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PubMed1991

A prospective study of sodium-lithium countertransport and hypertension in Utah.

A 7-year prospective study of a cohort of 1,458 normotensive adults from Utah pedigrees, screened from 1980 to 1985, was done to determine whether baseline levels of sodium-lithium countertransport were associated with an increased risk of future hypertension. Subsequent new hypertension (n = 39) was ascertained in 1989 from detailed follow-up medical questionnaires (67% response). Previous segregation analyses on a subset of these pedigree members who responded (n = 342) using family relationships in addition to countertransport levels have shown statistically inferred major gene segregation of sodium-lithium countertransport levels. In the normotensive adults inferred by segregation analysis to carry the recessive major gene for high sodium-lithium countertransport, new-onset hypertension occurred in 18.8% (3 of 16) compared with 3.7% (12 of 326) in the low sodium-lithium countertransport genotype group (relative risk, 4.6 [1.6, 13.9]; p = 0.03). However, an elevated baseline sodium-lithium countertransport level without genotype information from segregation analysis did not increase the risk of future hypertension in the complete cohort of adult pedigree members (relative risk, 1.02 [0.85, 1.22]). Adjustment for other risk factors reduced the relative risk to 0.90 (0.72, 1.11). We conclude that the presence of a major gene for sodium-lithium countertransport or another closely linked gene, rather than the actual level of sodium-lithium countertransport, may increase the risk of hypertension onset. High sodium-lithium countertransport levels do not increase the risk of future hypertension for individuals in whom only polygenic and environmental effects determine sodium-lithium countertransport level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

[Inheritance of hypodontia in Kerry Blue Terrier dogs].

Integral segregation analysis, which earlier proved efficient in studying complex hereditary diseases in humans and have been introduced in animal genetics for several years, was used to analyze the inheritance of hypodontia by premolars in Kerry Blue Terrier dogs. Dental formulas have been determined in 598 out of 911 animals united into a single large, complex pedigree. The results of integrated segregation analysis indicated heterogeneous genetic control of different forms of hypodontia. The geneses of different premolars in dogs have been demonstrated to be described by different models of inheritance: the absence of the second premolars can be described by the recessive major-gene model, whereas the agenesis of the fourth premolars have a more complex genetic mechanism and cannot be described by the model of a simple major-gene control.

Animals↗
PubMed1994

Parental origin of germ-line and somatic mutations in the retinoblastoma gene.

Segregation analysis of polymorphic sites within the retinoblastoma (RB) gene and on chromosome 13, as well as the parental origin of the lost allele in the tumor, were analyzed in 24 families with RB patients. Four mutant alleles transmitted through the germ-line and seven de novo germ-line mutant alleles were identified in 11 patients with hereditary RB. Segregation analysis within the RB gene and on chromosome 13 was useful for DNA diagnosis of susceptibility to RB in relatives of hereditary patients, even if mutations were not identified. All seven de novo germ-line mutant alleles were paternally derived. The bias toward the paternal allele for de novo germ-line mutations of the RB gene was statistically significant. Seven paternal alleles and six maternal alleles were lost in 13 non-hereditary RB tumors with no bias in the parental origin of the somatic allele loss. These results suggest that the physical environment or a deficiency in DNA repair during spermatogenesis may be associated with significant risk factors for de novo germ-line mutations.

Alleles↗
PubMed1994

Variability of serum thyroglobulin levels is determined by a major gene.

OBJECTIVE: There are large variations in the circulating concentrations of thyroglobulin. The purpose of this study was to explore the possibility of a genetic basis for the variability of serum concentration of thyroglobulin (Tg) in euthyroid individuals. DESIGN: The serum concentration of thyroglobulin (Tg) varies several-fold in euthyroid individuals. Other circulating proteins also show wide normal ranges of concentration and these variations have been shown to have a genetic as well as an environmental basis. To explore the possibility of a genetic basis for variability in serum Tg levels, an analysis was made of serum Tg levels in 44 pairs of identical twins and 66 nuclear families who were euthyroid and thyroid autoantibody negative (thereby eliminating subclinical autoimmune thyroid disease and Tg autoantibody interference with the Tg assay). RESULTS: Each pair of identical twins tended to have a similar Tg level and the overall correlation was highly significant (r = 0.734, P < 0.001). There was no relation between Tg and TSH levels in the twins (r = 0.119; P = 0.366). Segregation analysis of the 66 families showed that where both parents had Tg levels above the overall median for the subjects (males, 19 micrograms/l; females, 33 micrograms/l), 73% of the offspring also had concentrations above these levels, compared with 30% of the offspring when one parent had a high Tg level and only 16% in families where neither parent had a high Tg level. CONCLUSIONS: Complex segregation analysis using the computer program Pointer suggested that variability in Tg levels was the result of a major dominant-like gene effect (accounting for 80% of the variability) combined with a multifactorial component. Thyroglobulin, a template for thyroid hormone production, is also a major thyroid autoantigen and inherited variations in serum Tg levels may have implications for the pathogenesis of autoimmune thyroid disease.

