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PubMed1986

The offspring of twins as sampling units in pedigree analysis of congenital anomalies.

A statistical model was developed to determine the likelihood of a twin kinship, that is, the offspring of a pair of monozygotic or dizygotic twins under three types of inheritance: sporadic, single locus fetal genetic, and single locus maternal genetic. Samples of 8,000 kinships were simulated for a discrete trait under various hypotheses, and the likelihood determined for each type of etiology. The results indicated that the pedigree analysis procedures formulated here could efficiently detect sporadic or single locus effects with a power approaching 100%, although the parameter estimates obtained were slightly biased. Further analyses revealed that the type of pedigree analysis formulated in this study was found to have equivalent power for equal or unequal frequencies of kinships by the sex and zygosity of the twin parent. It was suggested that further studies be carried out that included the twins and spouses in the likelihood equations, as well as tests of more sophisticated models.

Congenital Abnormalities↗

PubMed2005

Neuregulin 1 gene and variations in perceptual aberration of schizotypal personality in adolescents.

BACKGROUND: We test the hypothesis that the neuregulin 1 (NRG1 ) gene at chromosome 8p22-p12, which has been implicated as a susceptibility gene to schizophrenia, is associated with variations in schizotypal personality in non-clinical populations. METHOD: A randomly selected sample of 905 adolescents were assessed for their personality features using the Perceptual Aberration Scale (PAS) and the Schizotypal Personality Questionnaire (SPQ) and genotyped for three single nucleotide polymorphisms (SNP8NRG221533, rs3924999, and rs2954041) at the NRG1 gene. Relations between the three genetic variants and continuous schizotypal personality scores were evaluated using ANOVA for single-locus analyses and haplotype trend regression test for multi-locus analyses. RESULTS: Single locus analysis showed that the A allele of rs3924999, a functional polymorphism in exon 2, had the largest effect size and exhibited a prominent allele-dose trend effect for the PAS score. Haplotype analyses using the haplotype trend regression test indicated that the A allele of rs3924999 was mainly responsible for the association with the PAS but not with the SPQ or its three factors, and the magnitude of significance was not strengthened by the combination of this allele with adjacent locus. CONCLUSIONS: Our study provides the first evidence for the association of NRG1 with schizotypal personality and indicates a possible role of NRG1 in the genetic etiology of schizophrenia through perceptual aberrations.

Adolescent↗

PubMed2005

Epistatic pleiotropy and the genetic architecture of covariation within early and late-developing skull trait complexes in mice.

The role of epistasis as a source of trait variation is well established, but its role as a source of covariation among traits (i.e., as a source of "epistatic pleiotropy") is rarely considered. In this study we examine the relative importance of epistatic pleiotropy in producing covariation within early and late-developing skull trait complexes in a population of mice derived from an intercross of the Large and Small inbred strains. Significant epistasis was found for several pairwise combinations of the 21 quantitative trait loci (QTL) affecting early developing traits and among the 20 QTL affecting late-developing traits. The majority of the epistatic effects were restricted to single traits but epistatic pleiotropy still contributed significantly to covariances. Because of their proportionally larger effects on variances than on covariances, epistatic effects tended to reduce within-group correlations of traits and reduce their overall degree of integration. The expected contributions of single-locus and two-locus epistatic pleiotropic QTL effects to the genetic covariance between traits were analyzed using a two-locus population genetic model. The model demonstrates that, for single-locus or epistatic pleiotropy to contribute to trait covariances in the study population, both traits must show the same pattern of single-locus or epistatic effects. As a result, a large number of the cases where loci show pleiotropic effects do not contribute to the covariance between traits in this population because the loci show a different pattern of effect on the different traits. In general, covariance patterns produced by single-locus and epistatic pleiotropy predicted by the model agreed well with actual values calculated from the QTL analysis. Nearly all single-locus and epistatic pleiotropic effects contributed positive components to covariances between traits, suggesting that genetic integration in the skull is achieved by a complex combination of pleiotropic effects.

Age Factors↗

PubMed2001

Genetic epidemiology of visceral leishmaniasis in northeastern Brazil.

