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PubMed2001

A transmission/disequilibrium test that allows for genotyping errors in the analysis of single-nucleotide polymorphism data.

The present study assesses the effects of genotyping errors on the type I error rate of a particular transmission/disequilibrium test (TDT(std)), which assumes that data are errorless, and introduces a new transmission/disequilibrium test (TDT(ae)) that allows for random genotyping errors. We evaluate the type I error rate and power of the TDT(ae) under a variety of simulations and perform a power comparison between the TDT(std) and the TDT(ae), for errorless data. Both the TDT(std) and the TDT(ae) statistics are computed as two times a log-likelihood difference, and both are asymptotically distributed as chi(2) with 1 df. Genotype data for trios are simulated under a null hypothesis and under an alternative (power) hypothesis. For each simulation, errors are introduced randomly via a computer algorithm with different probabilities (called "allelic error rates"). The TDT(std) statistic is computed on all trios that show Mendelian consistency, whereas the TDT(ae) statistic is computed on all trios. The results indicate that TDT(std) shows a significant increase in type I error when applied to data in which inconsistent trios are removed. This type I error increases both with an increase in sample size and with an increase in the allelic error rates. TDT(ae) always maintains correct type I error rates for the simulations considered. Factors affecting the power of the TDT(ae) are discussed. Finally, the power of TDT(std) is at least that of TDT(ae) for simulations with errorless data. Because data are rarely error free, we recommend that researchers use methods, such as the TDT(ae), that allow for errors in genotype data.

Alleles↗
PubMed1993

Segregation analysis of random amplified polymorphic DNA (RAPD) markers in Picea abies Karst.

The reliability of arbitrarily primed amplification products was tested. The segregation analysis of 266 amplification products obtained using 17 different 10-mer oligonucleotides in 34 megagametophytes from a single tree of Picea abies was carried out. Fifty-four out of the 165 variable bands fit the 1:1 segregation ratio expected for Mendelian traits. The segregation ratio of a subset of six RAPD markers in five other individuals from the same population confirmed their genetic nature. Our results strengthen the evidence previously reported that RAPDs markers can be considered Mendelian traits useful in the detection of genetic variability among both different individuals and populations.

Base Sequence↗
PubMed2002

Probability of detection of genotyping errors and mutations as inheritance inconsistencies in nuclear-family data.

Gene-mapping studies routinely rely on checking for Mendelian transmission of marker alleles in a pedigree, as a means of screening for genotyping errors and mutations, with the implicit assumption that, if a pedigree is consistent with Mendel's laws of inheritance, then there are no genotyping errors. However, the occurrence of inheritance inconsistencies alone is an inadequate measure of the number of genotyping errors, since the rate of occurrence depends on the number and relationships of genotyped pedigree members, the type of errors, and the distribution of marker-allele frequencies. In this article, we calculate the expected probability of detection of a genotyping error or mutation as an inheritance inconsistency in nuclear-family data, as a function of both the number of genotyped parents and offspring and the marker-allele frequency distribution. Through computer simulation, we explore the sensitivity of our analytic calculations to the underlying error model. Under a random-allele-error model, we find that detection rates are 51%-77% for multiallelic markers and 13%-75% for biallelic markers; detection rates are generally lower when the error occurs in a parent than in an offspring, unless a large number of offspring are genotyped. Errors are especially difficult to detect for biallelic markers with equally frequent alleles, even when both parents are genotyped; in this case, the maximum detection rate is 34% for four-person nuclear families. Error detection in families in which parents are not genotyped is limited, even with multiallelic markers. Given these results, we recommend that additional error checking (e.g., on the basis of multipoint analysis) be performed, beyond routine checking for Mendelian consistency. Furthermore, our results permit assessment of the plausibility of an observed number of inheritance inconsistencies for a family, allowing the detection of likely pedigree-rather than genotyping-errors in the early stages of a genome scan. Such early assessments are valuable in either the targeting of families for resampling or discontinued genotyping.

