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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↗
PubMed1987

Kinetic and segregational analysis of mitochondrial DNA recombination in yeast.

A pair of yeast strains of opposite mating type was constructed to contain polymorphisms at three loci on the mitochondrial genome--the 21 S rRNA gene, var1, and cob--such that parental and recombinant forms of these genes could be easily detected by Southern blot analysis. These polymorphisms were used to measure in a single cross gene conversions at the 21 S rRNA and var1 loci and a reciprocal recombination at cob. For all three loci, recombination initiates at about the same time, 4 to 6 h after mixing cells, and increases with similar kinetics over a 24-h period. The segregation of parental and recombinant forms of these genes was then followed by pedigree analysis. The results, which show a high variance in the distribution of parental and recombinant forms of all three genes in cells derived from both the first bud and the mother zygote, are consistent with the segregation of a small number of mitochondrial DNA molecules from the zygote to diploid buds. Based on these results and previous experiments of this type, a limited "zone of mixing" of parental mitochondrial DNA molecules probably exists in the zygote. The extent of sampling from this zone, together with the intrinsic properties of the recombination events themselves, is likely to determine the observed pattern of recombination of mitochondrial DNA sequences at the population level.

Alleles↗
PubMed1983

Familial atypical multiple mole-melanoma (FAMMM) syndrome: segregation analysis.

Genetic analysis was performed on four kindreds with clinical and pathological verification of the FAMMM syndrome. There were 80 affected or at risk members in these families. A segregation ratio of 0.47 was observed, which is consistent with an autosomal dominant mode of inheritance. Three obligate gene carriers who lacked any FAMMM phenotypic manifestations were observed and the rate of penetrance for the FAMMM gene was calculated to be 0.93. Cancer at all anatomical sites (exclusive of cutaneous malignant melanoma and intraocular malignant melanoma) showed a five-fold increase (p less than 0.004) in risk for gene carriers when age corrected and compared to the population expectation. Although there was an apparent excess of carcinoma of the lung, pancreas, and breast, the number of family members studied with specific organ cancer was too small; therefore, a larger sample size will be needed to verify this apparent excess. Our findings warrant further investigation in additional FAMMM kindreds.

Adult↗
PubMed1988

Structural and segregation analysis of the type II collagen gene (COL2A1) in some heritable chondrodysplasias.

Seventy-seven persons with a variety of heritable chondrodysplasias were screened for gross rearrangements of the structural gene encoding the major cartilage collagen, collagen II. None was found. Segregation of the locus (COL2A1) was studied in 19 pedigrees using three restriction site dimorphisms (shown by PvuII, HindIII, and BamHI) and a length polymorphism as linkage markers. Discordant segregation between COL2A1 and the mutant locus was seen in pedigrees with multiple epiphyseal dysplasia, autosomal recessive spondyloepiphyseal dysplasia tarda, hypochondroplasia, pseudoachondroplasia, diaphyseal aclasis, and trichorhinophalangeal syndrome. One pedigree with diastrophic dysplasia was weakly concordant. Autosomal dominant spondyloepiphyseal dysplasia tarda and metaphyseal chondrodysplasia (type Schmid) were not informative. We conclude that mutations of the collagen II gene are not a common feature of the heritable chondrodysplasias. Since the chondrocyte binding protein, chondrocalcin, is also encoded at COL2A1 our conclusions apply equally to this gene.

Calcium-Binding Proteins↗
PubMed1986

DNA "fingerprints" and segregation analysis of multiple markers in human pedigrees.

Tandem-repetitive DNA hybridization probes based on a putative human recombination signal detect multiple polymorphic minisatellite fragments in human DNA. The genetic complexity of the resulting individual-specific DNA "fingerprints" was investigated by studying a large sibship affected by neurofibromatosis and a more extensive pedigree segregating for two different hemoglobinopathies. The segregation of up to 41 different heterozygous DNA fragments from each parent could be analyzed in a single sibship, using two different repeat probes. Most of these variable DNA fragments could not be paired as alleles, to an extent which suggests that the DNA fingerprints are together derived from approximately 60 heterozygous loci (approximately 120 variable fragments), only a proportion of which can be scored in a given individual. Two or three of the DNA fragments detected by one probe showed tight linkage and may be derived from long minisatellite(s) that are cleaved to produce more than one polymorphic DNA fragment. Excluding allelic and linked DNA fragments, almost all remaining scorable fragments segregated independently, allowing up to 34 unlinked loci to be examined simultaneously. These loci are scattered over most or all of the human autosomes. Minisatellite probes are therefore suitable for rapid marker generation and can be applied to linkage analysis in human pedigrees.