Familial clustering of disease, racial differences in asymptomatic:disease ratios, and studies of mice all point to a genetic component for disease susceptibility in visceral leishmaniasis. Analysis of 87 multi-case pedigrees (824 individuals; 138 nuclear families) from a region of northeastern Brazil endemic for Leishmania chagasi demonstrates a high relative risk ratio (lambda(2S) = 34) to further siblings of affected sibling pairs. Complex segregation analysis using POINTER and COMDS show that all single locus models, as well as polygenic and multifactorial models, provide a significantly (P < 0.001) better fit to the data than a sporadic model. Of the genetic models, the general single locus model was not significantly different from additive or dominant single locus models, all of which gave a gene frequency for the putative disease susceptibility allele of approximately 0.002. The general single locus model was strongly favored (P < 0.001) over a recessive single gene model. Using POINTER, polygenic and multifactorial models were clearly rejected (P < 0.001 in all cases) in favor of the general single locus model. Using COMDS, the analysis was extended to consider two locus models. Results under a general two-locus model did not differ significantly from the dominant, additive, or general single locus models. Under this model, one locus was estimated at a gene frequency of 0.0017, i.e., in the same range as the disease susceptibility locus for the most favored single gene models, with the second locus at a much lower frequency of 0.0002. Hence, the data support the hypothesis that a single major gene may be important in determining disease susceptibility in this population. To identify the gene(s) involved, a genome scan with replication using two subsets of these larger pedigrees with power to detect linkage is in progress.

Adolescent↗

PubMed1999

Regional inference with averaged P values increases the power to detect linkage.

Controversy exists with respect to the choice of an appropriate critical value when testing for linkage in a genomic screen. A number of critical values have been proposed for single-locus and multi-locus linkage analyses. In this study, criteria based on multiple single-locus analyses (i.e., regional test criteria) are evaluated using simulation methods for three different map densities. Tests based on single loci, multiple consecutive single loci, and moving averages of consecutive single loci are considered. Appropriate critical values are determined based on results from simulations under the null hypothesis of no linkage. The power of each "regional test " was compared to the power of a single-locus test. Results suggest that the best power was found when averaging P values over an interval size of 9-15 cM, and that testing the average of P values from two consecutive loci is superior to testing each single locus separately. The increase in power ranged from 7- 29% over the simulations considered.

Bias↗

PubMed1985

Gametophytic self-incompatibility is controlled by a single major locus on chromosome 1 in Lycopersicon peruvianum.

By using a number of previously mapped enzyme-coding genes as genetic markers, it has been possible to scan the genome of Lycopersicon peruvianum for gene(s) controlling the gametophytic self-incompatibility reaction. Regardless of genetic background or level of inbreeding, only a single locus (S), mapping to chromosome 1, was found to control the self-incompatibility reaction. Despite the widespread occurrence of this form of self-incompatibility in higher plants, to the best of our knowledge, the locus underlying the response has not been confirmed previously through genetic mapping, and the results cast doubts on hypotheses requiring multifactoral or dynamic control of gametophytic self-incompatibility.

Journal Article↗

PubMed1981

Origin of the triosephosphate isomerase isozymes in humans: genetic evidence for the expression of a single structural locus.

A genetic approach is used to ascertain that a single structural locus for triosephosphate isomerase (TPI) (E.C.5.3.1.1.) is expressed in rapidly dividing human lymphoblasts. This approach is made possible through the identification of a rare electrophoretic variant of human TPI. The variant phenotype is expressed by the TPI-B isozyme in both erythrocytes and peripheral lymphocytes. The variant phenotype is also expressed in the thermostability and electrophoretic pattern of the TPI-A isozyme in mitogen-stimulated lymphoblasts, indicating that TPI-A and TPI-B are products of the same structural locus. These findings are in contrast to the recent conclusions of Yuan et al. based upon structural analysis, suggesting that the TPI-A and TPI-B isozymes are products of distinct structural loci.

Carbohydrate Epimerases↗

PubMed1997

[Forensic hematology genetics--paternity testing].

In Switzerland paternity investigations are carried out using DNA analysis only since 1991. DNA patterns are inherited and only with the exception of genetically identical twins they are different in everyone and therefore unique to an individual. Hence DNA-systems are an excellent tool to resolve paternity disputes. DNA polymorphisms used for paternity diagnosis are length polymorphisms of the highly polymorphic VNTR loci [variable number of tandem repeats]. The most frequently applied systems are the DNA single locus systems. In addition to the DNA single locus systems the application of PCR (PCR = polymerase chain reaction) based DNA systems has increased particularly in difficult deficiency cases or in cases where only small evidential samples or partially degraded DNA are available. Normally four independent DNA single probes are used to produce a DNA profile from the mother, the child and the alleged father. A child inherits half the DNA patterns from its mother and the other half from its true biological father. If an alleged father doesn't possess the paternal specific DNA pattern in his DNA profile he is excluded from the paternity. In case of non-exclusion the probability for paternity is calculated according to Essen-Möller. When applying four highly polymorphic DNA single locus systems the biostatistical evaluation leads always to W-values exceeding 99.8% [= required value for positive proof of paternity]. DNA analysis is currently the best available method to achieve such effective conclusions in paternity investigations.