Alleles↗
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↗
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↗
PubMed2000

Evidence for major genes influencing pulmonary function in the NHLBI family heart study.

Segregation analysis was performed on the pulmonary measures forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the ratio of FEV1/FVC in 455 randomly ascertained families from the NHLBI Family Heart Study (FHS). Gender specific standardized residuals were used as the phenotypic variable in both familial correlation and segregation analyses. These residuals represented adjustments for the effects of age, age(2), age(3), Body Mass Index (BMI, kg/m(2)), height, the ratio of waist to hip measurements (WHR), the presence of coronary heart disease, smoking history, and pack years for current smokers. Sibling correlations were not different from parent-offspring correlations for all three traits, and heritability estimates for FEV1, FVC, and the FEV1/FVC ratio were 0. 515, 0.540, and 0.449, respectively. Segregation analysis of FEV1, a trait that measures airflow, indicated that a dominant major gene best fits the data, although a residual familial correlation supports the presence of an additional polygenic or common environmental component. For FVC, a trait that measures lung volume, alternative models could not be statistically differentiated, but the transmission probabilities do not support a Mendelian major gene. The best model for FEV1/FVC ratio is a non-Mendelian codominant model, perhaps due to the mixing of the individual underlying distributions influencing airflow and lung volume. These results support the hypothesis that complex relationships exist for lung function traits and that multiple genes and environmental factors influence lung function.

Anthropometry↗
PubMed1965

GENETIC CONTROL IN GUINEA PIGS OF IMMUNE RESPONSE TO CONJUGATES OF HAPTENS AND POLY-L-LYSINE.

Random-bred Hartley strain guinea pigs which do not respond immunologically to conjugates of hapten and poly-L-lysine mere mated with heterozygous guinea pigs which do. These responders were considered heterozygous for this trait since their mating resulted in at least one nonresponder offspring. Of 31 offspring from 10 breeding pairs (nonresponder x heterozygous responder) 14 were responders. There was no evidence that this trait is sex-linked. This finding confirms the view that, in guinea pigs, development of an immune response to the aforementioned conjugates is a genetically transmitted autosomal, unigenic Mendelian dominant trait.

Animals↗
PubMed1993

Artifactual variation in randomly amplified polymorphic DNA banding patterns.

Randomly amplified polymorphic DNA (RAPD) and arbitrarily primed PCR (AP-PCR) represent novel DNA polymorphism assays that involve the amplification of random DNA segments using PCR and oligonucleotide primers of arbitrary sequence. Products defining the polymorphisms exhibit Mendelian inheritance and thus possess tremendous potential utility as genetic markers in a diverse array of scientific disciplines. Amplification profiles for specific oligonucleotide primers are highly dependent on the specific conditions of the reaction; banding patterns may thus vary extensively because of inconsistencies in a number of reaction parameters. Artifactual variation represents a potential problem in surveys of genetic variation in natural populations and must be discriminated from true polymorphism for the applications of RAPD to be both accurate and reliable.

Base Sequence↗
PubMed1996

Segregation analysis of two lung function indices in a random sample of young families: the Humboldt Family Study.

