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Results for “Mendelian Randomization”

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PubMed1989

Kg, a new low-frequency red cell antigen responsible for hemolytic disease of the newborn.

Hemolytic disease of the newborn in a Japanese infant led to studies which indicate that an antibody detected in the maternal serum is recognizing a hitherto unknown red cell antigen. The antigen, which we have named Kg, was found in two generations of the family and it is inherited as a Mendelian dominant character. The maternal serum failed to react with the red cells of more than 600 random Japanese blood donors, 64 red cell samples known to possess low-frequency antigens and all but one of 75 red cell samples known to lack high-frequency antigens without recognized low-frequency antigens. The father's red cells were tested extensively for established low-frequency antigens; only Dia was demonstrated and the maternal antibody was shown not to contain anti-Dia.

ABO Blood-Group System↗

PubMed1994

Limits of resolution of genetic linkage studies: implications for the positional cloning of human disease genes.

Positional cloning studies to identify disease genes are being carried out for many human genetic diseases. Such studies often include a genome-scan linkage analysis to identify the rough chromosomal location of a disease gene, fine structure genetic mapping to define and narrow the chromosomal interval in which the disease gene may be located, and physical mapping and gene identification in the genetically defined interval to clone the disease gene. During the planning of a positional cloning study, it is important to know that, if linkage is found, the genetic interval identified is likely to be sufficiently narrow to be dissected efficiently by methods of physical mapping and gene identification. Thus, we wish to know the limits of resolution of a genetic linkage study. In this paper, I determine for Mendelian diseases the distributions and moments of three measures of linkage resolution: (1) in a set of N chromosomes, the distance between the nearest crossovers that flank a disease locus, (2) the distance between the nearest genetic markers that flank the pair of flanking crossovers after a genome scan, and (3) the distance between the nearest flanking markers after additional randomly placed markers are generated and typed in an identified interval. These results provide explicit sample-size guidelines for future positional cloning studies of Mendelian diseases and make possible a more objective evaluation of whether a proposed positional cloning study is likely to be successful. I also briefly discuss the more difficult problem of linkage resolution for complex genetic diseases.

Chromosome Mapping↗

PubMed1996

Successful crosses and molecular tetrad and progeny analyses demonstrate heterothallism in Mycosphaerella graminicola.

Monospore isolates of Mycosphaerella graminicola considered to originate from one ascus were analysed by the polymerase chain reaction (PCR) with 32 RAPD primers. Eighteen of these revealed three classes of polymorphisms, which enabled a RAPD-based tetrad analysis. Four pairs of isolates resulting from a single diploid nucleus were determined. A procedure to cross these isolates was developed to investigate the mating system. Three of six crosses were successful, and the segregation of mating types in accordance with the tetrad analysis strongly points to a bipolar heterothallic mating system in M. graminicola. Random ascospore progenies from the successful crosses, each comprising 54 isolates, were studied with three primers to determine the mode of inheritance of the RAPD markers. Mendelian segregation and recombination of RAPD markers was observed in all progenies.

Base Sequence↗

PubMed2003

Robustness of inference on measured covariates to misspecification of genetic random effects in family studies.

Family studies to identify disease-related genes frequently collect only families with multiple cases. It is often desirable to determine if risk factors that are known to influence disease risk in the general population also play a role in the study families. If so, these factors should be incorporated into the genetic analysis to control for confounding. Pfeiffer et al. [2001 Biometrika 88: 933-948] proposed a variance components or random effects model to account for common familial effects and for different genetic correlations among family members. After adjusting for ascertainment, they found maximum likelihood estimates of the measured exposure effects. Although it is appealing that this model accounts for genetic correlations as well as for the ascertainment of families, in order to perform an analysis one needs to specify the distribution of random genetic effects. The current work investigates the robustness of the proposed model with respect to various misspecifications of genetic random effects in simulations. When the true underlying genetic mechanism is polygenic with a small dominant component, or Mendelian with low allele frequency and penetrance, the effects of misspecification on the estimation of fixed effects in the model are negligible. The model is applied to data from a family study on nasopharyngeal carcinoma in Taiwan.

Analysis of Variance↗

PubMed2000

Disease-causing mutations in the human genome.

UNLABELLED: A considerable number of gene mutations has now been reported in a total of more than 1000 different human genes. Data on these mutations and their associated phenotypes have been collated and are available online through two major databases: Online Mendelian Inheritance in Man in Baltimore and the Human Gene Mutation Database in Cardiff. Since the non-randomness of mutation is determined largely by the local DNA sequence environment, the study of mutation may not only yield information on underlying mechanisms but also lead to the optimization of mutation search strategies. CONCLUSION: There is a high frequency of CG to TG or CA mutations in the human genome due to deamination of 5' methyl-cytosine. The second most common type of mutations in human disorders is short deletions or insertions of less than 20 nucleotides.