Adolescent↗
PubMed1991

Familiality of breast cancer and socioeconomic status in blacks.

Familial patterns of the occurrence of breast cancer were studied in a population-based case-control series of black women from the Cancer and Steroid Hormone study. The risks of breast cancer among relatives of breast cancer cases were compared to those of controls who were matched for age and locale. Using the term "proband" to indicate either case or control status, significant predictors of risk to the relatives of probands included case/control status of the proband and the number of years of education completed by the proband. Genetic segregation analysis of the case families using external risks generated from SEER data indicated that the familial aggregation was consistent with Mendelian recessive transmission of a single major gene. The use of internally estimated risks, which are much less stable than the SEER risks, no longer permitted discrimination among the major locus models examined. To avoid possible reporting bias, we also performed segregation analysis on families of probands who had completed at least 12 years of education. The results from this analysis reflected the results from the entire data.

Adult↗
PubMed1996

Genetic transmission of susceptibility to cancer in families of children with soft tissue sarcomas.

BACKGROUND: This article presents analysis of clinical and family data for 239 patients with childhood soft tissue sarcoma (STS) treated at the Institut Gustave Roussy in Villejuif. METHODS: A molecular study was performed to detect germline p53 mutations in the 44 families in which at least 1 relative developed cancer before the age of 46 or in which the proband had a second neoplasm. Mutations were found in five families. Standardized incidence ratio calculation and segregation analysis were used to study cancer occurrence in 4448 relatives, including first- and second-degree relatives and first cousins. RESULTS: An excess of brain tumors was observed in all relatives, and of breast carcinoma and STS in first-degree relatives of patients with STS. An excess of breast carcinoma was observed only in young mothers of patients with rhabdomyosarcoma. This excess might be mostly linked to the presence of a germline p53 mutation because it was no more significant when excluding families in which such a mutation existed. No association between breast carcinoma in the mother and rhabdomyosarcoma of the genitourinary tract in the proband was observed. This should be kept in mind when developing a screening strategy for breast carcinoma in mothers of patients with STS. Segregation analysis showed evidence for transmission of an autosomal dominant gene with complete penetrance by the age of 84. The genetic component was explained primarily by p53 germline mutations. CONCLUSIONS: These results show that most relatives of patients with STS are at the same risk for cancer as the general population.

Adult↗
PubMed1998

Characterization of frequent polymorphisms in intron 2 of CYP21: application to analysis of segregation of CYP21 alleles.

The gene encoding adrenal steroid 21-hydroxylase, CYP21, is located in the MHC class III region. Most cases of congenital adrenal hyperplasia (CAH) are caused by mutations in this gene, and most mutations appear to arise from gene conversion-like events involving the transfer of deleterious sequences from the pseudogene, CYP21P, which is located within 30 kb of CYP21. Approximately 20-30% of mutations are caused by deletions of CYP21. The second intron of CYP21 is polymorphic, and several base substitutions that include nt395, nt453, and nt601 have been reported; however, the frequencies of these polymorphisms are unknown. Using a combination of cleavase fragment length polymorphism analysis and direct sequencing, we examined the sequence of intron 2 in seven wild-type CYP21 genes and determined the frequency of polymorphisms at nt395, nt453, and nt601 in 48 chromosomes from the parental generation of Centre d'Etude du Polymorphisme Humain families. The observed frequencies of bases at these positions were as follows: 395C, 0.17; 395T, 0.83; 453C, 0.71; 453T, 0.29; 601A, 0.1; and 601C, 0.9. Using a PCR/restriction digestion approach to examine these intragenic markers, we could follow the segregation of alleles in informative families with 21-hydroxylase deficiency and identify deletions of CYP21. We emphasize that this method should be used in conjunction with other molecular genetic techniques for diagnosis of CAH. In addition to their potential use in families with CAH, these markers may be of use in genetic studies of the MHC in humans.

