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PubMed2002

A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas.

The etiology of RCC is incompletely understood and the inherited genetic contribution uncertain. Although there are rare mendelian forms of RCC stemming from inherited mutations, most cases are thought to be sporadic. We sought to determine the extent of familial aggregation among Icelandic RCC patients in general. Medical and pathologic records for all patients diagnosed with RCC in Iceland between 1955 and 1999 were reviewed. This included a total of 1,078 RCC cases, 660 males and 418 females. With the use of an extensive computerized database containing genealogic information on 630,000 people in Iceland during the past 11 centuries, several analyses were conducted to determine whether the patients were more related to each other than members drawn at random from the population. Patients with RCC were significantly more related to each other than were subjects in matched groups of controls. This relatedness extended beyond the nuclear family. RRs were significantly greater than 1.0 for siblings, parents and cousins of probands. RRs were 2-3 for first-degree relatives and 1.6 for third-degree relatives. The risk of RCC is significantly higher for members of the extended family of an affected individual, as well as the nuclear family. Our results indicate that germline mutations are significantly involved in what has been defined as sporadic RCC.

Adult↗

PubMed1983

Evaluation of random cDNA clones as probes for human restriction fragment polymorphisms.

The purpose of this study was to evaluate the usefulness of randomly isolated human cDNA clones as probes for human restriction fragment polymorphisms. Clones were chosen from two human cDNA libraries and tested by hybridization against Southern blots of genomic DNA prepared from nine individuals. Three types of hybridization patterns were seen with the individual clones tested, those representative of single copy genes, others representative of gene families, and one characteristic of a mitochondrial gene. Only two of these cDNA clones revealed any polymorphisms among the individuals tested: pDK-08 and RW12, both representative of gene families. Both revealed independent polymorphisms with several of the restriction enzymes tested, and inheritance of these polymorphisms as Mendelian alleles was verified by human pedigree analysis. The results are discussed with regard to the usefulness of such cDNA clones in revealing polymorphisms in human genetic analysis.

Cloning, Molecular↗

PubMedDate not supplied

Commingling and segregation analysis of serum uric acid in five North American populations: the Lipid Research Clinics family study.

The role of major genes in the expression of serum uric acid (UA) levels was investigated in data collected from five clinics of the Lipid Research Clinics (LRC) family study. Over 2,000 randomly ascertained individuals were analyzed. The UA distributions were homogeneous among the five LRC clinics and between the parental and offspring generations. This result suggested that the data could be pooled across clinics, thereby increasing the statistical power associated with larger sample sizes for testing various null hypotheses. Additionally, a mixture of three normal distributions best characterized the combined-clinics data. Segregation patterns were examined in the untransformed data, as well as in a more conservative (and biologically meaningful) log transformation. Prior to log transformation, both major and multifactorial effects were detected. The major effect was not transmissible, i.e., was not compatible with Mendelian transmission, and accounted for 39% of the variance in UA levels. However, after the log transform was applied to the data and the segregation analysis was repeated, support for the major effect disappeared altogether and only the multifactorial component remained, accounting for 50% of the variation in offspring and 19% in patients.

Adolescent↗

PubMed1996

Evidence for a major gene for type II diabetes and linkage analyses with selected candidate genes in Mexican-Americans.

We have carried out two independent family studies in low-income Mexican-Americans from San Antonio, Texas. In the first study, probands were ascertained at random without regard to any medical condition (658 examined individuals from 50 families), and in the second study, probands were subjects with type II diabetes identified in a prior epidemiological survey (523 examined individuals from 29 families). Pedigrees ranging in size from 2 to 45 family members (median 11) in the first study and from 2 to 50 family members (median 12) in the second study were examined. Diabetes was diagnosed according to World Health Organization criteria. In both sets of families, segregation analyses revealed support for a major gene with an autosomal dominant mode of inheritance influencing early age of onset of diabetes. Non-Mendelian inheritance was rejected in both data sets. Individuals with the early age of onset allele had a mean age of diabetes onset of 51 years in the first data set and 60 years in the second data set. In the first data set, the major gene accounted for approximately 70% of the phenotypic variance in age of onset of diabetes, and there were no residual family effects once the major gene effect was taken into account. In the second data set, the major gene accounted for approximately 50% of the phenotypic variance, and residual family effects were statistically significant. Linkage analyses were performed with 11 candidate genes, and tight linkage with diabetes was rejected for Rh blood group, glucose transporter 2, fatty acid-binding protein, tumor necrosis factor beta, glucokinase, and lipoprotein lipase. A logarithm of odds (LOD) score of 0.92 at a recombination fraction of 0.05 was observed for insulin receptor substrate 1. This LOD score corresponds to a chi2 of 4.24 (P = 0.039).

