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PubMed2001

Segregation analysis of asthma and respiratory allergy in population-based samples of families.

Class A regressive multiple logistic segregation models with a sibling covariate were used to investigate the underlying determinants of asthma and respiratory allergy (defined from specific IgE levels to inhaled allergens) in the randomly recruited Caucasian families from the Genetic Analysis Workshop 12 asthma data sets--Perth, Busselton, and Southampton. For asthma, both a purely multifactorial model and a major gene (dominant or recessive) model with multifactorial effects fitted the data. For respiratory allergy, a dominant, dominant with multifactorial effects and a purely multifactorial model all fitted the data. However, homogeneity of the three studies was rejected for both traits indicating that the three populations are significantly different and should be analyzed separately. This finding has implications for the meta-analysis of asthma linkage studies.

Adult↗
PubMed2000

Meiotic segregation analysis of RB1 alleles in retinoblastoma pedigrees by use of single-sperm typing.

In hereditary retinoblastoma, different epidemiological studies have indicated a preferential paternal transmission of mutant retinoblastoma alleles to offspring, suggesting the occurrence of a meiotic drive. To investigate this mechanism, we analyzed sperm samples from six individuals from five unrelated families affected with hereditary retinoblastoma. Single-sperm typing techniques were performed for each sample by study of two informative short tandem repeats located either in or close to the retinoblastoma gene (RB1). The segregation probability of mutant RB1 alleles in sperm samples was assessed by use of the SPERMSEG program, which includes experimental parameters, recombination fractions between the markers, and segregation parameters. A total of 2,952 single sperm from the six donors were analyzed. We detected a significant segregation distortion in the data as a whole (P=.0099) and a significant heterogeneity in the segregation rate across donors (.0092). Further analysis shows that this result can be explained by segregation distortion in favor of the normal allele in one donor only and that it does not provide evidence of a significant segregation distortion in the other donors. The segregation distortion favoring the mutant RB1 allele does not seem to occur during spermatogenesis, and, thus, meiotic drive may result either from various mechanisms, including a fertilization advantage or a better mobility in sperm bearing a mutant RB1 gene, or from the existence of a defectively imprinted gene located on the human X chromosome.

Adult↗
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↗
PubMed1993

Effect of ignoring genotype-environment interaction on segregation analysis of quantitative traits.

Thirty replicates of 200 nuclear families (6 members each) were generated under three GxE interaction models. Segregation analyses of these data were performed using a regressive model taking into account an interaction effect or not. Results showed that ignoring the GxE interaction markedly decreased the power for accepting a major gene and led to serious bias in parameter estimates.

Adult↗
PubMed2000

Segregation analysis of urinary albumin excretion in families with type 2 diabetes.

Elevated urinary albumin excretion (UAE) is a predictor of the development of nephropathy and cardiovascular mortality. To study whether genetic factors may determine UAE, we examined familial aggregation of UAE in 96 large multigenerational pedigrees ascertained for type 2 diabetes. A total of 1,269 subjects had UAE measured as the urinary albumin-to-creatinine ratio (ACR). This included 630 subjects with type 2 diabetes and 639 subjects without diabetes. A significant correlation (Spearman's correlation 0.34, P < 0.001) was found between the median ACR values determined separately in nondiabetic and diabetic members of the same family. To determine whether this familial aggregation of ACR could be explained by the transmission of 1 or more major genes and thus be suitable for gene mapping studies, segregation analyses were performed. In these analyses, ACR was modeled as a continuous trait with the inclusion of age, sex, and duration of diabetes as covariates. Likelihood ratio tests were performed to test competing hypotheses, and Akaike's information criterion was used to determine the most parsimonious models. The Mendelian model with multifactorial inheritance was supported more strongly than Mendelian inheritance alone. These analyses suggested that the best model for ACR levels was multifactorial with evidence for a common major gene. When the analyses were repeated for diabetic subjects only, the evidence for Mendelian inheritance was improved, although a single major locus with additional multifactorial effects was more strongly supported. The results from the current study suggest that levels of UAE are determined by a mixture of genes with large and small effects as well as other measured covariates, such as diabetes.

Adult↗
PubMed2000

Segregation analysis of apolipoproteins A-1 and B-100 measured before and after an exercise training program: the HERITAGE Family Study.

