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PubMed2003

[Study on the relationship between some genetic factors and peak bone mineral density in Beijing young women].

OBJECTIVE: To evaluate the relationship between the peak bone mineral density (PBMD) and vitamin D receptor (VDR), estrogen receptor (ER) allelic variants in Beijing young women. METHODS: From March, 2000 to July, 2001, one hundred and fifty-nine young healthy women (25 - 37 years old) in Beijing were voluntarily enrolled in the study. (1) BMD were measured by dual energy X-ray absorptiometry (DXEA) at lumbar and hip. (2) The polymorphism of VDR and ER genes were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). (3) The relationship between BMD and polymorphism of VDR and ER genes were examined. RESULTS: (1) Lumber BMD was positively correlated to height, weight and body mass index (BMI), whereas, the femoral neck BMD only to weight, and the other sites of hip BMD to BMI. (2) Although subjects with the VDR bb genotype had higher BMD than those with Bb genotype at lumber, femoral neck, inter and troch, no significant difference was found (P > 0.05). (3) In Ward triangle, subjects with ER PP genotype had significantly lower BMD than those in ER Pp and pp genotypes (P < 0.05). (4) Women with BbPP genotype combination had lower BMD levels at lumber and hip, and with bbPP and Bbpp genotypes combination significantly higher lumber BMD levels than BbPP genotype (P < 0.05). However, the differences of BMD among subjects with different VDR and ER genotypes became not significant after adjusting the confounder of body weight. CONCLUSIONS: (1) Body weight and BMI play important roles to PBMD of Beijing women. (2) There was no significant difference of BMD levels between VDR genotypes at any site. (3) PvuII polymorphism of ER gene was associated with low Ward triangle BMD. (4) There was significant relationship between the combination of ER and VDR polymorphisms at lumbar and hip BMD. Our data suggest that genetic variation at the ER locus, singly and in relation to the VDR locus, may influence the attainment and maintenance of peak bone mass in young women.

Absorptiometry, Photon↗

PubMed1990

X chromosome linked immunodeficiency.

Six human immunodeficiency diseases have been associated with the X chromosome by family studies. Genetic mapping with restriction fragment length polymorphisms (RFLPs) has permitted assignment of these diseases to specific loci on the X chromosome. Each of the disease entities maps to a single locus, confirming that the diagnostic criteria describe single diseases. X-linked chronic granulomatous disease and Wiskott-Aldrich syndrome map to loci on the short arm of the X chromosome; X-linked severe combined immunodeficiency, X-linked agammaglobulinemia, X-linked immunodeficiency with hyper-IgM, and X-linked lymphoproliferative syndrome map to loci on the long arm. Lyon's hypothesis predicts that these X-linked immunodeficiencies may be detectable in carriers of the diseases as a result of X chromosome inactivation of the normal disease gene. Four of the immunodeficiency diseases, X-linked agammaglobulinemia, X-linked severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and X-linked chronic granulomatous disease, affect cellular development so that carriers have a monomorphic population of immunocytes. The specific immunocyte development affected in carriers varies according to the disease. Genetic mapping of the diseases, with a collection of informative RFLPs, provides a tool that permits probability-based prenatal diagnosis. Carrier detection complements the RFLP-based genetic mapping, serving to confirm X-linkage in carriers.

Chromosome Mapping↗

PubMed2006

Segregation analysis of restless legs syndrome: possible evidence for a major gene in a family study using blinded diagnoses.

OBJECTIVE: The objective of this study was to ascertain the most likely inheritance pattern of restless legs syndrome (RLS) using segregation analysis. METHODS: Probands were RLS patients presenting to the Neurology and Sleep clinics of the Johns-Hopkins Bayview medical center with willing first and second degree relatives. Blinded diagnosis was made in those who exhibited the four diagnostic features of RLS. Analysis was performed on RLS as a dichotomous trait and considering age of onset models on 590 phenotyped subjects from 77 pedigrees. RESULTS: All non-genetic models were rejected considering RLS as a dichotomous trait. A single locus Mendelian dominant model with gender as a covariate had best fit with allele frequency of 0.077 and complete penetrance. RLS frequency in non-carrier subjects was estimated to be 0.14. Two underlying distributions of age of onset, with a possible dichotomy at 26.3 years, were identified. Contrary to the results for RLS as a dichotomous trait, age of onset models did not indicate single major gene inheritance. CONCLUSION: This segregation analysis suggests that the pattern of segregation is consistent with that of a single major locus, when RLS is treated as a dichotomous trait without considering age of onset. The high rate of phenocopies matches known population frequencies and taken with significant residual familial effects and the lack of evidence for a major gene controlling age of onset, indicates that non-genetic causes of RLS may exist and RLS is a complex disorder.