Adrenal Hyperplasia, Congenital↗
PubMedDate not supplied

[Mode of inheritance of idiopathic generalized non-myoclonic epilepsy in families investigated by studying members with idiopathic epilepsy with tonic-clonic crises on waking. Antioquia, Colombia].

In attempt to identify the possible role of mayor genes, multifactorial inheritance, and cohort effects in the susceptibility to idiopathic epilepsy with generalized tonic clonic seizures of the awakening type (GTCS), complex segregation analysis was performed in 196 nuclear families ascertained through affected with probands with idiopathic epilepsy with GTCS belonging to the Paisa community of Antioquia (Colombia). Models postulating no transmission, single mayor locus (dominant and recessive) only, and multifactorial component only, were rejected. The models postulating no polygenic component to transmission, and no transmission of the major effect were also rejected. Thus far, complex segregation analysis suggested that a major autosomal codominant allele together with a multifactorial component (mixed model) best explains clustering of idiopathic epilepsy with GTCS in families of the Paisa community. The deficit of transmission of heterozygotes (0.17) is compatible with the existence of epistasis acting on a major gene whose frequency was estimated to be 0.0211. Its transmission variance accounts for 81% of the susceptibility to idiopathic epilepsy with GTCS. The complementary variance (19%) is due to polygenic component.

Adolescent↗
PubMed1990

Localization of the growth hormone gene to the distal half of mouse chromosome 11.

A DNA fragment size variant for the growth hormone gene, Gh, has been identified among inbred strains of mice. The inbred strains SM/J and CAST/Ei carry the less frequent allele Ghb and 11 other strains carry the Gha allele. Segregation analysis of data from two crosses involving SM/J and NZB/BINJ and a cross involving BALB/cJ and CAST/Ei confirmed the assignment of Gh to mouse chromosome 11 and placed the locus 2.6 +/- 1.8 map units distal to Erba (avian erythroblastosis oncogene A), a position consistent with the assignment of the Gh locus to the q22-q24 region of chromosome 17 on the human map. Segregation analysis also refined the location of Sparc (secreted acidic cysteine-rich glycoprotein) on mouse chromosome 11 to a position 16.7 +/- 4.2 map units proximal to Evi-2 (ecotropic viral integration site 2).

Alleles↗
PubMed2005

Macrophage scavenger receptor 1 999C>T (R293X) mutation and risk of prostate cancer.

BACKGROUND: Variants in the gene encoding the macrophage scavenger receptor 1 (MSR1(4)) protein have been identified in men with prostate cancer, and several small studies have suggested that the 999C>T (R293X) protein-truncating mutation may be associated with an increased risk for this disease. METHODS: Using large case-control, cohort, and prostate cancer family studies conducted in several Western countries, we tested for the 999C>T mutation in 2,943 men with invasive prostate carcinoma, including 401 males from multiple-case families, 1,982 cases unselected for age, and 575 men diagnosed before the age of 56 years, and in 2,870 male controls. Risk ratios were estimated by unconditional logistic regression adjusting for country and by a modified segregation analysis. A meta-analysis was conducted pooling our data with published data. RESULTS: The prevalence of MSR1*999C>T mutation carriers was 0.027 (SE, 0.003) in cases and 0.022 (SE, 0.002) in controls, and did not differ by country, ethnicity, or source. The adjusted risk ratio for prostate cancer associated with being a 999C>T carrier was 1.31 [95% confidence interval (CI), 0.93-1.84; P = 0.16]. The modified segregation analysis estimated the risk ratio to be 1.20 (95% CI, 0.87-1.66; P = 0.16). The risk ratio estimated from the meta-analysis was 1.34 (95% CI, 0.94-1.89; P = 0.10). CONCLUSION: Our large-scale analysis of case and controls from several countries found no evidence that the 999C>T mutation is associated with increased risk of prostate cancer. The meta-analysis suggests it is unlikely that this mutation confers more than a 2-fold increased risk.

Aged↗
PubMed1999

Are unpaired chromosomes spermicidal?: A maximum-likelihood analysis of segregation and meiotic drive in Drosophila melanogaster males deficient for the ribosomal-dna.

Meiosis in Drosophila melanogaster males is achiasmate and requires special systems to ensure normal segregation. Several situations that yield frequent nondisjunction also produce high levels of chromatin-dependent sperm lethality, suggesting the possibility of a simple and direct connection between defective disjunction and defective sperm development. One hypothesis that has been offered is that pairing not only ensures disjunction, but also changes the physical state of chromosomes so that they can be packaged in sperm. Here, I present an analysis of extensive data on disjunction and sperm survival in rDNA-deficient males collected by B. McKee and D. Lindsley. This analysis demonstrates that, although nondisjunction and sperm lethality are indeed correlated, the basis of this is not the presence of unpaired chromosomes in the sperm. Chromosomes that have failed to disjoin are not themselves spermicidal.

