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PubMed2007

Cytological and molecular characterization of a novel monogenic dominant GMS in Brassica napus L.

A novel genic male sterile (GMS) line in Brassica napus L., which was identified in 1999, was found to be controlled by a monogenic dominant gene, which we have designated as MDGMS. The microspores of the MDGMS abort before the degradation of the tapetal cell layer. The F1 fertility from any fertile lines crossed with MDGMS segregated and the ratio was close to 1:1. Bulked segregation analysis (BSA) was employed to identify random amplified polymorphic DNA (RAPD) markers linked to the Ms gene in MDGMS. Among 880 random 10-mer oligonucleotide primers screened against the bulk DNA of sterile and fertile, one primer S243 (5'-CTATGCCGAC-3') gave a repeatable 1500-bp DNA polymorphic segment S243(1500) between the two bulks. Analysis of individual plants of each bulks and other types of GMS and cytoplasmic male sterility (CMS) lines suggest that the RAPD marker S243(1500) is closely linked to the MDGMS locus in rapeseed. This RAPD marker has been converted into sequence characterized amplified region (SCAR) marker to aid identification of male-fertility genotypes in segregating progenies of MDGMS in marker-assisted selection (MAS) breeding programs.

Alleles↗
PubMed1993

An autologistic model for the genetic analysis of familial binary data.

Regressive logistic models specify the probability distribution of familial binary traits by conditioning each individual's phenotype on those of preceding relatives; therefore, the expression of the joint probability of the familial data necessitates ordering the observations. In the present paper, we propose an autologistic model of this familial dependence structure, which does not require specification of a particular ordering of the phenotypic observations. Genetic effects are introduced into the model in order to perform segregation analysis that is aimed at detecting the role of a major locus in the expression of familial phenotypes. In this model, the conditional probabilities have a logistic form, and large patterns of dependence between relatives can be considered with a simple interpretation of the parameters measuring the relationship between two phenotypes. The model is compared with the regressive logistic approach in terms of odds ratios and by using a simulation study.

Computer Simulation↗
PubMed1979

Reproductive risk of t(13q14q) carriers: case report and review.

We report a four-generation kindred with a balanced 13q14q Robertsonian translocation. The proband had the Down sydrome, due to trisomy of chromosome 21; he also carried the balanced D-group translocation. S segregation analysis of 86 sibships was performed to examine the risk of t(13q14q) carrier parents having trisomy 21, 47,XXY, or trisomy 13 children by which a number of families were ascertained. None of these disorders recurred after birth of the propositi. The frequency of abortions was not different from that of the general population. The conditional segregation ratio for balanced translocation carriers among the phenotypically normal offspring of carrier parents was 0.55 +/- 0.04.

Abortion, Spontaneous↗
PubMed2005

Ancient origin of the CAG expansion causing Huntington disease in a Spanish population.

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized clinically by progressive motor impairment, cognitive decline, and emotional deterioration. The disease is caused by the abnormal expansion of a CAG trinucleotide repeat in the first exon of the huntingtin gene in chromosome 4p16.3. HD is spread worldwide and it is generally accepted that few mutational events account for the origin of the pathogenic CAG expansion in most populations. We have investigated the genetic history of HD mutation in 83 family probands from the Land of Valencia, in Eastern Spain. An analysis of the HD/CCG repeat in informative families suggested that at least two main chromosomes were associated in the Valencian population, one associated with allele 7 (77 mutant chromosomes) and one associated with allele 10 (two mutant chromosomes). Haplotype A-7-A (H1) was observed in 47 out of 48 phase-known mutant chromosomes, obtained by segregation analysis, through the haplotype analysis of rs1313770-HD/CCG-rs82334, as it also was in 120 out of 166 chromosomes constructed by means of the PHASE program. The genetic history and geographical distribution of the main haplotype H1 were both studied by constructing extended haplotypes with flanking short tandem repeats (STRs) D4S106 and D4S3034. We found that we were able to determine the age of the CAG expansion associated with the haplotype H1 as being between 4,700 and 10,000 years ago. Furthermore, we observed a nonhomogenous distribution in the different regions associated with the different extended haplotypes of the ancestral haplotype H1, suggesting that local founder effects have occurred.

Alleles↗
PubMed2004

Autosomal dominant familial exudative vitreoretinopathy in two Japanese families with FZD4 mutations (H69Y and C181R).