Alleles↗

PubMed2005

Allopolyploidy in wheat induces rapid and heritable alterations in DNA methylation patterns of cellular genes and mobile elements.

Whereas accumulating recent evidences indicate that allopolyploid formation in plants is accompanied by rapid and non-Mendelian genomic changes, some other works showed genomic stasis in both nascent and natural allopolyploids. To further study the issue, we performed global DNA fingerprinting of a newly synthesized allohexaploid wheat and its natural counterpart, the common wheat, by AFLP analysis. It was found that ca. 20% bands showed deviation from parental additivity in both synthetic and the natural common wheat. Sequence analysis indicates that a majority of the changed bands represent known-function genes and transposable elements. DNA gel blot analysis showed that the main type of changes in the amphiploid is epigenetic in nature, i.e., alteration in DNA methylation patterns. Two types of alterations in methylation, random and non-random, were detected, and both types were stably inherited. Possible causes and implications of the epigenetic changes in allopolyploid genome evolution and speciation are discussed.

DNA Methylation↗

PubMed1990

A study of the inheritance of susceptibility to bovine spongiform encephalopathy.

A genetic study of 75 cases of bovine spongiform encephalopathy (BSE) of which 51 were confirmed by histopathology in 29 pedigree and seven non-pedigree herds of Holstein Friesian cattle revealed that 73 per cent of 60 BSE cases had first or second degree relatives also affected. All the 44 cases assigned to families could be traced back in the previous three generations to one cow and 11 bulls, which were of Canadian Holstein or Dutch Friesian heredity. No single common ancestor could be identified in the parentage of BSE-affected animals in pedigree studies up to six or more generations. The number of common ancestors and the degree of relatedness of the affected animals in a multiple-case herd was no more than would be expected from the breeding structure of the herd. The segregation ratio of affected cows in the proband generation within sire and maternal grandsire sibships in 12 pedigree herds was not inconsistent with Mendelian expectation for autosomal recessive inheritance with complete penetrance. The data analysed shows that the disease itself is not simply inherited. However, there remains a real possibility that the susceptibility of individual animals to BSE is inherited. This should be taken into account in current and future research on the aetiology and control of the disease.

Animals↗

PubMed1986

Dispersal polymorphisms in subdivided populations.

Price's method for analyzing natural selection in subdivided populations is applied to the problem of dispersal polymorphism strategies in a stable habitat. The results agree with the more traditional Mendelian models for this same problem that have recently been published. Further, by using Price's method, the results obtained are simpler and more general, and the causal evolutionary mechanisms underlying the predicted patterns are more easily recognized. The most interesting new result is that the equilibrium proportion of dispersed individuals is a simple function of the risk of dispersing and the regression coefficient of relatedness among individuals who, in the absence of dispersal, would compete for a limited, local resource. This regression coefficient refers to the genotypes that control the dispersal phenotype. For example, when mothers control the phenotype of their progeny, then the regression is from the mother onto an offspring chosen randomly from the local group before dispersal; while when offspring control their own phenotype, the regression is taken directly from offspring onto a randomly chosen cohort member before dispersal. This use of controlling genotypes to calculate regressions explains the form of the parent-offspring conflict over dispersal noted by previous authors. The simplicity and generality of these results suggest that Price's method is a useful approach for studying the class of phenomena known as "games among relatives".

Genotype↗

PubMed1993

The analysis of paternity and maternity in the marine hydrozoan Hydractinia symbiolongicarpus using randomly amplified polymorphic DNA (RAPD) markers.