Complex segregation analyses of apolipoproteins (apo) A-1 and B-100 were performed in a sample of 520 individuals from 99 white families who participated in the HERITAGE Family Study. In these sedentary families, plasma apo A-1 and B-100 concentrations were measured before and after a 20-week endurance exercise training program. Baseline apo A-1 and B-100 were adjusted for the effects of age (age-adjusted baseline apo A-1 and B-100) and for the effects of age and BMI (age-BMI-adjusted baseline apo A-1 and B-100). The change in response to training was computed as a simple Delta (posttraining minus baseline) and was adjusted for age and the baseline (age-baseline-adjusted apo A-1 and B-100 responses to training). In the present study, a major gene could not be inferred for baseline apo A-1. Rather, we found a major effect along with a multifactorial effect accounting for 8% to 9% and 51% to 56% of the variance, respectively. In addition, no clear evidence supported a major-gene effect for its response to training, whereas the transmission of a major effect from parents to offspring was ambiguous, ie, genetic in nature or familial environmental in origin. The major effect accounted for 15% of the variance, with an additional 21% and 58% of the variance being accounted for by a multifactorial effect in parents and offspring, respectively. It is interesting to have obtained evidence of a putative recessive major locus for baseline apo B-100, which accounted for 50% to 56% of the variance, with an additional 25% to 29% of the variance due to a multifactorial effect. In contrast, no major effect for its response to training was identified, although a multifactorial effect was found that accounted for 27% of the variance. The novel findings arising from the present study are summarized as follows. Baseline apo A-1 and its response to training were influenced by a major effect and a multifactorial effect. Baseline apo B-100 was influenced by a putative major recessive gene with a multifactorial component, but its response to training was influenced solely by a multifactorial component in these sedentary families.

Adolescent↗
PubMed1993

Segregation analysis for high density lipoprotein in the Berkeley data.

Transmission models for high density lipoprotein (HDL) were evaluated in the Berkeley data set through segregation analyses using S.A.G.E. These preliminary analyses indicate that among the models fitted, an additive model with non-Mendelian transmission probabilities provides a good fit for HDL, suggesting the possibility of a significant environmental component in the transmission of HDL. After adjustment for triglyceride, however, Mendelian models for a major gene seem to provide as good a fit as non-Mendelian models but the results do not permit distinction between a dominant model and an additive model.

California↗
PubMed1985

Segregation analysis of a marker localised Xp21.2-Xp21.3 in Duchenne and Becker muscular dystrophy families.

A DNA marker C7, localised Xp21.1-Xp21.3, has been studied in kindreds segregating for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). In DMD families four crossovers were observed in 38 informative meioses between C7 and the DMD locus (theta = 0.12, z max = +2.72). In BMD families no recombinants were observed in the 16 informative meioses studied. These data are consistent with the localisation of the mutations in these disorders being in the same region of Xp21. Studies in families also segregating for the DNA marker 754 support the previously reported physical order of these loci as X centromere-754-DMD-BMD-C7-X telomere. A recombination fraction of 0.11 (z max = +5.58) was found between DMD-754 by combining our previously published data with the data presented here. C7 and 754 thus provide good bridging markers for the diagnosis of DMD and BMD.

Chromosome Banding↗
PubMed1990

Segregation analysis of the X-chromosome in a family with Rett syndrome in two generations.

We report on the first family in which Rett syndrome (RTS) appeared in two consecutive generations. The index case is a 12-year-old girl (classical RTS); her maternal aunt, age 44 years, has mild RTS. Clinically, the family illustrates the wide phenotypic variability between cases, particularly in severity of neurological manifestations. We have analyzed the short arm of the X-chromosome of the family with gene technology. This did not uncover any genetic marker for diagnosis, but it did suggest how the syndrome might have segregated in the family. A cytogenetic analysis gave no information about chromosome abnormalities.

Adult↗
PubMed1998

Segregation analysis of cutaneous melanoma in Queensland.

To investigate whether the familial clustering of cutaneous melanoma is consistent with Mendelian inheritance of a major autosomal gene, maximum likelihood segregation analyses were performed in a population-based sample of 1,912 families ascertained through a proband with melanoma diagnosed in Queensland between 1982 and 1990. Analyses were performed with the S.A.G.E. statistical package, using the REGTL program for a binary trait with a variable age of onset. We sought medical confirmation for all family members reported to have had melanoma, and only medically verified cases among relatives were included in the analyses. The hypothesis of codominant Mendelian inheritance gave a significantly better fit to the data than either dominant or recessive Mendelian inheritance, or environmental transmission. Overall, both Mendelian inheritance of a single major gene, and purely environmental transmission were rejected (P < 0.001). In both the single major gene and environmental models, there was strong evidence of familial dependence in melanoma occurrence (P < 0.001). These results are consistent with reported genetic heterogeneity in melanoma inheritance and suggest that other familial factors, such as pigmentation, skin type, and sun exposure habits, may play an important role in the familial clustering of melanoma.

Adult↗
PubMed1988

Segregation analysis of leprosy in families of northern Thailand.

Sixty-three families with multiple instances of leprosy were identified through a major leprosy treatment center in northern Thailand. Complex segregation analyses for single major genes or polygenic inheritance were performed using the maximum-likelihood routine POINTER to determine the most likely etiologic model of genetic susceptibility. Liability differences between men and women were considered in these models. When individuals were considered to be affected because they had any form of leprosy, a generalized major gene model with nearly dominant parameters on the liability scale, but additive penetrances, was found to be the most likely. When only those individuals who had tuberculoid forms of leprosy were considered to be affected, a recessive model was found to be the most likely; however, the discrimination between various models was poor. Further analyses are necessary to delineate genetic mechanisms to explain these apparently divergent results. In particular, methods of testing two locus models should be considered.