The Humboldt Family Study was conducted in the town of Humboldt, Saskatchewan, in 1993. Familial correlations and segregation analyses of lung function were carried out in 799 individuals in 214 nuclear families that included 214 fathers, 214 mothers, and 371 children. Forced expiratory volume in 1 second (FEV1) and maximal mid-expiratory flow rate (MMFR) were first regressed on age, height, weight, and their quadratic and cubic terms as well as on smoking status in four groups separately (mothers, fathers, daughters, and sons), with terms significant at the 0.10 level being retained. Residual phenotypes were standardized within the four groups. Class D regressive models were used to perform familial correlations and segregation analyses. For both FEV1 and MMFR, father-mother correlations were not significantly different from zero, and mother-offspring, father-offspring, and sibling-sibling correlations showed no statistically significant difference from each other. Based on the "polygenic" models, the estimated intraclass correlation is 0.132 (+/- 0.035) for FEV1 and 0.171 (+/- 0.039) for MMFR, and the narrow-sense heritability is 0.264 for FEV1 and 0.342 for MMFR. Segregation analysis shows that the "mixed" model with both single locus and polygenic components had a better fit for FEV1 than single-locus or polygenic only models. However, the model which included a nontransmitted environmental factor [tau(AA) = tau(AB) = tau(BB) = qA] and polygenic loci had a better fit than the Mendelian model [tau(AA) = 1, tau(AB) = 1/2, tau(BB) = 0] [Akaike's information criterion (AIC) = 2219.47 vs. AIC = 2222.14]. For MMFR, the Mendelian "mixed" model gave a nonsignificant improvement in loge likelihood compared to the simple polygenic model. Comparison of the single-locus model and Mendelian "mixed" model shows no difference in fitting the data. This study suggests that FEV1 and MMFR are controlled by many loci with no major effects and/or common environmental factors.

Adolescent↗
PubMed2026

Multivariate, Multi-Omic Analysis in 799,429 Individuals Identifies 134 Loci Associated with Somatoform Traits.

INTRODUCTION: Somatoform traits (e.g., health anxiety, somatic preoccupation, and bodily distress symptoms) are prevalent and pose challenges to clinical practice. Understanding their genetic basis could improve diagnostic and therapeutic approaches. METHODS: Using available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multi-omic analysis of four somatoform traits - fatigue, irritable bowel syndrome, pain intensity, and health satisfaction - in 799,429 individuals genetically similar to European reference panels. RESULTS: The GWAS identified 134 loci associated with a somatoform common factor, including 44 loci not significant in the input GWAS and 8 novel loci for somatoform traits. Novel loci were mechanistically informative, mapping to the DNM1 gene and the protocadherin gene cluster (PCDHA1-4), which are involved in nociceptor sensitization and synaptogenesis, respectively. Gene-property analyses highlighted an enrichment of genes involved in synaptic transmission and enriched expression in 11 brain tissues and the pituitary. Across two brain transcriptomic datasets, we identified 16 high-confidence genes whose expression in enriched tissues was associated with somatoform traits. There was substantial polygenic overlap (76-83%) between the somatoform and externalizing, internalizing, and general psychopathology factors. Somatoform polygenic scores were associated with obesity, type 2 diabetes, and tobacco use disorder in independent biobanks. Drug repurposing analyses suggested potential therapeutic targets, including MEK inhibitors, while Mendelian randomization analyses indicated potentially protective effects of gut microbiota. DISCUSSION: Consistent with emerging medical and genetic knowledge, somatoform traits have a shared etiology and considerable polygenic overlap with psychopathology. The biological insights from drug repurposing and Mendelian randomization analyses could provide promising avenues for treatment development.

Genetics↗
PubMed2003

Detection of universal variable fragments as markers for genetic studies. A novel technology for DNA fingerprinting.

A novel DNA technology enables the detection of universal variable fragments (UVF), thus revealing genetic variation without a priori sequence information. The detection of UVF markers is based on two amplifications of genomic DNA with the polymerase chain reaction. In the first amplification, two short oligonucleotide primers produce a large number of fragments. One primer is based on a microsatellite sequence, whereas the second primer can have any sequence. In the second amplification, the length of the primers is increased in order to decrease the number of amplicons. This enables the selection of polymorphic fragments. Restriction digestion can be used to further increase the number of polymorphisms. Until now, we have demonstrated UVF in several different species. In addition, with the present study we have contributed to the linkage map of the rabbit by localizing 11 UVF markers on different linkage groups. Mendelian inheritance was shown in this linkage study through a backcross of two inbred rabbit strains. The power of the UVF technique is based on the selection for microsatellite variation in combination with the detection of single-nucleotide polymorphisms. UVF thus offers the possibility of increasing the clustering of markers and localizing genes in species for which sequence information is either not present or only scarcely present.