Alleles↗
PubMed1986

Reciprocal translocations between acrocentrics: segregational analysis in twenty-nine families with unbalanced progeny.

This study comprises 29 families with 42 unbalanced offspring in which reciprocal interacrocentric translocations (RIATs) were identified by banding. The observed unbalances were due to adjacent-1 (42.9%), adjacent-2 (28.6%) and 3:1 (28.6%) segregations. The concordance between the observed and expected segregations was 85.7% according to the Jalbert et al. (1980) criteria. 17.2% of the RIATs led to unbalances by 2 different segregations. 78.6% of the cases were maternal in origin. The overall incidence of spontaneous abortion was 37%. Corrected recurrence risks of unbalanced liveborn offspring for female and male carriers were seemingly similar: 17.8% and 12.5% respectively. These data indicate that RIATS exhibit (as distinctive features) an approximate 4:3:3 ratio for adjacent-1, adjacent-2 and 3:1 segregations, and a proneness to produce unbalances by different segregations.

Abortion, Spontaneous↗
PubMed1996

Segregation analysis of physician-diagnosed asthma in Hispanic and non-Hispanic white families. A recessive component?

The inheritance of asthma, evident from its high family concordance, is not well understood. To investigate whether asthma may be inherited through a major gene with two alleles, segregation analyses were conducted in 3,369 individuals from 906 nuclear families enrolled, without selection, in a longitudinal study of respiratory health in Tucson, Arizona. Physician-diagnosed asthma and its age of onset were ascertained for each family member when children were at a mean age of 7 yr. Age of asthma diagnosis was allowed for in analyses, and the impact of the covariate total serum IgE level on age of onset was examined. Segregation analyses were conducted with and without residual family effects, with and without the covariate IgE. The hypothesis of a single two-allele locus for asthma was rejected. However, depending on the method of assessment of the residual familial effects, either a polygenic/multifactorial mode of inheritance alone, or an oligogenic model with some evidence of a recessive component present in the population with the high frequency of 0.67, were compatible with the data. Results were unchanged with the addition of the covariate IgE.

Adult↗
PubMed1999

Segregation analysis of obsessive-compulsive disorder using symptom-based factor scores.

Obsessive-compulsive disorder (OCD) is a complex psychiatric disorder characterized by recurring obsessions or compulsions that cause significant distress to the patient or significantly interfere with the patient's normal home, work, or social activities [Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC: American Psychiatric Association, 1994]. Twin and family studies have suggested that OCD has a significant genetic component. We performed complex segregation analyses using POINTER with families ascertained through an OCD-affected proband. In an attempt to resolve the phenotypic heterogeneity observed among individuals with OCD these segregation analyses used four factor-analytic symptom dimensions to subset the family sample based upon probands' symptom factor scores. Analysis of the entire sample allowed rejection of only the no transmission model; that model was also rejected in all subsequent analyses. Limiting the analyses to families with at least one OCD-affected member in addition to the proband (the demonstrably familial form of OCD) allowed rejection of all models except the mixed model. Analyses limited to families of high-factor-3 (symmetry and ordering symptoms) probands led to rejection of the polygenic model, indicating the involvement of a major locus. Additionally, the relative risk of OCD or subclinical OCD was 1.7 for relatives of probands with a factor 3 score greater than zero compared with relatives of probands with a low factor score. The symptoms attributed to high factor 3 scores (symmetry and ordering) may constitute a genetically significant symptomatic subtype of OCD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:669-675, 1999.

Aging↗
PubMed1998

Segregation analysis of pulmonary function among families in the Framingham Study.