Aged↗

PubMed1984

Segregation analysis of schizophrenia and related disorders.

Segregation analysis was applied to 79 nuclear families ascertained through chronic schizophrenic probands. Analysis was performed on the diagnosis of schizophrenia alone and on schizophrenia and schizotypal personality disorder (milder phenotype) combined. The models used were the transmission probability model and the mixed model. Because the disease is associated with reduced fertility, all likelihoods were calculated conditional on parental phenotypes. However, compatibility of the mating-type distribution predicted by each model with the observed was also examined. In all analyses, results suggested consistency with genetic transmission. In the analysis of schizophrenia alone, discrimination among models was difficult. In the analysis including the milder phenotypes, all single-locus models without polygenic background were excluded, while pure polygenic inheritance could not be eliminated. The polygenic model also gave good agreement with supplementary observations (lifetime disease incidences, mating-type distribution, and monozygotic twin concordance). The estimated components of variance for the polygenic model were: polygenes (H) 81.9%; common sib environment (B) 6.9%; random environment (R) 11.2%. Although the polygenic model was parsimonious, segregation analysis and the supplementary observations were also consistent with a mixed model, with a single major locus making a large contribution to genetic liability. Such a locus is more likely to be recessive than dominant, with a high gene frequency and low penetrance. The most likely recessive mixed model gave the following partition of liability variance: major locus, 62.9%; polygenes, 19.5%; common sib environment, 6.6%; and random environment, 11.0%.

Adolescent↗

PubMed1991

Population and family data of RFLP's using selected single- and multi-locus systems.

The multi-locus systems (MLS) 33.15 and 33.6 (Jeffreys et al 1985a) and the single-locus systems (SLS) MS 1, MS 8, MS 31 and MS 43 (Wong et al. 1987) were investigated. The number of bands and the rate of band sharing were determined for both multi-locus systems and compared to the results of an English survey. Additionally 73 families were investigated using the multi-locus probes and the results compared to those obtained for the traditional blood grouping systems. The results were in full agreement so that no evidence of new mutations could be found. The fragment distribution was calculated for each of the 4 single-locus systems and compared to the values reported in an English survey (Smith et al. 1990b). Distinct discrepancies were seen in the systems MS 1 and MS 8. Family analyses were carried out for the 4 single-locus systems and compared to English data (Jeffreys et al. 1988) to look for any indications of possible new mutations. Only one isolated exclusion could be demonstrated with MS 1.

Chromosome Mapping↗

PubMed1990

Gene mapping in Alport families with different basement membrane antigenic phenotypes.

The present study was undertaken to determine whether differences among Alport kindreds in the antigenic phenotypes of their basement membranes result from defects at distinct genetic loci or from allelic mutations at a single locus. We analyzed linkage of the Alport gene to polymorphic loci on the X chromosome in three families with Alport syndrome. In two of the families, epidermal basement membranes of affected members showed altered immunohistologic reactivity with a discriminating antibody (FNS1) that identified a 26 kD peptide in the NCl domain of basement membrane collagen. In the third family epidermal basement membranes of affected individuals reacted normally with the antibody. The disease gene mapped to the Xq21-q22 region of the long arm of the X chromosome in the two families with altered basement membrane antigenicity and in the family with normal basement membrane antigens. We conclude that Alport syndrome in each of these kindreds arose from allelic mutations at a single genetic locus, although we cannot at this time exclude the possibility that two or more tightly linked genes are involved. As the genes for the known chains of type IV collagen are on chromosome 13, our findings suggest that the Alport gene may encode a new basement membrane collagen chain.

Antibodies↗

PubMedDate not supplied

Location of the self-incompatibility locus in an RFLP and RAPD map of Brassica oleracea.

A single locus controlling self-incompatibility (SI) was located on an RFLP and RAPD linkage map of Brassica oleracea by assaying for SI phenotype and segregation of an RFLP locus detected by the cloned St gene SLG6. The map was developed using an F2 population derived from a cabbage x broccoli cross and included 112 RFLP and 47 RAPD loci arranged into nine main linkage groups covering 921 cM. A portion of the population was assayed for St reaction by pollinating with the broccoli parent. The SI reactions cosegregated precisely with the RFLP locus detected by SLG6, and this locus mapped to linkage group 2.

Brassica↗

PubMed1992

Mechanisms of inherited deficiencies of multiple UDP-glucuronosyltransferase isoforms in two patients with Crigler-Najjar syndrome, type I.