Animals↗
PubMed1995

Evidence for a major gene for cortical cataract.

PURPOSE: To examine the possible presence of a major gene determining susceptibility to cortical cataract. METHODS: The percentage of the lens area involved with cortical opacity, summed over both eyes, was evaluated in 1275 individuals from the Beaver Dam Eye Study. After adjusting for the effects of age and sex, these measures of cortical cataract were subjected to sibling correlational analysis, commingling analysis, and segregation analysis. The Box and Cox power transformation was applied to the data for the commingling and segregation analyses. Using regressive models, four modes of transmission were examined, and under each mode three hypotheses and a general model were fitted by maximum likelihood and compared. RESULTS: Sister-sister and brother-brother correlations of the adjusted measures of cortical cataract are significant and similar; the brother-sister correlation is not significantly different either from these correlations or from zero. Two commingled distributions give the best fit to the data, especially after power transformation. Under each of four modes of transmission, the hypothesis that best fits the data is one in which there are only two distributions (and, hence, dominance under mendelian transmission), the power transformation parameter is fixed at the estimate obtained from commingling analysis, and there is residual sibling correlation. The data thus suggest the existence of a major effect for cortical cataract. Random environmental influences can be rejected as a cause of this major effect. Our analysis indicates the existence of a significant effect of sex on the residual variance. Allowing for this, the data suggest transmission of a single major gene, though this may not be the sole cause of the commingled distributions. CONCLUSIONS: Assuming a common variance for the two sexes, a single major gene can account for 58% of the variability of age- and sex-adjusted measures of cortical cataract. With the variance sex dependent, a major gene can account for 75% and 45% of the total variability among males and females, respectively.

Adult↗
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↗
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↗
PubMed1995

Genetic mapping and non-Mendelian segregation of mating type loci in the oomycete, Phytophthora infestans.

DNA markers linked to the determinants of mating type in the oomycete, Phytophthora infestans, were identified and used to address the genetic basis of heterothallism in the normally diploid fungus. Thirteen loci linked to the A1 and A2 mating types were initially identified by bulked segregant analysis using random amplified polymorphic DNA markers (RAPDs) and subsequently scored in three crosses polymorphisms (SSCP), cleaved amplified polymorphisms (CAPS), or allele-specific polymerase chain reaction markers (AS-PCR). All DNA markers mapped to a single region, consistent with a single locus determining both mating types. Long-range restriction mapping also demonstrated the linkage of the markers to one region and delimited the mating type locus to a 100-kb region. The interval containing the mating type locus displayed non-Mendelian segregation as only two of the four expected genotypes were detected in progeny. This is consistent with a system of balance lethal loci near the mating type locus. A model for mating type determination is presented in which the balanced lethals exclude form progeny those with potentially conflicting combinations of mating type alleles, such as those simultaneously expressing A1 and A2 functions.

Base Sequence↗
PubMed1986

A DNA probe detecting multiple haplotypes of the human Y chromosome.

We have characterized a DNA probe (49f) that detects about 15 Y-specific TaqI bands corresponding to a low-copy number sequence. Five of these bands, each representing a single DNA fragment, can either be present, absent, or variable in length. Familial segregation studies have shown that the variations of these fragments are inherited in a Mendelian fashion and strictly Y-linked. A survey of 44 male individuals indicated that the five variable TaqI fragments detected by probe 49f can be considered as five independent allelic series. Each series represents the different and mutually exclusive allelic forms observed for a single DNA fragment. A total of 16 haplotypes, each defined by a different combination of the various forms of each of these five restriction fragment length polymorphisms, were observed among the 44 scored individuals. These TaqI restriction polymorphisms are not observed with other restriction digests and have therefore been attributed to point mutations. The five polymorphic fragments map to Yq11, a region that does not recombine with the X chromosome and are therefore not redistributed. This implies that an apparently independent reassortment of one of these series with respect to the others can be explained only on the basis of mutations that occurred several times (or reverted) during evolution of the Y chromosome. However, an examination of the different combinations of two or more allelic series suggests that some alleles are not randomly distributed and raises the possibility of establishing a genealogy of the human Y chromosome.