BACKGROUND: Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder characterized by impaired vascularization of parts of the peripheral retina. Autosomal dominant FEVR (adFEVR), a major form of FEVR and assigned to chromosome 11q13-23 (EVR1) locus, is caused by deletion mutations in the C- terminal region of the frizzled-4 (FZD4) gene. This paper describes the clinical phenotype of adFEVR in two Japanese families with two different mutations in the FZD4 gene. METHODS: We encountered three Japanese patients with adFEVR and studied them using mutation analysis of the FZD4 gene with PCR, sequencing, and a restriction enzyme digestion. RESULTS: Two previously unreported missense mutations, p.H69Y and p.C181R, were identified in the N-terminal extra- cellular region of two of the patients. This region was highly conserved among other vertebrate species and FZD family members, unlike the C-terminal region. Co-segregation analysis revealed that all affected individuals carried one of these mutations, while unaffected individuals did not. The mutations were not detected in normal individuals (n=120). The affected individuals had mild to severe retinal abnormalities. CONCLUSIONS: FZD4 mutations in either the N- or C-terminal region underlie adFEVR, which indicates that FZD4 plays an important role in retinal angiogenesis. Analysis of FZD4 mutations in families with adFEVR is useful for genetic counseling and for early diagnosis

Amino Acid Sequence↗
PubMed1995

Familial acromegaly: a specific clinical entity--further evidence from the genetic study of a three-generation family.

Familial acromegaly is a very rare inherited disorder, characterized by the clustering within a single family of several related cases with somatotroph adenomas and acromegaly. The causes of these dominantly inherited pituitary tumours remain unknown. Although these families have a clinical presentation distinct from that of multiple endocrine neoplasia type 1 (MEN-1), the question of this syndrome as being linked to the MEN-1 locus has remained open. Our aim was to study a three-generation family with cases of acromegaly in a mother and her son, to explore better the clinical presentation of the disease, its pattern of inheritance and to test the hypothesis of a genetic linkage to the MEN-1 locus using closely linked polymorphic genetic markers. The refined analysis of 15 unaffected relatives revealed miscellaneous non-specific endocrine dysfunctions and the presence of multiple lipomata, as noted previously in some cases. Moreover, the notion of acromegalo-gigantism in the maternal grandmother and an incomplete penetrance appeared even more typical, suggesting that familial acromegaly is a specific clinical entity. Finally, under the hypotheses assumed for segregation analysis, no clinical, biological or genetic evidence of linkage to the MEN-1 locus could be retained in this family. However, these conclusions were limited because of incomplete penetrance and uncertain definition of the carrier status. Therefore, we conclude that further identification of the genetic predisposition to familial acromegaly might be obtained from the combined molecular genetic analysis of several families presenting with the same clinical features.

Acromegaly↗
PubMed1992

Genetic predisposition to breast cancer.

Breast cancer is the most common cancer among American women. Because metastatic breast cancer is an incurable disease, efforts to decrease breast cancer mortality have focused on early detection and improved treatment. Identification and analysis of a specific genetic susceptibility could permit detection of susceptible women and greatly increase the understanding of the initial step that eventually leads to cancer. Because susceptibility loci have been recognized as sites that often are altered during tumor progression, the identification and cloning of such loci could be important in developing cancer therapies. In this article, the progress being made in segregation analysis, linkage analysis, and cloning of breast cancer susceptibility loci is reviewed. The evidence for genetic inheritance is most consistent with dominant inheritance for at least three major susceptibility loci. Proliferative breast disease has been hypothesized to be an inherited lesion in breast cancer kindreds with both premenopausal and postmenopausal probands. Currently, there are many genetic markers for mapping the human genome. Technologic advances have progressed from restriction fragment length polymorphisms to highly polymorphic markers. Using this technology, breast cancer susceptibility in some kindreds with an early onset has been shown to be linked to chromosome 17q. Gene isolation eventually will follow with an increased understanding of the percentage of breast cancer cases that are a result of this genetic locus. Li-Fraumeni syndrome, which often is expressed as breast cancer, is due to mutations in the p53 gene. Characterization of the syndrome and its relationship to the altered gene should proceed rapidly. There is also a group of families exhibiting a genetic susceptibility that is not due to either of these loci. Together, these findings indicate that there are at least three separate major loci segregating for breast cancer susceptibility. With the current initiative to map and sequence the entire human genome and the advances that recently have been reported, a detailed molecular understanding of breast cancer predisposition can be envisaged.

Age Factors↗
PubMed2003

Linkage disequilibrium analysis of the human adenosine deaminase (ada) gene provides evidence for a lack of correlation between hot spots of equal and unequal homologous recombination.