Animals↗
PubMed1991

Autosomal dominant inheritance of autoantibodies to thyroid peroxidase and thyroglobulin--studies in families not selected for autoimmune thyroid disease.

Recently the tendency to produce autoantibodies to thyroid peroxidase (TPO Ab) and thyroglobulin (Tg Ab) was shown to be inherited as an autosomal dominant characteristic in women but not in men. Because of potential bias in this study which was carried out in families with autoimmune thyroid disease (AITD), the inheritance of thyroid autoantibodies has been evaluated in 49 families unselected for autoimmune thyroid disease. Among these families (24 with facioscapulohumeral disease, 10 with Friedreich's ataxia, and 15 with schizophrenia) the prevalences of TPO Ab and Tg Ab were 27.8% and 26.7%, respectively, in women and 9.2% and 11.7%, respectively, in men. In 40 families where one or more individual had TPO Ab and/or Tg Ab, segregation analysis showed that the tendency to make antibodies was consistent with a Mendelian dominant trait in women but not in men. In young women, however, the prevalence of both TPO Ab and Tg Ab increased with age, rising from 14% and 10%, respectively, at age 15-24 to 35% and 40% at age 35-44. As this is inconsistent with a simple dominant hypothesis, a further segregation analysis by age was carried out in the families unselected for thyroid disease together with 16 pedigrees with AITD previously studied and two additional large AITD families. The results of the combined analysis provided strong support for the hypothesis of dominant inheritance but also showed significant reduction in gene expression among women aged 15-24 yr.

Adolescent↗
PubMed2003

Identification and mapping of resistance gene analogs and a white rust resistance locus in Brassica rapa ssp. oleifera.

The objective of this investigation was to tag a locus for white rust resistance in a Brassica rapa ssp. oleifera F(2) population segregating for this trait, using bulked segregant analysis with random amplified polymorphic DNA (RAPD) markers, linkage mapping and a candidate gene approach based on resistance gene analogs (RGAs). The resistance source was the Finnish line Bor4109. The reaction against white rust races 7a and 7v was scored in 20 seedlings from each self-pollinated F(2 )individual. The proportion of resistant plants among these F(3) families varied from 0 to 67%. Bulked segregant analysis did not reveal any markers linked with resistance and, therefore, a linkage map with 81 markers was created. A locus that accounted for 18.4% of the variation in resistance to white rust was mapped to linkage group (LG) 2 near the RAPD marker Z19a. During the study, a bacterial resistance gene homologous to Arabidopsis RPS2 and six different RGAs were sequenced. RPS2 and five of the RGAs were mapped to linkage groups LG1, LG4 and LG9. Unfortunately, none of the RGAs could be shown to be associated with white rust resistance.

Amino Acid Sequence↗
PubMed2006

Genetic epidemiology of vitiligo: a study of 815 probands and their families from south China.

BACKGROUND: Genetic factors are thought to be involved in the development of vitiligo. AIM: To explore the possible genetic model of vitiligo by analyzing the genetic characteristics of 815 patients and their families from south China (Zhejiang Province). METHODS: Data for 815 patients with vitiligo were obtained by questionnaire. The inheritance pattern estimation, heritability calculation, and complex segregation analysis were performed using the Penrose method, Falconer regression method, and SAGE-REGTL program, respectively. RESULTS: In 815 vitiligo probands, 128 (15.7%) had a family history. The ratio of the sibling prevalence rate to the population prevalence rate (s/q) approached 1/square root q using the Penrose calculation, and the heritability degrees of vitiligo in the first- and second-degree relatives were 59.6% and 55.2%, respectively. The complex segregation analysis suggested that the dominant model was the best-fit genetic model for vitiligo. CONCLUSIONS: Genetic factors play an important role in the occurrence of vitiligo, and the genetic model of vitiligo in this population is consistent with a polygenetic or multifactorial inheritance in a dominant major gene pattern.

Adult↗
PubMed1982

On the heredity of retinitis pigmentosa.