For organisms in which direct observation of mating and subsequent dispersal of offspring and relatives is impossible, patterns of reproductive success and genealogical relationship can only be established using genetic markers. The ideal genetic assay would (1) employ highly polymorphic genetic markers for distinguishing among individuals; (2) use little tissue for analysing early life-history stages; and (3) require minimal investment in time and money for population level studies. From this perspective, DNA polymorphisms revealed by PCR amplification using random ten-base primers [Randomly Amplified Polymorphic DNA (PCR-RAPD) or Arbitrarily Primed DNA (AP-PCR)] have great potential. However, the evidence that RAPD/AP markers are both heritable and can be repeatably amplified remains controversial. This study characterizes patterns of inheritance and polymorphism of RAPD markers in the free-spawning, colonial marine hydrozoan Hydractinia symbiolongicarpus. In all cases, the amplification products were identical among extractions from the same clone. Of 56 primers screened, 13 had sufficient polymorphism and scoreability for an analysis of parentage and higher-order genetic relationships in three matings. These primers generated 156 unique amplification products (putative loci), of which 133 were polymorphic. All but four of these loci were inherited as dominant mendelian markers. Our study suggests that the presence of a marker represents a single allele at a locus; however, what appear to be single null alleles may actually comprise several segregating alleles. When the identity of neither parent was known a priori, inclusion (unique markers present in offspring and only one of the potential parents) proved to be more efficient than exclusion for assigning offspring to parents. The most powerful approach, however, was cluster analysis of all presence/absence information for the marker bands. Clustering avoided the pitfalls caused by the appearance of occasional nonparental bands, and constructed a hierarchical framework that correctly reflected all genealogical relationships.

Animals↗

PubMed2000

Segregation analysis of serum uric acid in the NHLBI Family Heart Study.

Segregation analysis was performed on the serum uric acid measurements from 523 randomly ascertained Caucasian families from the NHLBI Family Heart Study. Gender-specific standardized residuals were used as the phenotypic variable in both familial correlation and segregation analysis. Uric acid residuals were adjusted for age, age2, age3, body mass index (kg/m2), creatinine level, aspirin use (yes/no), total drinks (per week), HOMA insulin resistance index [(glucose * insulin)/22.5], diuretic use (yes/no), and triglyceride level. Sibling correlations (r=0.193) and parent-offspring correlations (r=0.217) were significantly different from zero, but these two familial correlations were not significantly different from one another. After adjustment for covariates, the heritability estimate for serum uric acid was 0.399. Segregation analysis rejected the "no major gene" model but was unable to discriminate between an "environmental" and a "Mendelian major gene" model. These results support the hypothesis that uric acid is a multifactorial trait possibly influenced by more than one major gene, modifying genes, and environmental factors.

Arteriosclerosis↗

PubMed2006

Accounting for heterogeneous variances in multitrait evaluation of Jersey type traits.

The multitrait genetic evaluation system for type traits was modified to estimate adjustments for heterogeneous variance (HV) simultaneously with estimated breeding values (EBV) for final score and 14 linear traits. Each variance within herd, year, and parity was regressed toward a predicted variance, which was determined by fitting a model with fixed effects of the mean final score for herd, size of the contemporary group, appraisal month, and year-season and a random effect for herd-appraisal date. Herd-appraisal date was included as a random effect to regress the observed heterogeneity for a given herd-appraisal date toward the fixed effects. Method R was used to estimate variances for the heterogeneity model in each EBV iteration. To evaluate the effect of the adjustment, parent averages were calculated from evaluations with recent appraisals removed. The adjustment slightly improved correlations within birth year between those parent averages and EBV from current data on bulls for most traits, but did not improve correlations for final score, strength, dairy form, teat length, or foot angle. Annual trends for EBV were lower with HV adjustment than for unadjusted EBV for all traits except final score and rump angle for cows and rump width for bulls, which were essentially unchanged. Standard deviations of Mendelian sampling (evaluation minus mean of parent evaluations) declined less over time for HV-adjusted than for unadjusted evaluations. The slope at year 2000 of Mendelian-sampling standard deviations from HV-adjusted evaluations ranged from 10.0% for udder depth to 42.7% for teat length compared with the slope for unadjusted evaluations. This HV adjustment, which was implemented for USDA evaluations in May 2001 for Jerseys and in 2002 for other breeds, improves the accuracy of evaluations, particularly comparisons over time, by accounting for the change in variation.