Crigler-Najjar syndrome, type I (CN-I) is a potentially lethal disorder characterized by severe unconjugated hyperbilirubinemia resulting from a recessively inherited deficiency of hepatic UDP-glucuronosyl-transferase (UGT) activity toward bilirubin (B-UGT). Two forms of B-UGT exist in human liver. mRNAs for these two forms and that for another isoform with activity toward simple phenols (P-UGT) have unique 5' regions, but their 3' regions are identical. The three mRNA species are derived from a single locus; the unique 5' regions are encoded by single unique exons and the identical 3' regions consist of four consecutive exons that are shared by all three isoforms. In this paper, we determined genetic lesions in two CN-I patients with deficiency of hepatic B-UGT and P-UGT activities. In one patient, there was a C----T substitution in exon 4 (common region) predicting the substitution of a serine residue with a phenylalanine residue; this mutation was present in the identical region of B-UGT and P-UGT mRNAs. In the other patient, a C----T substitution in exon 2 (common region) of the B-UGT/P-UGT locus resulted in a premature stop codon. This exon (132 nt) was absent in heptic B-UGT and P-UGT mRNAs of this patient due to exon skipping during pre-mRNA processing. Sequence abnormality of three distinct mRNA species explains the abnormality of multiple UGT isoforms in these patients. Presence of identical abnormalities in the common regions of the three mRNAs is consistent with the finding that the common 3' regions of the two B-UGT mRNAs and the P-UGT mRNA are encoded by four shared exons.

Androsterone↗

PubMed2003

Effect of nucleotide excision repair on ENU-induced mutation in female germ cells of Drosophila melanogaster.

The role of nucleotide excision repair (NER) in the repair of alkylation damage in the germ cells of higher eukaryotes has been studied mainly by treating postmeiotic male germ cells. Little is known about repair in actively repairing female germ cells. In this study, we treated NER-deficient (ner(-)) mus201(D1) Drosophila females with N-ethyl-N-nitrosourea (ENU) and determined both the mutant frequencies in the multiple locus recessive lethal (RL) test and in the single locus vermilion gene and determined the ENU mutation spectrum in the vermilion gene. The results show that ENU is mutagenic in all cell stages and that the induced frequencies increase with cell maturation, from oogonia to mature oocytes. In addition, the induced spectrum consists mainly of A:T-->T:A transversions (43.8%), A:T-->G:C transitions (21.9%), and A:T-->C:G transversions (15.6%). G:C-->A:T (3.1%) transitions, other transversions (9.4%), frameshifts (3.1%), and deletions (3.1%) were also found. Comparison of these results with those previously obtained for repair-proficient (ner(+)) female germ cells reveal: 1) Differences in the RL and vermilion mutation frequencies for ner(+) and ner(-) germ cells, indicating that NER is involved in the repair of ENU-induced damage to these cells. 2) At least 15.6% of mutations in ner(-) cells may be the consequence of N-ethylation damage and mutations of this type were not detected in ner(+) cells. 3) Although differences were found in transition frequencies between ENU-treated ner(+) and ner(-) germ cells (52.2% vs. 25%), suggesting that a functional NER is involved in processing O-ethylated damage, the role of NER in repairing O-ethylated adducts is uncertain.

Animals↗

PubMed2000

A two-locus forensic match probability for subdivided populations.

A two-locus match probability is presented that incorporates the effects of within-subpopulation inbreeding (consanguinity) in addition to population subdivision. The usual practice of calculating multi-locus match probabilities as the product of single-locus probabilities assumes independence between loci. There are a number of population genetics phenomena that can violate this assumption: in addition to consanguinity, which increases homozygosity at all loci simultaneously, gametic disequilibrium will introduce dependence into DNA profiles. However, in forensics the latter problem is usually addressed in part by the careful choice of unlinked loci. Hence, as is conventional, we assume gametic equilibrium here, and focus instead on between-locus dependence due to consanguinity. The resulting match probability formulae are an extension of existing methods in the literature, and are shown to be more conservative than these methods in the case of double homozygote matches. For two-locus profiles involving one or more heterozygous genotypes, results are similar to, or smaller than, the existing approaches.

Alleles↗

PubMed1982

Biochemical polymorphisms in South African freshwater fish. Isoenzyme patterns in fish of the families Cyprinidae and Salmonidae.