The linkage disequilibrium (LD) pattern within the adenosine deaminase (ADA) gene was analyzed by studying 13 polymorphic loci in 137 families from two European and three African populations. Evidence for the presence of a 12-kb meiotic crossover hot spot, spanning part of the first and the second intron and flanked by regions of reduced recombination activity, was obtained. Moreover, segregation analysis of 113 informative meioses revealed two recombination events that are internal or overlap the 12-kb region, thus suggesting a recombination rate for the hot-spot region about 50-fold higher than the mean rate across the human genome. Within the hot spot, a 144-bp palindromic sequence was also identified and its possible involvement in the recombination process is discussed. The 12-kb region characterized by the low degree of LD does not include the 3.2-kb region that is deleted, as a result of recurrent unequal homologous recombination between two Alu elements, in patients affected by autosomal severe combined immunodeficiency. This observation provides the first evidence for an absence of correlation between hot spots of equal and unequal homologous recombination.

Adenosine Deaminase↗
PubMed2006

High genetic variability of the Streptococcus thermophilus cse central part, a repeat rich region required for full cell segregation activity.

The cse gene of Streptococcus thermophilus encodes an extracytoplasmic protein involved in cell segregation. The Cse protein consists of two putative domains: a cell wall attachment LysM domain and a catalytic CHAP domain. These two domains are spaced by an interdomain linker, known as Var-Cse, previously reported to be highly divergent between two S. thermophilus strains. The aim of this study was to assess the extent of this intraspecific variability and the functional involvement of the var-cse region in cell segregation. Analysis of the var-cse sequence of 19 different strains allowed detection of 11 different alleles, varying from 390 bp to 543 bp, all containing interspersed and tandem nucleotides repeats. Overall, 11 different repeat units were identified and some series of these small repeats, named supermotifs, form large repeats. Results suggested that var-cse evolved by deletion of all or part of the repeats and by duplication of repeats or supermotifs. Moreover, sequence analysis of the whole cse locus revealed that the cse ORF is mosaic suggesting that var-cse polymorphism resulted from horizontal transfer. The partial deletion of the var-cse region of the S. thermophilus strain CNRZ368 led to the lengthening of the number of cells per streptococcal chain, indicating that this region is required for full cell segregation in S. thermophilus strain CNRZ368.

Alleles↗
PubMed1984

Polymorphism and inheritance of serum esterases and beta-globulins in the paradise fish (Macropodus opercularis; Anabantidae).

Electrophoretic variants of serum esterases and beta-globulins in two subspecies of paradise fish (Macropodus opercularis) were studied. Four esterase loci (Est-1, Est-2, Est-3 and Est-4), a single transferrin (Tf) and another major beta-globulin locus (Bg) were identified by segregational analysis. Est-3 seems to be a monomorphic locus. Three alleles of Est-1, two of Est-2, two of Est-4, four of Tf and two alleles of Bg were found in the laboratory population. None of these loci were closely linked. Electrophoretic patterns of F1 hybrids confirmed the monomeric structures of each of the studied proteins. Allelic segregation at the Tf and Bg loci was normal in F2 and backcross populations. In crosses of the two Macropodus subspecies there were deviations from Mendelian ratios because of missing recombinant esterase phenotypes. Each of these would have been homozygous Est-2f/f. We suppose that Est-2f/f causes lethality in the early phase of development, except in the Est-1c/c, Est-2f/f combination characteristic of the parental subspecies M.o. concolor.

Alleles↗
PubMed1999

Expression of ptc and gli genes in talpid3 suggests bifurcation in Shh pathway.

talpid3 is an embryonic-lethal chicken mutation in a molecularly un-characterised autosomal gene. The recessive, pleiotropic phenotype includes polydactylous limbs with morphologically similar digits. Previous analysis established that hox-D and bmp genes, that are normally expressed posteriorly in the limb bud in response to a localised, posterior source of Sonic Hedgehog (Shh) are expressed symmetrically across the entire anteroposterior axis in talpid3 limb buds. In contrast, Shh expression itself is unaffected. Here we examine expression of patched (ptc), which encodes a component of the Shh receptor, and is probably itself a direct target of Shh signalling, to establish whether talpid3 acts in the Shh pathway. We find that ptc expression is significantly reduced in talpid3 embryos. We also demonstrate that talpid3 function is not required for Shh signal production but is required for normal response to Shh signals, implicating talpid3 in transduction of Shh signals in responding cells. Our analysis of expression of putative components of the Shh pathway, gli1, gli3 and coupTFII shows that genes regulated by Shh are either ectopically expressed or no longer responsive to Shh signals in talpid3 limbs, suggesting possible bifurcation in the Shh pathway. We also describe genetic mapping of gli1, ptc, shh and smoothened in chickens and confirm by co-segregation analysis that none of these genes correspond to talpid3.