Animals↗

PubMed1998

Major locus influencing plasma APO-A1 levels also controls plasma HDL3-C concentrations.

Elevated plasma levels of apolipoprotein A1 (APO-A1) and high-density lipoprotein cholesterol (HDL-C) are important protective factors for atherosclerosis and coronary heart disease. Using the data on plasma concentrations of APO-A1, and HDL-C particles HDL2-C and HDL3-C in 970 Israeli individuals belonging to 228 pedigrees, we tested the hypothesis that a major locus influencing interindividual variation in APO-A1 levels also controls interindividual variation in HDL3-C and HDL2-C levels. Univariate and bivariate complex segregation analyses, as implemented in two statistical packages (MAN-3 and PAP-4.0) were applied to test the hypothesis. The results of the analysis clearly indicated the possibility of major gene involvement in the determination of plasma concentration variation of each of the 3 study variables. The results provide strong evidence in support of our hypothesis that HDL3-C genetic variation fully depends on the APO-A1 major locus. In particular, environmental and sporadic models were strongly rejected (P < 0.001) in bivariate analysis. The hypothesis of no pleiotropic effect of the putative APO-A1 locus on HDL3-C transmission was also unequivocally rejected (P < 0.001), while the bivariate Mendelian model was accepted (P > 0.05). The results of bivariate analysis of APO-A1 effect on HDL2-C were not clear. They indicated the possibility of the existence of slight genetic covariation between the two variables, and as yet we were unable to decipher the mode of covariation with the applied models.

Apolipoprotein A-I↗

PubMed2003

Robust asymptotic sampling theory for correlations in pedigrees.

Methods to unravel the genetic determinants of non-Mendelian diseases lie at the next frontier of statistical approaches for human genetics. It is generally agreed that, before proceeding with segregation or linkage analysis, the trait under study ought to be shown to exhibit familial correlation. By coding dichotomous traits as binary variables, a single robust approach in the estimation of pedigree correlations, rather than two distinct approaches, can be used to assess the potential heritability of a trait, and, latterly, to examine the mode of inheritance. The asymptotic theory to conduct hypothesis tests and confidence intervals for correlations among different members of nuclear families is well established but is applicable only if the nuclear families are independent. As a further contribution to the literature, we derive the asymptotic sampling distribution of correlations between random variables among arbitrary pairs of members in extended families for the Pearson product-moment estimator with generalized weights. This derivation is done without assuming normality of the traits. The sampling distribution is shown to be asymptotically normal to first order, and hence large-sample hypothesis tests and confidence intervals with estimates of the variances and correlation coefficients are proposed. Discussion concludes with an example and a suggestion for future research.

ABO Blood-Group System↗

PubMed1992

Strategies based on marker information for the study of human diseases.

The goals and the ways of using genetic marker information when studying human disease are very different according to whether the disease or sub-entity of the disease is mendelian or if a 'disease gene' in the sense of a rare mutated allele does not exist but rather common genetic risk factors, each one normal if considered alone. In the former case, genetic markers are used in the aim of localizing the defective gene and a systematic screening of the genome seems to be an efficient strategy provided there is not too much ambiguity in the correspondence between phenotypes and genotypes. In the latter case, the goal is to find risk factors allowing us to predict better the risk for an individual and to define different risk groups resulting in greater power to show the potential role of other factors (genetic or environmental). In this situation, the use of the lod score method with random markers presents several disadvantages: first, the multiple testing problem is particularly crucial; second, false rejection of linkage may be induced by misspecification of the model describing the genetic basis of the disease; and last, the power of detecting linkage may be low. A strategy focusing on 'candidate gene' markers may be then more efficient.

Chromosome Mapping↗

PubMed2026

Active components and potential mechanisms of Wuzhuyu decoction in the treatment of ethanol-induced acute gastric mucosal injury: a network pharmacology and experimental verification.