Isoenzyme patterns were studied in local populations of the carp (Cyprinus carpio) and the bream (Sarotherodon mossambicus) of the Cyprinid family, and in the trout (Salmo giardneri) of the family Salmonidae. Homogenates of heart muscle extracts were used in the identification of PGI, NADP-IDH, PGM and 6-PGD. Polymorphisms found and gene frequencies obtained are discussed separately for each enzyme and species or population. In the bream, variation was found only at the PGI locus. In the carp only the PGM locus was polymorphic whereas both PGM and IDH showed variation in the trout. The variation at the PGM locus in the trout cannot support the three locus model suggested elsewhere and clearly indicates a single locus for the monomeric enzyme. The large variety of NADP-IDH types in trout not only illucidates the complexity of this locus but confirms a disomic mode of inheritance. Genetic differences in the trout populations could be related to possible advantages for management purposes.

Animals↗

PubMed1978

The generalized sib pair IBD distribution: its use in the detection of linkage.

General expression for the distribution of identity by descent (IBD) scores at a marker locus have been derived given neither, one or both sibs affected with a disorder determined by a linked trait locus with arbitrary gene frequency and penetrance vector. It is shown that the distirbution of IBD scores depends only on the additive and dominance variances and the population prevalence of the disorder. A one-sided test is suggested as an appropriate means of statistically testing the hypothesis that the recombination fraction is significantly less than 1/2. This sib pair approach is designed primarily to detect the presence of a critical disease susceptibility locus but when the assumptions of the incompletely penetrant single locus model are correct the methodology proposed here results in consistent estimates of the recombination fraction. The affected sib pair methodology seems especially suited to traits determined by single loci with non-Mendelian transmission.

Alleles↗

PubMed2007

Complementary sex determination in the parasitoid wasp Cotesia vestalis (C. plutellae).

In the Hymenoptera, single locus complementary sex determination (sl-CSD) describes a system where males develop either from unfertilized haploid eggs or from fertilized diploid eggs that are homozygous at a single polymorphic sex locus. Diploid males are often inviable or sterile, and are produced more frequently under inbreeding. Within families where sl-CSD has been demonstrated, we predict that sl-CSD should be more likely in species with solitary development than in species where siblings develop gregariously (and likely inbreed). We examine this prediction in the parasitoid wasp genus Cotesia, which contains both solitary and gregarious species. Previous studies have shown that sl-CSD is absent in two gregarious species of Cotesia, but present in one gregarious species. Here, we demonstrate CSD in the solitary Cotesia vestalis, using microsatellite markers. Diploid sons are produced by inbred, but not outbred, females. However, frequencies of diploid males were lower than expected under sl-CSD, suggesting that CSD in C. vestalis involves more than one locus.

Animals↗

PubMed2002

Redundancy in tumor necrosis factor (TNF) and lymphotoxin (LT) signaling in vivo: mice with inactivation of the entire TNF/LT locus versus single-knockout mice.

Homologous genes and gene products often have redundant physiological functions. Members of the tumor necrosis factor (TNF) family of cytokines can signal activation, proliferation, differentiation, costimulation, inhibition, or cell death, depending on the type and status of the target cell. TNF, lymphotoxin alpha (LTalpha), and LTbeta form a subfamily of a larger family of TNF-related ligands with their genes being linked within a compact 12-kb cluster inside the major histocompatibility complex locus. Singly TNF-, LTalpha-, and LTbeta-deficient mice share several phenotypic features, suggesting that TNF/LT signaling pathways may regulate overlapping sets of target genes. In order to directly address the issue of redundancy of TNF/LT signaling, we used the Cre-loxP recombination system to create mice with a deletion of the entire TNF/LT locus. Mice with a triple LTbeta/TNF/LTalpha deficiency essentially manifest a combination of LT and TNF single-knockout phenotypes, except for microarchitecture of the spleen, where the disorder of lymphoid cell positioning and functional T- and B-cell compartmentalization is severer than that found in TNF or LT single-knockout mice. Thus, our data support the notion that TNF and LT have largely nonredundant functions in vivo.

Animals↗

PubMed1990

Structure and expression of the pulmonary surfactant protein SP-C gene in the mouse.