Adult↗
PubMed1992

Biostatistical basis of individualization and segregation analysis using the multilocus DNA probe MZ 1.3: results of a collaborative study.

A collaborative study using the multilocus minisatellite DNA probe MZ 1.3 was carried out to investigate segregation information, mutation rate, DNA fragment frequencies as well as band sharing characteristics. The fingerprint patterns of 393 children as well as 694 unrelated individuals were analysed after digestion of DNA with the restriction enzyme HinfI. A mutation rate of 1% per meiosis or 0.04% per band was found with a mean number of 26 bands/individual. It was shown that maternal and paternal fragments are inherited in equal proportions. Population frequencies of restriction fragments demonstrated a distribution with increasing frequencies in the small fragment size range below 10 kb as well as the absence of very common or very rare fragments. Our data can be used to calculate simple exclusion probabilities based on the number of non-maternal bands in the child.

Biometry↗
PubMed1998

Sperm segregation analysis of a complex chromosome rearrangement, 2;22;11, by whole chromosome painting.

Using the human sperm-hamster oocyte fusion technique and whole chromosome painting, we studied sperm chromosome segregation in a male heterozygous for a complex chromosome rearrangement, 46,XY,-2, +der(2)t(2;11)(q13; q23),-11,+der(11)t(11;22)(q23;q11.2),-22, +der(22)t(2;22)(q13; q11.2). A total of 208 sperm complements were analyzed. The frequency of sperm carrying a normal or a balanced complement was 13.5% (9.62% and 3.85%, respectively). The frequency of unbalanced sperm was 86.5% (64.9% from 3:3 segregation, including 30 different types; 20.7% from 4:2 segregation, including 21 different types; and 0.96% from 5:1 segregation, including 2 different types). The sex ratio, determined in 134 sperm complements, did not differ from the expected 1:1 ratio. The results obtained in this study are compatible with the formation, during the synaptic process, of a complex hexavalent figure involving chromosomes 2, 11, and 22. The behavior and segregation of this complex figure would explain the high frequency (86.5%) of unbalanced complements observed in this carrier.

Animals↗
PubMed1985

Segregation analysis of a translocation (16;21)(p11;q22) in a large pedigree.

A large family with an inherited reciprocal translocation (16;21) is described. An unbalanced karyotype due to adjacent-1 segregation was documented in 6 cases, whereas 25 children dying within the first year of life and 4 individuals dying at later ages probably had the same abnormality. Therefore minimal and maximal risk estimates were calculated to be 6.0% and 26.5% for female, respectively, 4.8% and 33.3% for male translocation heterozygotes. Among the karyotyped phenotypically normal offspring of male as well as female carriers the ratio of normal children to balanced carriers was not different from 1:1.

Chromosomes, Human, 16-18↗
PubMed1995

Segregation analysis of four translocations, t(2;18), t(3;15), t(5;7), and t(10;12), by sperm chromosome studies and a review of the literature.

We examined the meiotic segregation patterns of 444 sperm cells belonging to four reciprocal translocation carriers, t(2;18)(p21;q11.2), t(3;15)(q26.2; q26.1), t(5;7)(q13; p15.1), and t(10;12)(q26.1;p13.3). For the t(2;18) carrier, the frequencies of alternate, adjacent-1, adjacent-2, and 3:1 segregations were 41.9%, 35.2%, 14.4%, and 8.4%, respectively. For the t(3;15) carrier, the segregation pattern was 48% alternate, 36% adjacent-1, 12% adjacent-2, 2% 3:1, and 2% 4:0. One cell was the result of a 4:0 segregation. For the t(5;7) heterozygote, the corresponding segregation frequencies were 40.2%, 26.2%, 16.6%, and 17.0%. This translocation heterozygote showed a higher number of 3:1 segregations than adjacent-2 segregations, which is unusual. The t(10;12) segregations were 61.1%, 26.3%, 6.9%, and 5.6%. The percentages of chromosome abnormalities unrelated to the translocation ranged from 0% to 0.6% for aneuploidy and from 5.5% to 10.9% for structural abnormalities. These frequencies are within the ranges for control donors. Sperm chromosome data from the literature on the segregation of 30 reciprocal translocations were reviewed.

Adult↗
PubMed1989

Genetic segregation analysis of familial mitral valve prolapse shows no linkage to fibrillar collagen genes.

Three pedigrees were identified in which mitral valve prolapse seemed to be inherited as a mendelian autosomal dominant trait. The segregation of the genes encoding the major fibrillar collagens present in valve tissue, collagens I and III, was analysed by use of restriction enzyme site variants as genetic markers. In one pedigree there was discordance between the segregation of the disease and markers for all three collagen genes. In another, there was discordance between the disease and markers for both collagen I loci. This is evidence against the disease being generally the result of mutations of the genes encoding the major fibrillar collagens.

Collagen↗