5-Methylcytosine↗

PubMed2006

Strategy for mapping quantitative trait loci (QTL) by using human metapopulations.

AIM: To present a novel strategy for mapping quantitative trait loci (QTL), using human metapopulations. The strategy is based on the expectation that in geographic clusters of small and distinct human isolates, a combination of founder effect and genetic drift can dramatically increase population frequency of rare QTL variants with large effect. In such cases, the distribution of QT measurements in an (affected) isolate is expected to deviate from that observed in neighboring isolates. METHODS: We tested this hypothesis in 9 villages from a larger Croatian isolate resource, where 7 Mendelian disorders have been previously reported. The values of 10 physiological and biochemical QTs were measured in a random sample of 1001 individuals (100 inhabitants of each of 9 villages and 101 immigrant controls). RESULTS: Significant over- or under- representation of individuals from specific villages in extreme ends of standardized QT measurement distribution was found 10 times more frequently than expected by chance. The large majority of such clusters of individuals with extreme QT values (34/36, 94.4%) originated from the 6 villages with the most pronounced geographic isolation and endogamy. CONCLUSION: Early epidemiological assessment supports the feasibility of the proposed strategy. Clusters of individuals with extreme QT values responsible for over-representation of single villages can usually be linked to a larger pedigree and may be useful for further QTL mapping, using linkage analysis.

Body Height↗

PubMed1999

Mapping quantitative trait loci for complex binary traits in outbred populations.

Complex binary traits have a dichotomous phenotypic expression but do not show a simple Mendelian segregation ratio. These traits are considered to be jointly controlled by the actions of several genes and a random environmental effect. The binary phenotype and the underlying factor are assumed to be linked through a threshold model. The underlying factor, referred to as the liability, is treated as a regular but unobservable quantitative character. Mapping quantitative trait loci (QTL) can be performed directly on the liability. Methods of QTL mapping for the liability of a complex binary trait have been well developed in line-crossing experiments. However, such a method is not available in outbred populations which usually consist of many independent pedigrees (families). In this study, we develop a method to analyse jointly multiple families of an outbred population. The method is developed based on a fixed-model approach, i.e. the QTL effects, rather than the variance, are estimated and tested. After the test, the estimated effects are then converted into a single estimate of the QTL variance by taking into consideration errors in the estimated effects. The QTL effects and variance-covariance matrix of the estimates are obtained by a fast Fisher-scoring method. Monte Carlo simulations show that the method is not only powerful but also generates very accurate estimates of QTL variances.

Algorithms↗

PubMed1998

Transposition of the mariner element from Drosophila mauritiana in zebrafish.

With the increased popularity of zebrafish (Danio rerio) for mutagenesis studies, efficient methods for manipulation of its genome are needed. One approach is the use of a transposable element as a vector for gene transfer in this species. We report here the transformation of zebrafish and germ-line transmission of the mariner element from Drosophila mauritiana. The mariner element was selected because its transposition is independent of host-specific factors. One- to two-cell-stage zebrafish embryos were coinjected with a supercoiled plasmid carrying the nonautonomous mariner element peach and mRNA encoding the transposase. Surviving larvae were reared to adulthood, and the transmission of peach to the F1 generation was tested by PCR. Four of the 12 founders, following plasmid injections on 2 different days, transmitted the element to their progeny. Inheritance of the transgene from the F1 to the F2 generation showed a Mendelian pattern. No plasmid sequences were detected by PCR or Southern blot analysis, indicating transposition of peach rather than random integration of the plasmid DNA. These data provide evidence of transformation of a vertebrate with a transposable element and support the host-independent mechanism for transposition of the mariner element. We suggest this system could be used for insertional mutagenesis or for identifying active regions of the genome in the zebrafish.

Animals↗

PubMedDate not supplied

Rheumatic fever susceptibility in four ascertainments: regressive segregation on a geometric ascertainment pattern.

On resolving the ascertainment biases of the observed data in the geometric continuum vaffected-1 x P(sibship), where 0 less than v----infinity, four published ascertainments of rheumatic fever show excellent conformation with Mendelian recessive segregation, even in multiplex sibships. In two surveys in which ascertainment bias is near or a little above random sampling (v = 1), this conclusion is further corroborated by classical segregation analysis. The other two surveys have bias trends declining (v less than 1) very much below random sampling. Such levels of ascertainment bias, if defined through the ascertainment probability parameter pi, would be out of range because the range is from single ascertainment, where pi----0 to random sampling where pi = 1 and probability cannot exceed unity. Highly successful antimicrobial measures that would reduce the number of diseased sibs independent of the distribution of susceptible sibs could produce a dissociation of the gene-to-"rheumatic" relationship and thus explains the declining ascertainment bias.