Animals↗
PubMed2003

[Spastin gene mutation in Chinese patients with hereditary spastic paraplegia].

OBJECTIVE: To investigate the mutation characteristics of spastin gene in Chinese patients with hereditary spastic paraplegia (HSP) and thus provide a basis for the gene diagnosis of HSP. METHODS: Mutation of spastin gene was screened by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) combined with DNA direct sequencing in 31 unrelated affected HSP individuals in China, of whom 22 were from autosomal dominant families and 9 were sporadic HSP patients. Co-segregation analysis was carried out after the finding of abnormal SSCP bands. RESULTS: Six cases were found to have abnormal SCP bands, and among them, two missense mutations (T1258A, A1293G in exon 8) and one deletion mutation (1667delACT or 1668delCTA or 1669delTAC in exon 14) were found and all of them were not reported previously. They were all co-segregated with the disease and were localized within the functional domain of spastin gene. Besides, T1258A was seen in two unrelated families. CONCLUSION: The mutation rate (18.2%) in autosomal dominant HSP in Chinese patients is comparatively low. Point mutation is the major mutation type and exon 8 may be the mutation hot spot.

Adenosine Triphosphatases↗
PubMed1997

A comprehensive analysis of complex traits in problem 2A.

We used descriptive analysis to investigate the relationship between affection status and five quantitative traits (Q1-Q5) in Problem 2A and results suggested the five quantitative traits fall into two groups. The first group comprised three strongly correlated traits, Q1-Q3, which underlie affection status, and the second group comprised Q4 and Q5, which are not directly related to affection status. Segregation and linkage analyses of traits Q1-Q3 and affection status from the first replicate detected one of the major loci for Q1 (MG1) linked to marker 14 on chromosome 5 (D5G14). Because our segregation analysis failed to show evidence of a major locus effect on Q2, and we overlooked the interaction between MG3 and sex, we did not detect either MG2 or MG3. Using Haseman-Elston sib-pair analysis [Haseman and Elston, 1972], we also examined the statistical power of Q1 and type I error rate (using the environmental factor as an index), for the remaining 199 replicates in the context of a genome screen.

Chromosome Mapping↗
PubMed1989

The polymorphic Fc gamma receptor II gene maps to human chromosome 1q.

Human receptors for IgG (Fc gamma R) play important roles in the immune response. Expression of the human Fc gamma RII gene may be relevant in immune complex related disorders such as systemic lupus erythematosus and Sjogren's syndrome. We have used spot blot analysis of dual laser-sorted human chromosomes to localize the Fc gamma RII gene to human chromosome 1. Spot blot analysis of sorted derivative chromosomes sublocalized the gene to the chromosome 1 long arm (1q12----q25.1). This subchromosomal localization involved reassigning a reciprocal chromosome translocation breakpoint. We also identified Xmn I and Taq I Fc gamma RII polymorphic restriction sites that arose before the races diverged. These common Xmn I and Taq I polymorphisms are predicted to be informative for segregation analysis with human diseases in 85% of all matings.

Antigens, Differentiation↗
PubMed2026

Expanding the Genomic Spectrum of NHLRC2-Associated FINCA Disease: Integrated Bioinformatic Characterization of a Novel Deep Intronic Variant Predicted to Activate a Pseudoexon.

NHLRC2-associated FINCA disease is an ultra-rare autosomal recessive multisystem disorder caused by biallelic pathogenic variants in NHLRC2. Its mutational spectrum and genotype-phenotype correlations remain incompletely defined, and the contribution of non-coding variants is poorly understood. Here, we report a male infant with a severe FINCA-like phenotype, including early-onset hemolytic anemia, pulmonary involvement, neurodevelopmental impairment, growth failure, recurrent infections, and fatal progression at 8.5 months. Whole-genome sequencing identified a compound heterozygous NHLRC2 genotype comprising the previously reported pathogenic missense variant c.442G>T (p.Asp148Tyr) and a novel deep intronic variant, c.331+6863A>G. Segregation analysis confirmed inheritance from different parents. Integrated genomic and splicing analysis predicted that c.331+6863A>G creates a strong cryptic donor splice site and supports pseudoexon inclusion. Reconstruction of the predicted aberrant transcript indicated premature termination and potential susceptibility to nonsense-mediated mRNA decay. To our knowledge, this is the first reported deep intronic NHLRC2 variant predicted to activate pseudoexon inclusion. Although experimental validation was unavailable, convergent clinical, segregation, population, and computational evidence supports c.331+6863A>G as the most plausible second disease-associated allele. This case expands the genomic spectrum of NHLRC2-associated FINCA disease and highlights the diagnostic value of phenotype-driven whole-genome sequencing.