Blood Group Antigens↗

PubMed2006

Two-stage two-locus models in genome-wide association.

Studies in model organisms suggest that epistasis may play an important role in the etiology of complex diseases and traits in humans. With the era of large-scale genome-wide association studies fast approaching, it is important to quantify whether it will be possible to detect interacting loci using realistic sample sizes in humans and to what extent undetected epistasis will adversely affect power to detect association when single-locus approaches are employed. We therefore investigated the power to detect association for an extensive range of two-locus quantitative trait models that incorporated varying degrees of epistasis. We compared the power to detect association using a single-locus model that ignored interaction effects, a full two-locus model that allowed for interactions, and, most important, two two-stage strategies whereby a subset of loci initially identified using single-locus tests were analyzed using the full two-locus model. Despite the penalty introduced by multiple testing, fitting the full two-locus model performed better than single-locus tests for many of the situations considered, particularly when compared with attempts to detect both individual loci. Using a two-stage strategy reduced the computational burden associated with performing an exhaustive two-locus search across the genome but was not as powerful as the exhaustive search when loci interacted. Two-stage approaches also increased the risk of missing interacting loci that contributed little effect at the margins. Based on our extensive simulations, our results suggest that an exhaustive search involving all pairwise combinations of markers across the genome might provide a useful complement to single-locus scans in identifying interacting loci that contribute to moderate proportions of the phenotypic variance.

Alleles↗

PubMed1994

Isolation and characterization of hypervariable sequences from tsetse fly genome.

A Glossina brevipalpis Newstead genomic library, constructed using a Charomid 9-36 vector, was used to isolate putative clones that hybridize to polymorphic regions of the tsetse genome. Five types of probes, that reveal individual DNA polymorphic in humans and higher animal species, were used to screen 300 tsetse Charomid clones; 15% of the clones hybridized with at least one probe. Twenty four recombinants were further characterized by Southern blotting hybridization using DNA isolated from individual tsetse fly from Glossina morsitans centralis Machado. Two classes of DNA profiles were obtained upon hybridization with the recombinant inserts. The first, termed the "multilocus profile" displayed a complex DNA pattern of multiple components whilst the second, referred to as the "single locus profile" revealed one or two bands in each individual. Of the 24 recombinant inserts tested, 13 were multilocus probes and the remainder were single locus probes, each of which hybridized to a single location when G. m. centralis DNA had been cleaved with EcoRI. These single locus probes revealed a low level of genetic variability among individual flies from an inbred colony. The hybridization profiles using multilocus and single locus probes were also obtained on DNA from individual Glossina palpalis palpalis Robineau-Desvoidy and Glossina palpalis gambienis Vanderplank and some of the G. brevipalpis recombinant clones also detected multilocus profiles in honey bees and man.

Animals↗

PubMed1991

DNA fingerprinting: its application in forensic case work.

Forensic serology deals with cases of disputed paternity and criminal stains. The spectacular improvement using DNA-profiling is best demonstrated with cases of criminal stains where with the same ease as a suspect can be identified, an innocent person can be excluded. In cases with band-shifting, a statistical definition of a match applying Bayes theorem as a decision making tool seems mandatory since matching or non-matching cannot be treated as a binary event. Good postmortem DNA stability is found in brain cortex, lymph nodes and psoas muscle. DNA fingerprinting is also a perfect tool to investigate disputed identity of blood alcohol samples. In paternity cases, we recommend both multi locus and single locus probes in kinship cases, e.g. in mother-child-putative father cases as well as father-daughter and brother-sister incest cases, grandparent cases and two-men cases. For the biostatistical evaluation of SLP patterns the formal genetics for a system of multiple allelism is used and for multi locus probes the model of multiple diallelism is applicable.

Crime↗

PubMed1983

Apparent resistance to mutagenesis by ionizing radiation, and some other unusual responses.