Genomic and cDNA clones encoding the murine pulmonary surfactant protein SP-C were isolated and sequenced to provide the primary amino acid sequence of the murine SP-C polypeptide and the structural organization of the SP-C gene locus. Murine SP-C is encoded by a single locus spanning approximately 3.2 kilobases of genomic DNA. The gene is composed of six exons and five introns, and its structure is closely related to the human SP-C gene. The primary transcript for the murine SP-C preprotein of Mr = 21,000 has an overall nucleotide identity of 80% with the coding sequence of the human precursor. The active airway peptide of 33-35 amino acids was even more closely related to the human SP-C airway peptide, sharing 95% identity at the amino acid level. The most significant structural difference between the murine and human SP-C genes was an increased size of the first intron in the murine SP-C gene. A single mRNA encoding murine SP-C of 0.8 kilobase was detected only in lung tissue, and SP-C mRNA was more abundant in neonatal and postnatal lung tissue than in fetal lung tissue. The nucleotide sequence of the promoter and 5'-flanking regions of the murine SP-C gene shared considerable identity with the human SP-C gene. Transgenic mice bearing a chimeric gene composed of the 5'-flanking and promoter regions of the human SP-C gene and the bacterial chloramphenicol acetyltransferase reporter gene were generated, demonstrating that lung-specific and developmental expression was conferred by these 5'-sequences. The chimeric gene was selectively expressed in preparations of respiratory epithelial cells, but was not expressed in alveolar macrophages isolated from the transgenic mice. The shared structural organization and developmental and tissue-specific expression of the SP-C gene between the mouse and human demonstrate considerable phylogenetic conservation of this gene and protein.

Amino Acid Sequence↗

PubMed1978

A comparison of the genetic infrastructure of the Ye'cuana and the Yanomama: a likelihood analysis of genotypic variation among populations.

A general procedure is described for measuring and testing population differences in gametic frequencies. The total dispersion among populations is subdivided in hierachical fashion. The multiple-locus treatment is simply the sum of the single-locus analyses, provided gametic equilibrium obtains among the loci. In the event that gametic equilibrium does not obtain, correlations among loci need to be dealt with.--The analysis is then used to examine the genetic infrastructure of two Indian tribes from South America, the Ye'cuana (Makiritare) and the Yanomama. From historical evidence, we may identify several "clusters" of villages within each tribe. The demographic and cultural practices affecting village formation and the maintenance of peer integrity are rather different in these tribes, however, and lead us to postulate rather different patterns of genetic variation among villages. Analyses of five codominant two-allele loci, four dominant two-allele loci and two complex loci (with four codominant haplotypes each) demonstrate that Yanomama clusters are more disparate than Ye'cuana clusters, as would have been predicted on sociocultural grounds.

Blood Group Antigens↗

PubMedDate not supplied

A reappraisal of Mls genetics.

Although the minor lymphocyte stimulatory locus (Mls) system was originally described as a single-locus, multiple-allelic system, allelism among the genes which encode Mlsa, Mlsc and Mlsd has not been demonstrated formally. In this report, genetic linkage between genes encoding Mlsa and Mlsc was studied by testing responses of unprimed T cells, as well as Mlsa- and Mlsc-specific T cell clones, to the progeny of (AKR/J x C3H/HeJ) F1 x B10.BR [(Mlsa x Mlsc)F1 x Mlsb] crosses. In addition, the configuration of Mls genes expressed by CBA/J (Mlsd) was evaluated by examining the response pattern of a panel of Mlsd-specific clones to (CBA/J x B10.BR)F1 x B10.BR stimulators. Results of these segregation analyses indicated that the Mls system is composed of at least two independent and unlinked genes which encode, respectively, the determinants identified as Mlsa and Mlsc.

Alleles↗

PubMed1991

Genetic and physical mapping of the patatin genes in potato and tomato.

Genes for the major storage protein of potato, patatin, have been mapped genetically and physically in both the potato and tomato genomes. In potato, all patatin genes detected by the cDNA clone pGM01 map to a single locus at the end of the long arm of chromosome 8. By means of pulsed field gel electrophoresis (PFGE) it was possible further to delimit this locus, containing 10-15 copies of the gene, to a maximum size of 1.4 million base pairs. Hybridizations with class-specific clones suggest that the locus is at least partially divided into domains containing the two major types of patatin genes, class I and II. In tomato, patatin-homologous sequences were found to reside at the orthologous locus at the end of chromosome 8. The approximately three copies in tomato were localized by PFGE to a single fragment of 300 kilobases. Whereas the class II-specific 5' promoter sequences reside in tomato at the same locus as the coding sequences, the single class I-specific copy of the 5' promoter sequences was localized on chromosome 3 with no coding sequence attached to it. A clone from this chromosome 3 locus of tomato was isolated and by restriction fragment length polymorphism mapping it could be further shown that a similar class I-specific sequence also exists on chromosome 3 of potato. As in tomato, this copy on chromosome 3 is not linked to a coding sequence for patatin. The results are discussed with respect to genome evolution and PFGE analysis of complex gene families.

Carboxylic Ester Hydrolases↗