Familial aggregation of cross-sectional pulmonary function was examined in 5,003 subjects from 1,408 families participating in the Framingham Study. Subjects, who were members of either the Original Cohort (recruited from 1948 to 1952) or the Offspring Cohort (recruited from 1971 to 1974), underwent spirometry at a mean age of 53 yr. The effects of age, height, weight, and smoking status on FEV1 were evaluated through linear-regression analysis, with separate models for men and women in each cohort. The gender- and cohort-specific standardized residual FEV1 from these models was used as the phenotypic variable in familial correlation and segregation analyses to assess inheritance patterns. In models that assumed no major gene determining FEV1, correlation of pulmonary function was greater for mothers and offspring than for fathers and offspring (p[mo] = 0.190, p[fo] = 0.112; p = 0.06), and sibling correlation exceeded parent-offspring correlation (p[sib] = 0.225; p < 0.01). By comparison with a general model, in which transmission probabilities and residual familial correlations are arbitrary, models that imposed a Mendelian gene were rejected (p < 0.001). A model with no parent-offspring transmission of a major factor, but with residual familial correlation, provided as good a fit as the general model, suggesting that environmental and/or polygenic genetic influences determine FEV1.

Body Height↗
PubMed1994

Segregation analysis and RFLP mapping of the R1 and R3 alleles conferring race-specific resistance to Phytophthora infestans in progeny of dihaploid potato parents.

Phytophthora infestans (Mont.) de Bary is the most important fungal pathogen of the potato (Solanum tuberosum). The introduction of major genes for resistance from the wild species S. demissum into potato cultivars is the earliest example of breeding for resistance using wild germplasm in this crop. Eleven resistance alleles (R genes) are known, differing in the recognition of corresponding avirulence alleles of the fungus. The number of R loci, their positions on the genetic map and the allelic relationships between different R variants are not known, except that the R1 locus has been mapped to potato chromosome V. The objective of this work was the further genetic analysis of different R alleles in potato. Tetraploid potato cultivars carrying R alleles were reduced to the diploid level by inducing haploid parthenogenetic development of 2n female gametes. Of the 157 isolated primary dihaploids, 7 set seeds and carried the resistance alleles R1, R3 and R10 either individually or in combinations. Independent segregation of the dominant R1 and R3 alleles was demonstrated in two F1 populations of crosses among a dihaploid clone carrying R1 plus R3 and susceptible pollinators. Distorted segregation in favour of susceptibility was found for the R3 allele in 15 of 18 F1 populations analysed, whereas the R1 allele segregated with a 1:1 ratio as expected in five F1 populations. The mode of inheritance of the R10 allele could not be deduced as only very few F1 hybrids bearing R10 were obtained. Linkage analysis in two F1 populations between R1, R3 and RFLP markers of known position on the potato RFLP maps confirmed the position of the R1 locus on chromosome V and localized the second locus, R3, to a distal position on chromosome XI.

Alleles↗
PubMed2000

Complex segregation analysis provides compelling evidence for a major gene underlying obsessive-compulsive disorder and for heterogeneity by sex.

Evidence from twin and family studies supports a genetic etiology for obsessive-compulsive disorder (OCD). The purpose of this study was to test whether a major gene is implicated in a proportion of families with OCD. Complex segregation analyses of 153 families (80 case and 73 control), ascertained in the Johns Hopkins OCD Family Study, provided strong evidence for a major gene. A Mendelian-dominant model, with significant sex effects and with residual familial effects, best explained the observed data. Stratification of the sample by the sex of probands provided further evidence of heterogeneity with respect to familial aggregation. Segregation analyses of 86 families with a female proband and of the 67 families with a male proband suggested that a Mendelian-dominant model with familial residual effects was the most parsimonious model explaining the inheritance of OCD in both subgroups.

Adolescent↗
PubMed1998

Human malaria: segregation analysis of blood infection levels in a suburban area and a rural area in Burkina Faso.

The genetic control of blood infection levels in human malaria remains unclear. Case control studies have not demonstrated a strong association between candidate genes and blood parasite densities as opposed to surveys that have focused on severe malaria. As an alternative approach, we used segregation analyses to determine the genetic control of blood parasitemia. We surveyed 509 residents (53 pedigrees) in a rural area and 389 residents (41 pedigrees) in an urban area during 18 months. Each family was visited 20 times and 28 times in the urban area and in the rural area; the mean number of parasitemia measurements per subject was 12.1 in the town and 14.9 in the village. The intensity of transmission of Plasmodium falciparum was 8-fold higher in the rural area than in the urban area. Using the class D regressive model for both populations, we found that blood parasite densities were correlated between sibs. We obtained strong evidence for a major effect, but we found that the transmission of this major effect was not compatible with a simple Mendelian model, suggesting a more complex mode of inheritance. Moreover, there was a strong interaction between major effect and age, suggesting that the influence of the putative major gene may be more prominent in children than in adults. Further nonparametric linkage studies, such as sib pair analysis, that focus on children would help us better understand the genetic control of blood infection levels.