Adult↗

PubMed1983

A new low-frequency antigen, Hga (Hughes).

This paper describes a 'new' low-frequency antigen, Hga, which came to light during routine antibody identification tests. 3 families were investigated, 2 found during the screening of 5,434 random group O donors, giving a frequency of 1:2717. The families showed the antigen to be inherited as a Mendelian autosomal dominant character segregating independently of: Rh, MNS and is not linked to X or Y. No pure examples of the corresponding antibody have been discovered in testing 6,580 sera from normal donors in South Wales.

Blood Group Antigens↗

PubMed1996

Isolation and characterization of a cisplatin-resistant strain of Schizosaccharomyces pombe.

A cis-diamminedichloroplatinum [DDP (cisplatin)]-resistant population of Schizosaccharomyces pombe was developed through chronic exposure of the 972 h- strain to increasing concentrations of the drug. The resulting cells, designated wtr2, were 5.25-fold resistant to DDP, are resistance was retained by clone isolated from this population in the absence of drug for > or = 5 months. After backcrossing and isolation of a single clone, random spore analysis gave a segregation ratio close to 1:1 for DDP resistance and sensitivity. Tetrad analysis confirmed a mendelian 2:2 segregation, suggesting that a single nuclear gene was responsible for the DDP-resistant phenotype. Stable diploids obtained from the mating of a resistant spore carrying the ade6-216 marker with the mei2-102-ade6-210 meiosis-deficient mutant remained resistant, indicating that the resistant phenotype was expressed dominantly. There was no difference between the accumulation of the DDP analog [3H]dichloro(ethylenediamine)-platinum(II) into whole cells derived from the sensitive and the resistant spores obtained from the last backcross. The resistant clones from a single tetrad did not have an increased level of glutathione and were collaterally sensitive to cadmium and arsenite. We conclude that in S. pombe, a stable and dominant DDP-resistant phenotype can be mediated by a single allele, that the phenotype is not accompanied by cross-resistance to cadmium or arsenite, and that the mechanism is not associated with a significant alteration in glutathione level or DDP uptake.

Alleles↗

PubMed2002

Homozygous Tsix mutant mice reveal a sex-ratio distortion and revert to random X-inactivation.

Tsix controls X-chromosome inactivation (XCI) by blocking the accumulation of Xist RNA on the future active X chromosome. Deleting Tsix on one X chromosome (X(Delta)X) skews XCI toward the mutated X chromosome in the female soma. Here I have generated homozygous Tsix-null mice (X(Delta)X(Delta)) to test how deleting the second allele affects the choice of XCI. Homozygosity leads to extremely low fertility and reveals two previously unknown non-mendelian patterns of inheritance. First, the sex ratio is skewed against female births so that one daughter is born for every two to three sons. Second, the pattern of XCI unexpectedly returns to random in surviving X(Delta)X(Delta) mice. Thus, with respect to choice, mutation of Tsix yields a phenotypic abnormality in heterozygotes but not homozygotes. To reconcile the paradox of female loss with apparent reversion to random choice, I propose that deleting both Tsix alleles results in chaotic choice and that randomness in X(Delta)X(Delta) survivors reflects a fortuitous selection of distinct X chromosomes as active and inactive.

Animals↗

PubMed1998

Segregation analysis of Parkinson disease.

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

Adolescent↗

PubMed1976

Stochastic selection in both haplophase and diplophase.

A population genetic model incorporating the evolutionary forces of zygotic selection, gametic selection and non-Mendelian segregation has been analyzed for the case in which all selection coefficients and the segregation parameter are assumed to be random variables that are uncorrelated from generation to generation. The diffusion approximation of the model is developed, and the subsequent analysis shows that one of four limiting outcomes of the stochastic process may obtain--an allele may be fixed or lost almost surely and irrespective of the initial gene frequency, the gene frequency may converge to a unique stationary distribution, or an allele may be fixed or lost with probabilities depending on the initial gene frequency. These outcomes correspond rather closely with the possible outcomes of the deterministic model--fixation or loss of an allele, convergence to a stable equilibrium, or the existence of an unstable equilibrium.

Alleles↗

PubMed2006

Genealogical theory for random mating populations with two sexes.