OBJECTIVE: To investigate the underlying mechanisms and active components of Wuzhuyu decoction (, WD) in alleviating ethanol-induced acute gastric mucosal injury (GMI) using an integrated approach of network pharmacology and experimental verification. METHODS: Sprague-Dawley rats were randomly divided into six groups: control (Con), model (Mod), bismuth potassium citrate (BPC), WD at low (WD-L), medium (WD-M), and high (WD-H) doses. Following seven days of continuous intragastric administration of the respective treatments, an ethanol-induced gastric mucosal injury model was established in all groups except the control group by oral gavage of anhydrous ethanol. The gastric mucosal injury index was evaluated, and pathological changes were assessed viahematoxylin and eosin (HE) staining. Levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were measured by enzyme-linked immunosorbent assay (ELISA). The chemical composition was identified by ultra-performance liquid chromatography-tandem mass spectrometry. Active compounds were screened using the Swiss-absorption, distribution, metabolism, and excretion database, and their potential targets were predicted using the Swiss Target Prediction database and bioinformatics annotation database for molecular mechanism. Simultaneously, disease targets related to GMI were retrieved from the online mendelian inheritance in man and GeneCards databases. A protein-protein interaction (PPI) network was constructed, and functional enrichment analyses of gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed using the Metascape database. Key predictions from the network pharmacology analysis were subsequently verified through animal experiments. Protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Cleaved Caspase-3, and Cleaved Caspase-9 were analyzed by Western blot. Finally, molecular docking was performed using AutoDock Vina to investigate the interactions between the active components and core targets. RESULTS: WD treatment significantly reduced the gastric mucosal injury index and the levels of TNF-α, IL-1β, MDA, while it increased the activities of SOD and GSH-Px. Histopathological examination revealed marked improvement in gastric tissue morphology. A total of 145 compounds were identified in WD. Network pharmacology analysis identified 440 overlapping targets between WD and GMI. GO and KEGG enrichment analyses highlighted the apoptosis signaling pathway as a key mechanism for WD's protective effect against ethanol-induced GMI. Experimental validation demonstrated that WD treatment reduced the apoptosis of gastric mucosal epithelial cells, promoted the expression of Bcl-2, and inhibited the expression of Bax, Cleaved Caspase-3 and Cleaved Caspase-9. Molecular docking results indicated that dehydroevodiamine, rutaecarpine, evodiamine, hexahydrocurcumin, and isorhamnetin are potential active components in WD that contribute to the inhibition of apoptosis. CONCLUSIONS: WD alleviates ethanol-induced acute GMI, at least in part, by inhibiting the apoptosis. The primary active components responsible for this effect are dehydroevodiamine, rutaecarpine, evodiamine, hexahydrocurcumin, and isorhamnetin.

Drugs, Chinese Herbal↗

PubMed1992

Commingling and complex segregation analysis of fasting plasma glucose in the Lipid Research Clinics family study.

Commingling and segregation patterns of fasting plasma glucose (GL) were examined in family data from 5 clinics (Cincinnati, Stanford, Iowa, Minnesota, and Oklahoma) of the Lipid Research Clinics (LRC) family study. In addition to the primary question of whether there was a major gene for GL, a secondary purpose was to investigate the possibility of genetic heterogeneity among the 5 clinics. No statistical support was found for heterogeneity among clinics, either in the commingling of distributions or in the segregation patterns. For the combined clinics sample, both a major effect and a multifactorial component were significant. However, the major effect (accounting for 73% of the variance) was not found to be consistent with a major gene, as the hypothesis of Mendelian transmission was rejected. The most parsimonious model involved equal transmission probabilities, which suggests that the major effect is not transmitted from parents to offspring. Possible sources of this major non-Mendelian effect were explored. The multifactorial component accounted for 10% of the variance in GL levels, and no generational differences were noted. Although our study was unable to provide evidence in favor of a major gene effect, it should be noted that a major gene cannot be firmly refuted. For example, a variety of interactions, such as genotype-dependent age effects, could have masked the transmission probabilities.

Adolescent↗

PubMed2000

Characterization of early follicular cDNA library suggests evidence for genetic polymorphisms in the inbred strain C108 of Bombyx mori.