It is pointed out that in some species it is very difficult or even apparently impossible to get genetic visible marker mutants by means of ionizing radiation. Such results are not as a rule published. Species in which no mutants at all could be obtained, after what seem to be adequate efforts by several geneticists are Limnaea peregra, Rhynchosciara angelae, Coelopa frigida, Oncopeltus fasciatus, Dermestes maculatus. Published data on Sciara, Tribolium, Blattella, in which a relative difficulty in getting mutants is reported, are discussed and compared to many other forms in which obtaining marker mutants is on the contrary easy. What appears to be very abnormal mutagenesis is described in Drosophila busckii, which yielded an unusual frequency of autosomal dominants, and Drosophila nebulosa, in which only very poor mutants could be obtained. Possible reasons for all these departures from the usual are discussed. No firm conclusions are reached, but one is led to consider the possible effects of overall chromosome structure, presence or absence of heterochromatin, and multiplicity at the single locus or single polytene band level. There seems to be no relation between the rates of induction of dominant lethality and of point mutation for visible markers.

Animals↗

PubMed2000

Combined segregation and linkage analysis of 59 Hodgkin's disease families indicates the role of HLA determinants.

Through a literature search, we identified a total of 59 nuclear families with Hodgkin's disease (HD). The affected individuals in these families were HLA haplotyped. To evaluate the role of HLA-linked determinants of HD and investigate the mode of inheritance of familial HD, a combined segregation and linkage analysis was performed, together with a semi-parametric analysis of sib pairs. Amongst single locus models, a general single locus model showed no improvement over an additive model. However, a two locus additive model gave the best overall fit and a lod score of 3.55. We conclude that HD is most likely to be determined by both an HLA-associated major gene and other non-HLA genetic factors together with environmental effects.

HLA Antigens↗

PubMed1994

Transgenic complementation of the hy3 phytochrome B mutation and response to PHYB gene copy number in Arabidopsis.

A recombinant PHYB minigene (mPHYB) consisting of the complete Arabidopsis PHYB cDNA sequence fused to 2.3 kb of upstream PHYB promoter sequence has been introduced into wild-type Arabidopsis and into a strain containing the Bo64 allele of the hy3 mutation. The Bo64 mutant has previously been shown to contain a nonsense mutation in the PHYB coding sequence. Transformation of this strain with the mPHYB gene results in complementation of all of the mutant phenotypic characteristics tested including hypocotyl length and hypocotyl cell size, response to end-of-day far-red light, leaf morphology, chlorophyll level, and flowering time. Presence of the mPHYB transgene in a wild-type genetic background causes exaggeration of this same set of phenotypic characteristics, indicating that these diverse photo-morphogenic responses are sensitive to the copy number of the PHYB gene. The transgene inserts in the Bo64(mPHYB) and WT(mPHYB) lines are shown to be single locus and single copy and the immunologically detectable level of phytochrome B is shown to vary linearly with PHYB gene copy number. These results demonstrate a complex role for phytochrome B in Arabidopsis photo-morphogenesis and suggest that the expression level of this phytochrome gene is an important determinant of the intensity of light-induced plant responses.

Alleles↗

PubMedDate not supplied

Inheritance of retarded forebrain commissure development in fetal mice: results from classical crosses and recombinant inbred strains.

Deficiency of the adult corpus callosum in BALB/c mice shows incomplete penetrance and is clearly polygenic, whereas the defect in fetuses shows complete penetrance and a much less complex mode of inheritance. Retardation of the growth of the corpus callosum and the hippocampal commissure in the fetal mouse forebrain was expressed by a standard score (z) derived from body weight, such that a fetus with a score less than -2.0 was held to have commissures abnormally small for the body size. By this index, almost all C57BL/6 fetuses were normal, whereas BALB/c fetuses in the body weight range 0.5 to 1.0 g were often 5 standard deviations below the expected value of 0.0. In classical crosses between C57BL/6J and BALB/cWah, inheritance of the index of abnormality (z) was recessive, and about half of the fetuses in backcrosses to BALB/c were below -2.0. However, the distribution of scores was not bimodal. The results were consistent with a two-locus but not a single-locus difference between parent strains. Among the seven recombinant inbred strains derived from the By strains of C57BL/6 and BALB/c, there were three or possibly four distinct clusters of strains, which also suggested two-locus inheritance and excluded a single-locus difference. Although substantial retardation of commissure growth was evident in fetuses, deficiency or absence of the corpus callosum in weanling and adult By recombinant inbred mice was extremely rare in all strains except BALB/cByJ. These data confirm anatomical results showing that, in all but the most extremely retarded cases, the corpus callosum recovers from an obvious prenatal defect.