The aims of this study are: (1) to determine the frequencies of the various genetic forms of retinitis pigmentosa; and (2) to perform segregation analysis on autosomal dominant, autosomal recessive, and X-linked families. The families studied consisted of 2 series of patients at Moorfields Eye Hospital: (1) 426 families seen in the Genetic Clinic; and (2) 289 families seen in the Electrodiagnostic Department. Comparison between the 2 series identified biases of ascertainment, and it was estimated that the combined series included 53% of simplex cases and a minimum of 15% of X-linked families. Segregation analysis of the Genetic Clinic series showed good agreement with expectation in autosomal dominant and X-linked families, but indicated that no more than 70% of all simplex cases were autosomal recessive. The rest of the simplex cases were mildly affected and may represent fresh autosomal dominant mutations, autosomal dominant transmission with reduced penetrance, the heterozygous state of X-linked disease in some of the females, and phenocopies.

Female↗
PubMed1984

Identification of two cis-encoded HLA-DQ molecules that carry distinct alloantigenic specificities.

The monoclonal antibodies Genox 3.53, S1, and R1 define polymorphic epitopes localized to DQ molecules. All three antibodies showed a strong association with the HLA-DR antigens 1, 2, and w6 when tested on a panel of 68 unrelated individuals, suggesting that they all recognized the DQw1 allospecificity. However, segregation analysis and binding studies with a panel of HLA-D/DR homozygous cells indicated that these monoclonal antibodies defined two different alloantigens. Cells homozygous for DR 1, 2, or w6 expressed the epitopes defined by all three antibodies (i.e., S1, R1, and Ge) while cells homozygous for DR4 and DRw8 expressed only the S1 and R1 epitopes. Sequential immunoprecipitation analyses in S1+/R1+/Ge+ individuals, in which the three epitopes were shown by segregation analysis to be encoded by the same chromosome, revealed two distinct DQ-like molecules. While R1 and S1 appeared to reside on the same molecule, the epitope defined by Genox 3.53 was on a different molecule. Identical results were obtained with DR1-, DR2-, or DRw6-bearing cells. Thus it appears that DQw1-bearing individuals express two cis-encoded DQ-like molecules that carry distinct alloantigenic specificities.

Antibodies, Monoclonal↗
PubMed1989

Cytogenetic analysis of segregation distortion in Drosophila melanogaster: the cytological organization of the Responder (Rsp) locus.

The segregation distortion phenomenon occurs in Drosophila melanogaster males carrying an SD second chromosome and an SD+ homolog. In such males the SD chromosome is transmitted to the progeny more frequently than the expected 50% because of an abnormal differentiation of the SD+-bearing sperms. Three major loci are involved in this phenomenon: SD and Rsp, associated with the SD and SD+ chromosome, respectively, and E(SD). In the present work we performed a cytogenetic analysis of the Rsp locus which was known to map to the centromeric heterochromatin of the second chromosome. Hoechst- and N-banding techniques were used to characterize chromosomes carrying Responder insensitive (Rspi), Responder sensitive (Rsps) and Responder supersensitive (Rspss) alleles. Our results locate the Rsp locus to the h39 region of 2R heterochromatin. This region is a Hoechst-bright, N-banding negative heterochromatic block adjacent to the centromere. Quantitative variations of the h39 region were observed. The degree of sensitivity to Sd was found to be directly correlated with the physical size of that region, demonstrating that the Rsp locus is composed of repeated DNA.

Alleles↗
PubMed2000

Familial studies on the genetics of cardiovascular diseases: the Stanislas cohort.

In a given individual, the level of cardiovascular risk results from the combination of and interactions between genetic and environmental components. We choose to investigate segregation analysis of intermediate phenotypes in healthy nuclear families, belonging to the Stanislas cohort, a large familial cohort composed of 1006 families, which will be followed for 10 years. We developed a panel of 35 genetic markers including genes involved in lipid metabolism, regulation of blood pressure, thrombosis, platelet function, and endothelial cell adhesion. The allele frequencies of the studied polymorphisms were in agreement with those reported in other Caucasian populations. As an example of segregation analysis, we investigated carotid intima-media thickness (CIMT) variability in a subset sample of the Stanislas cohort. We found that about 30% of CIMT variability was attributable to genetic factors. Associations between CIMT and polymorphisms in apo CIII, cholesteryl ester transfer protein, methylene tetrahydrofolate reductase, and fibrinogen genes were observed and explained about 20% of CIMT variability in men. Furthermore, as another example of association studies, we investigated the relations between E-selectin polymorphisms and blood pressure interindividual variability and longitudinal changes in unrelated adults of this familial population. The E-selectin Phe554 allele was found associated with lower systolic blood pressure and diastolic blood pressure.

Adult↗