Recent work towards the completion of a saturated molecular genetic linkage map for the lepidopteran silkworm, Bombyx mori (n = 28), has provided evidence for existing polymorphisms in the inbred strain C108. Two inbred parental strains, p50 and C108, were crossed to produce the F1 (P/C) hybrid offspring. The populations used in this project were comprised of a combination of 29 F2 (F1 x F1) and 31 reciprocal backcross (P/C x C/C, P/C x P/P) progeny. All restriction fragment length polymorphisms (RFLPs) for the initial analysis were hybridized with anonymous probes derived from a random early follicular cDNA (Rcf) library from Bombyx. A total of 19 Rcf probes were selected as showing scorable codominant polymorphic patterns when screened against F2 and backcross DNAs digested with the restriction enzymes EcoRI, HindIII, or PstI, and Southern blotted to nylon membranes for hybridization. Of the newly reported Rcf probes, 7 (37%) were characterized as producing 'simple' polymorphic patterns, while 12 (63%) were characterized as producing 'complex' polymorphic patterns. Further characterization of the complex patterns subdivided this group into two general classes: polymorphisms that contained an additional allele, and multiple bands that contained an easily scored two banded polymorphism. Because the extra allele class was limited to the (P/C x C/C) backcross progeny, it is suggested that the inbred parental strain C108 harbors polymorphic loci that are inherited in a simple Mendelian fashion. A genetic analysis discussing plausible origins and maintenance of these polymorphisms is presented.

Animals↗

PubMed2004

Closing the gaps on human chromosome 19 revealed genes with a high density of repetitive tandemly arrayed elements.

The reported human genome sequence includes about 400 gaps of unknown sequence that were not found in the bacterial artificial chromosome (BAC) and cosmid libraries used for sequencing of the genome. These missing sequences correspond to approximately 1% of euchromatic regions of the human genome. Gap filling is a laborious process because it relies on analysis of random clones of numerous genomic BAC or cosmid libraries. In this work we demonstrate that closing the gaps can be accelerated by a selective recombinational capture of missing chromosomal segments in yeast. The use of both methodologies allowed us to close the four remaining gaps on the human chromosome 19. Analysis of the gap sequences revealed that they contain several abnormalities that could result in instability of the sequences in microbe hosts, including large blocks of micro- and minisatellites and a high density of Alu repeats. Sequencing of the gap regions, in both BAC and YAC forms, allowed us to generate a complete sequence of four genes, including the neuronal cell signaling gene SCK1/SLI. The SCK1/SLI gene contains a record number of minisatellites, most of which are polymorphic and transmitted through meiosis following a Mendelian inheritance. In conclusion, the use of the alternative recombinational cloning system in yeast may greatly accelerate work on closing the remaining gaps in the human genome (as well as in other complex genomes) to achieve the goal of annotation of all human genes.

Alu Elements↗

PubMed1996

Breakpoints in alpha, beta, and satellite III DNA sequences of chromosome 9 result in a variety of pericentric inversions.

Human chromosome 9 with a pericentric inversion involving the qh region is considered normal. It has probably evolved through breakage and reunion and is retained through mendelian inheritance without any apparent phenotypic consequences. Fluorescent in situ hybridisation (FISH) technique using alpha, beta, and satellite III DNA probes showed that the breakpoints are variable and can be localised in the alpha or in the satellite III and beta DNA regions or both. Three types of inversions are proposed which appear similar by CBG banding: pericentric inversions with two alphoid, one beta, and one satellite III hybridisation signals were classified as type A. Type B were those with two beta, one alpha, and one satellite III hybridisation signals, while type C was complex, and most likely involved two inversions, since two separate hybridisation signals were detected in each of the alphoid, beta satellite, and satellite III DNA regions. Based on eight cases, type A is likely to be the most frequent, but the frequencies, which at present appear non-random for these different types of inversions in the population, can only be estimated by studying a larger sample size. Inversion heteromorphisms may promote reshuffling of tandem arrays of DNA repeat sequences, thereby giving rise to new heteromorphic domains. Alternatively, the repetitive nature of the sequences lends to the structural variations observed within the inv(9) chromosomes (or any other abnormal chromosome that is the result of recombination between, or breakage within, repetitive DNA).

Chromosome Inversion↗