Agenesis of Corpus Callosum↗

PubMed2006

Absence of association between the multidrug resistance (MDR1) gene and inflammatory bowel disease.

OBJECTIVE: The multidrug resistance (MDR1) gene encodes for P-glycoprotein, a drug efflux pump. Mice deficient for the MDR1a gene spontaneously develop colitis. In humans, a polymorphism in exon 26 (C3435T) is associated with reduced expression levels and function of MDR1. Currently there are controversial data on the association between MDR1 and inflammatory bowel disease (IBD). The purpose of this study was to examine the involvement of this gene in IBD in a large population of Dutch patients with IBD and family-based controls. MATERIAL AND METHODS: A total of 781 IBD cases and 315 controls were investigated. CD phenotypes were determined according to the Vienna Classification. Individuals were genotyped for six single nucleotide polymorphisms (SNPs) close to and in the MDR1 locus. This included the C3435T variant and six microsatellite markers close to and in the MDR1 locus. Single locus association analysis, haplotype association analysis and haplotype sharing statistic (HSS) were used to search for differences between patients and controls. RESULTS: No association was observed for any of the SNPs with IBD as a group, or for ulcerative colitis, Crohn's disease and Crohn's disease phenotypes, either by single locus or haplotype association analysis or by HSS. CONCLUSIONS: No association was observed between the MDR1 gene and IBD. This suggests that it is unlikely that MDR1 plays a role in IBD susceptibility.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1980

Neural tube malformations: complex segregation analysis and recurrence risk.

A sample of 223 families with at least one child with anencephaly and/or spina bifida was ascertained in Southern Poland, where the incidence of neural tube malformations is 0.92/1,000. The recurrence risk in proband's sibs was 3.4%. The calculated heritability (h2) was 76%, implying a substantial contribution of genetic factors to the cause of neural tube defects. Complex segregation analysis was applied in an attempt to discriminate between the hypothesis of a single locus and that of quasi-continuity under multifactorial inheritance. The results excluded the hypothesis of dominant inheritance with full penetrance. The hypothesis of the two-allele model (at a single locus) fit the data with the same degree of exactness; however, for all hypotheses the estimated penetrance was low, and the phenocopy frequency was high. Less accurate conformity was observed for the multifactorial hypothesis. In view of very low penetrance and high frequency of phenocopies in single locus hypotheses and the finding that empirical data gave better support to the multifactorial model, the differences in chi 2 values should not be viewed as sufficient to discriminate between single locus and multifactorial models. The recurrence risks, assessed in the complex segregation analysis, showed an increase together with the growing number (r) of affected children. For constant r the recurrence risks decreased in successive pregnancies. Although discrimination between the mendelian and multifactorial inheritance models was incomplete, the risk values obtained can be employed in genetic counseling.

Anencephaly↗

PubMed1979

Is juvenile diabetes determined by a single gene closely linked to HLA?

The transmission behavior of insulin-dependent juvenile diabetes mellitus (JDM) has been studied with respect to its frequency in the relatives of JDM probands and its possible linkage to the HLA complex. Mathematical analysis shows that under a single locus hypothesis a very restricted range of incidence rates is possible in the full siblings of probands once the concordance rate in monozygotic (MZ) twins is specified. Specifically, for a given population prevalence of the disease, high concordance rates in MZ twins require high incidence rates in siblings, and low rates require low incidence rates, if a single locus model is th be valid. Moreover, if these rates do conform to a single locus model, then they give additional information about possible linkage between the purported JDM susceptibility gene and the HLA complex. By using observations on the identity by descent scores at the HLA locus of sibling pairs, both of whom are affected with JDM, it is shown that tight linkage of a disease susceptibility locus is possible only when the MZ twin and sibling incidence rates are low, whereas high rates support loose linkage. If the single locus model is rejected, then an alternative hypothesis, involving epistasis between a JDM susceptibility locus and genes in (or close to) the HLA complex can be suggested as a mechanism whereby JDM would appear to be linked to HLA within families while maintaining an association with HLA at the population level.

Diabetes Mellitus, Type 1↗