(I) gene (COL1A1) in two families, and to the alpha 2(I) gene (COL1A2) in one family. OI type IV segregated with COL1A2 in two families. In two OI type I families, the molecular genetic data were insufficient for exclusion of one gene. Four DNA polymorphisms were particularly informative for cosegregation analysis of OI in Italian kindreds.

Adult↗
PubMed1989

Linkage disequilibrium and CF allele segregation analysis in cystic fibrosis families in Northern Ireland.

Linkage disequilibrium and cystic fibrosis (CF) allele segregation were analysed in 46 CF families in Northern Ireland. The smaller (+) allele of the KM19/PstI polymorphism and the larger (-) allele of the XV-2c/TaqI polymorphism showed marked linkage disequilibrium with CF. This information can be used to alter the risk of an individual being a carrier of CF away from the expected population risk of 1 in 20. The high-risk genotypes K+K+ or X-X- have a risk of 1 in 10 and the low-risk genotypes K-K- or X+X+ have a risk of 1 in 50. A study of the segregation of CF alleles in the 46 families, using KM19 and Xv-2c, showed preferential inheritance of the paternal (79%), as opposed to the maternal (21%), CF allele by the heterozygous carriers. A mechanism that might explain this observation is discussed.

Alleles↗
PubMed1994

Segregation analysis of the mouse Rb(6.16) translocation in zygotes produced by heterozygous female carriers.

The segregation products in zygotes of females heterozygous for the mouse Rb(6.16) translocation were studied. Of 191 first-cleavage metaphase zygotes recovered from 16 females mated to chromosomally normal males, 132 were cytogenetically analyzed after sequential G- and C-banding. There were no products of adjacent segregation, since the six chromosomal imbalances were unrelated to the translocation. Alternate segregation was seen in 126 (95.5%) of the zygotes, with 85 being chromosomally normal and 41 carrying the translocation. These results indicate preferential alternate segregation and a significant deviation from the Mendelian 1:1 ratio (P < 0.005) for reciprocal alternate segregants, as seen earlier for males with this translocation. However, the approximately 2:1 ratio for normal-to-balanced segregants in females is lower than the ratios consistently seen for males. This supports the notion that there are different underlying causes of the distortion in the sexes.

Animals↗
PubMed1988

Segregation analysis with uncertain ascertainment: application to Fanconi anemia.

A Bayesian solution for making inferences about segregation parameters with no information about the ascertainment is presented. Inferences about the segregation probability and the probability of being sporadic are made through the posterior marginal distribution of these parameters after integrating out the ascertainment probability, the nuisance parameter. The method was tested with real and simulated data and performed well. Original Fanconi anemia data, for which no information about the ascertainment was available, were then analyzed, with results that confirmed a monogenic autosomal recessive mode of inheritance.

Anemia, Aplastic↗
PubMed1992

Fragile site (16) (q22). III. Segregation analysis.

The rare autosomal fragile site, fra (16) (q22), is the most common of all rare autosomal fragile sites and has a heterozygote frequency of about 5%. Evidence for it was found following the segregation expected from a simple codominant trait with complete penetrance; this is in contrast to a variety of other rare autosomal fragile sites. Based on the analysis of 12 families in which fra (16) (q22) is segregating, we found that, whereas complete penetrance could be confirmed, the transmitting parent was significantly more likely to be of the female sex. On the other hand, there was no evidence for preferential transmission to offspring of either sex.

Chromosome Fragile Sites↗
PubMed1986

Segregation analysis of balanced pericentric inversions in pedigree data.

The results of the recent European collaborative prenatal study suggested a segregation distortion of balanced pericentric inversions from carrier fathers but not carrier mothers (Boué & Gallano 1984). In an attempt to confirm these unexpected results, we examined 216 pedigrees with balanced pericentric inversions collected from three centers and from the literature. We were unable to detect any significant deviation from the expected 1:1 segregation of balanced pericentric inversions to normal karyotypes among the offspring of either carrier parent. To clarify the discrepancy between the studies, we reanalyzed the data from the prenatal study using all karyotyped individuals and, assuming conventional ascertainment rules, found a normal segregation pattern. We conclude that balanced pericentric inversions segregate normally in both males and females and that some retrospectively selected pedigrees were included as prospective in the prenatal study and this misclassification caused the apparent segregation distortion from carrier fathers.

Chromosome Inversion↗