Consider a random mating population that has N(m) males and N(f) females in each generation. Let us assume that at time 0 a random sample of n copies of a gene is taken from this population. Then, for models introduced by Wright [Evolution in Mendelian populations, Genetics 16 (1931) 97; Inbreeding and homozygosis, Proc. Nat. Acad. Wash. 19 (1933) 420; Evolution and the Genetics of Populations, The Theory of Gene Frequencies, vol. II, The University of Chicago, Chicago and London, 1969.], it is possible to obtain generalizations of the haploid theory of genealogical processes developed by Felsenstein . It is conjectured that these hold generally, regardless of the effective population size, if n<<min(N(m),N(f)). Generalizations are also proved to hold if n=2.

Animals↗

PubMed2006

Overdominant quantitative trait loci for yield and fitness in tomato.

Heterosis, or hybrid vigor, is a major genetic force that contributes to world food production. The genetic basis of heterosis is not clear, and the importance of loci with overdominant (ODO) effects is debated. One problem has been the use of whole-genome segregating populations, where interactions often mask the effects of individual loci. To assess the contribution of ODO to heterosis in the absence of epistasis, we carried out quantitative genetic and phenotypic analyses on a population of tomato (Solanum lycopersicum) introgression lines (ILs), which carry single marker-defined chromosome segments from the distantly related wild species Solanum pennellii. The ILs revealed 841 quantitative trait loci (QTL) for 35 diverse traits measured in the field on homozygous and heterozygous plants. ILs showing greater reproductive fitness were characterized by the prevalence of ODO QTL, which were virtually absent for the nonreproductive traits. ODO can result from true ODO due to allelic interactions of a single gene or from pseudoODO that involves linked loci with dominant alleles in repulsion. The fact that we detected dominant and recessive QTL for all phenotypic categories but ODO only for the reproductive traits indicates that pseudoODO due to random linkage is unlikely to explain heterosis in the ILs. Thus, we favor the true ODO model involving a single functional Mendelian locus. We propose that the alliance of ODO QTL with higher reproductive fitness was selected for in evolution and was domesticated by man to improve yields of crop plants.

Chromosomes, Plant↗

PubMed1997

Triplet repeat instability and DNA topology: an expansion model based on statistical mechanics.

The variance of writhe, the contribution of writhe to supercoiling, and the free energies of supercoiling were calculated for (CTG.CAG)n and (CGG.CCG)n triplet repeat sequences (TRS) by statistical mechanics from the bending and torsional moduli previously determined. Expansions of these sequences are inherited by non-mendelian transmission and are linked with several hereditary neuromuscular diseases. The variance of writhe was greater for the TRS than for random B-DNA. For random B-DNA, (CGG)n, and (CTG)n, the contribution of writhe to supercoiling was 70, 78, and 79%, whereas the free energy of supercoiling at a length of 10 kilobase pairs was 1040.RT, 760.RT, and 685.RT, respectively. These data indicate that the TRS are preferential sites for the partitioning of supercoiling. Calculations of the differences in free energy of supercoiling between the TRS and random B-DNA revealed a local minimum at approximately 520 base pairs. Human medical genetic studies have shown that individuals carrying up to 180-200 copies of TRS (540-600 base pairs, premutations) in the fragile X or myotonic dystrophy gene loci are usually asymptomatic, whereas large expansions (>200 repeats, full mutations), which lead to disease, are observed in their offspring. Therefore, the length corresponding to the local minimum in free energy of supercoiling correlates with the genetic breakpoint between premutation and full mutation. We propose that (a) TRS instability is mediated by DNA mispairing caused by the accumulation of supercoiling within the repeats, and (b) the expansions that take place at the premutation to full mutation threshold are associated with increased mispairing caused by the optimal partitioning of writhe within the TRS at this length.

DNA, Superhelical↗

PubMed2001

Two hits revisited again.

INTRODUCTION AND METHODS: Since the concept of the "two hit hypothesis" was introduced over 20 years ago, a wealth of genetic data has accumulated on the mutations found at tumour suppressor loci. Perhaps surprisingly, these data conceal large gaps in our knowledge which genetic and functional studies are beginning to uncover. The "two hit hypothesis" must be updated to take account of this new information. RESULTS AND DISCUSSION: Here, we discuss both the results of recent studies and some of the questions that they highlight. In particular, how valid are conclusions from inherited Mendelian syndromes when applied to sporadic cancers? Why is allelic loss so common and how does it occur? Are the "two hits" random or interdependent? Is abolition of protein function always optimal for tumorigenesis? Can "third hits" occur and, if so, why? How can mismatch repair deficiency and the methylator phenotype be incorporated into the "two hit" hypothesis? We suggest that the "two hit hypothesis" is not fixed but is evolving as our knowledge expands.

Humans↗