Humans↗
PubMed1992

Genetic determination of high-density lipoprotein-cholesterol and apolipoprotein A-1 plasma levels in a family study of cardiac catheterization patients.

Plasma levels of two lipoprotein risk factors, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-1 (apo A-1), have been shown to be negatively associated with the risk of developing coronary artery disease, and several reports have examined familial factors in HDL-C and apo A-1 levels. A number of studies suggest that shared genes influence familial resemblance of these lipoprotein levels far more than do shared environments. Possible mechanisms for the inheritance of these two risk factors (HDL-C and apo A-1 plasma levels) are explored using data from 390 individuals in 69 families ascertained through probands undergoing diagnostic cardiac catheterization. Segregation analysis was used to test a series of specific models of inheritance. Evidence for single-locus control of apo A-1 levels, with Mendelian transmission of a dominant allele leading to elevated apo A-1 levels, was seen in these families, although there was additional correlation among sibs present. This locus accounted for 48.6% and 37.2% of the total variation in apo A-1 levels in males and females, respectively. Similar evidence of segregation at a single locus controlling HDL-C levels was not seen in these families.

Adolescent↗
PubMed1989

Hyal-1, a locus determining serum hyaluronidase polymorphism, on chromosome 9 in mice.

Analysis of mouse serum hyaluronidase by polyacrylamide gel electrophoresis, with the substrate high-molecular-weight hyaluronan (hyaluronic acid) included in the gel performed in mice of two different strains, BALB/cBy and C57BL/6By, reveals a pattern of multiple enzyme forms specific for each genotype. In BALB/c serum, seven different forms are present, only one of which is found in C57BL/6 serum. Segregation analysis of the enzyme polymorphism in backcross progeny and in recombinant inbred and bilineal congenic lines shows that the difference is due to a single locus, which we have designated as Hyal-1. Hyal-1 is linked to the histocompatibility locus H-7, on chromosome 9.

Animals↗
PubMed1998

Paget's disease of bone: evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity.

Paget's disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis of the disease remains unclear. Previous genetic linkage studies have mapped the rare Paget's disease-like bone dysplasia familial expansile osteolysis (FEO) to chromosome 18q21-22, and recent work has shown evidence of linkage between this locus and Paget's disease in one family. Here we studied the relationship between the 18q21-22 locus and Paget's disease in eight large multiplex families from diverse ethnic backgrounds with inherited Paget's disease. Paget's disease was inherited as an autosomal dominant trait in all families, with high penetrance by the sixth decade. Analysis of seven highly polymorphic markers from chromosome 18q21-22 showed positive summated two-point log10 odds ratio (lodscores) of +2.97 with the marker D18S42 at a recombination fraction (theta) = 0.05, and of +2.95 with the marker D18S60 at theta = 0.00, values which are close to the cut-off of +3.0, which is generally accepted as evidence of linkage. Segregation analysis of the haplotypes and formal statistical analysis using the HOMOG program provided evidence for genetic heterogeneity, however, with evidence for linkage in five families and against linkage in the remaining three families (chi square 8.82; df = 2; p < 0.025). Multipoint linkage analysis in the five linked families showed lodscores of above +3.5 across the whole susceptibility region and a maximum summated lodscore of 3.89 at the marker D18S465. In the three nonlinked families, negative multipoint results were obtained for the whole region, with lodscores below -2.0 in one family, excluding this as a candidate locus for the disease. Our studies demonstrate the importance of hereditary factors in the pathogenesis of Paget's disease and confirm evidence of linkage between Paget's disease and chromosome 18q21-22 in some families. This raises the possibility that Paget's disease and FEO may share a common molecular basis, perhaps due to different mutations in the same gene or family of genes. Data from three families did not support evidence of linkage to 18q21-22 however, indicating that Paget's disease is genetically heterogeneous and suggests the presence of at least one additional locus which remains to be discovered.

Chromosome Aberrations↗