Adolescent↗
PubMed1987

Genetic etiology of gastric carcinoma: II. Segregation analysis of gastric pH, nitrate, and nitrite.

A study of gastric pH, nitrate, and nitrite in 110 families collected as part of a cohort from the Narino region of Colombia is presented. All three traits are familial and have a significant linearly increasing age trend. Gastric pH has a clear bimodal distribution but does not show Mendelian segregation. The nitrate distribution is slightly skewed, but generational heterogeneity explains the data best. Gastric nitrite is also biomodal with a clear break at concentration 1.08 micrograms/ml, and 74% of the observations at zero concentration; it shows a recessive Mendelian segregation with significant residual spouse correlation. This model also fits the data best when nitrite is dichotomized into detected (measurable) and undetected values. The estimated frequency of the recessive allele is .57, so that an estimated 32% of the population sampled are recessives. Recessives whose spouses have measurable nitrite have an estimated penetrance of 99.3% at age 30 years, whereas those whose spouses have zero or undetected nitrite have a penetrance of only 8.8% at age 30 years. It appears that gastric nitrite, and, from our previous study of these families, chronic atrophic gastritis are important biologic markers for the early identification of persons predisposed to gastric cancer.

Adult↗
PubMed1998

Segregation analysis of Parkinson disease.

Parkinson disease (PD) is a prevalent movement disorder of unknown cause whose incidence rises with increasing age. Nearly 20% of PD is familial, a small subset of which exhibits autosomal dominant transmission. However, in most families, the inheritance is not clear. To determine the most likely mode of inheritance of PD, we performed complex segregation analyses using kindreds of 136 PD patients randomly ascertained from a clinic population. The hypotheses of a nontransmissible environmental factor, no major gene or type (sporadic), and all Mendelian inheritance (dominant, recessive, additive, decreasing) were rejected (P <0.001). Familial clustering of PD in this data set is best explained by a rare familial factor which a) is transmitted in a nonMendelian fashion, and b) influences the age at onset of PD. If confirmed, our results have immediate implications in gene-mapping studies which often search for genes that behave in a Mendelian fashion that affect susceptibility rather than age at onset and long term implications in understanding the pathogenesis of PD.

Adolescent↗
PubMed1995

Complex segregation analysis of leprosy in southern Vietnam.

To investigate the nature of the genetic component controlling susceptibility to leprosy and its subtypes, 402 nuclear families were ascertained through a leprosy patient followed at the Dermatology Hospital in Ho Chi Minh City, Vietnam; 285 families were of Vietnamese origin and 117 were of Chinese origin with a higher proportion of lepromatous forms among Chinese patients. Segregation analyses were conducted using the model developed by Abel and Bonney [(1990) Genet Epidemiol 7:391-407], which accounted for variable age of onset and time-dependent covariates. Three phenotypes were considered: leprosy per se (all forms of leprosy together), nonlepromatous leprosy, and lepromatous leprosy. For each of this phenotype, analyses were performed on the whole sample and separately on the Vietnamese and the Chinese families. The results showed that a single Mendelian gene could not account for the familial distributions of leprosy per se and its two subtypes in the whole sample. However, these results were different according to the ethnic origin of the families. In the Vietnamese subsample, there was evidence for a codominant major gene with residual familial dependences for the leprosy per se phenotype, and borderline rejection of the Mendelian transmission hypothesis for the nonlepromatous phenotype. In Chinese families, strong rejection of Mendelian transmission was obtained in the analysis of leprosy per se, and no evidence for a familial component in the distribution of the nonlepromatous phenotype was observed. For the lepromatous phenotype, the discrimination between models was poor, and no definitive conclusion could be reached. Referring to immunological data, we suggest that these results could be explained by a heterogeneity in the definition of the lepromatous phenotype. It is likely that progress in the understanding of the genetic components involved in the expression of leprosy will come from a better definition of the phenotype under study, and immunological studies are ongoing in this population to investigate this hypothesis.

Adolescent↗