Alleles↗
PubMed1999

Cigarette smoking as a triggering factor of hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa is a chronic inflammatory skin disease involving the axillary, inguinal and anogenital regions and sometimes, in addition, the submammary or sacral areas. The etiology of this condition is unknown. OBJECTIVE: A matched-pair case-control study was performed to evaluate the influence of smoking habits on the manifestation of this disease. METHODS: Patients who had received surgical treatment for hidradenitis suppurativa in two dermatological centers completed a questionnaire dealing with family history, course of the disease and smoking habits. To form a randomized matched-pair control group, an equal number of patients admitted for various other skin diseases such as atopic dermatitis, varicose veins, skin tattoos, alopecia areata or melanoma was matched for sex and age and evaluated for smoking habits. Statistical analysis was performed by use of several chi2 tests in a cross-table setting. Moreover, a comparison to the expected smoking prevalence in Germany based on national statistics was performed. RESULTS: Out of 84 patients treated for hidradenitis suppurativa, 63 subjects (27 men, 36 women) completed the questionnaire. The rate of active cigarette smokers was 88.9% (56 patients), whereas 4 subjects (6.4%) had never smoked. 3 patients (4.8%) stated to be ex-smokers, but 2 of these had quit smoking only recently and after onset of the disease. The rate of smokers in the matched-pair control group was 46%. The significantly higher proportion of active smokers among patients with hidradenitis suppurativa can be expressed by an odds ratio of 9.4, the calculated 95% confidence interval was 3.7-23.7 (p < 0.001). The expected smoking prevalence in Germany was 26.7% according to national statistics. 73% of our patients had no family history of hidradenitis suppurativa whereas 27% reported at least one affected first-degree relative. CONCLUSION: From the exceedingly high rate of smokers among patients with this condition we conclude that cigarette smoking is a major triggering factor of hidradenitis suppurativa. Remarkably, the disease can be categorized as a smoking sequel that is neither of vascular nor neoplastic nature. Because familial occurrence was rather rarely reported, and because an environmental factor in the form of cigarette smoking appears to be of crucial importance to trigger the disease, we assume that the genetic basis of hidradenitis suppurativa is polygenic rather than mendelian. Smoking cessation should be encouraged particularly in patients with hidradenitis suppurativa although it is unknown whether this improves the course of the disease.

Adolescent↗
PubMed1996

The causes of essential hypertension.

1. Confusion between the criteria for defining and diagnosing hypertension may have misled the search for the causes of hypertension. 2. The systematic approach of molecular genetics appears to offer the best chance of explaining hypertension, but the attractions are partly offset by the large numbers required, and unproven record of the genetic techniques in finding functional mutations in complex human disorders. 3. Part of the evidence for the polygenic nature of essential hypertension derives from the variable response to a large number of different anti-hypertensive agents. Systematic investigation of this variability may provide a basis for dividing patients into genetically more homogeneous sub-groups, within which smaller numbers will be required to detect the genes responsible for the susceptibility to hypertension. 4. The proportion of hypertensive patients with affected siblings has been studied in 6000 patients from Addenbrookes Hospital and local general practices. A recurrence risk for hypertension of approximately 3.5 was found. 5. Approximately two-thirds of patients have no known affected siblings. The next largest group, about one third, is patients whose siblings are all hypertensive. In a small group, < 10% of all patients, half the siblings are hypertensive. 6. We conclude from these surprising findings that hypertension is not a continuous, multifactorial part of the normal blood pressure distribution. They suggest that several more single-gene disorders causing hypertension will be found. The sibships where all members are hypertensive are inconsistent with the segregation of Mendelian genetics and suggest the selection of some genes linked to hypertension at the time of gamete maturation.

Genetic Predisposition to Disease↗