Biomedical subjects
Publications and source records attributed to M Bahlo.
We present two Web interfaces that generate genetic maps for given sets of human or mouse microsatellite markers. The genetic maps are generated from available databases using linear interpolation of physical map distances to infer genetic map positions for missing markers in these databases.
BACKGROUND: Previous studies have suggested a strong genetic component to osteoarthritis (OA), especially that of the hand, and three linkage studies have suggested the existence of susceptibility loci in disparate regions of chromosome 2q. OBJECTIVE: To examine for linkage to 2q in a Tasmanian population of women and men with familial hand OA. METHODS: Hand OA (distal interphalangeal, carpometacarpal, and Heberden's nodes) was assessed by a combination of hand photographs and radiographs. A non-parametric linkage (NPL) analysis was performed on chromosome 2q of 69 members in 22 families with severe distal interphalangeal joint OA using Genehunter. A quantitative trait linkage analysis of a larger group of 456 members in 68 families was also performed using SOLAR. RESULTS: The maximum non-parametric linkage score was 1.05 (p=0.15) at marker IL1R1, close to the centromere. All components of hand OA scores had significant heritability in this dataset (28%-35%, all p<0.001). Despite this, the quantitative trait analysis (after adjustment for age and, where appropriate, sex) yielded maximum LOD scores of 0.90 for Heberden's nodes (both sexes combined), and 1.19 for carpometacarpal OA score (women only). CONCLUSIONS: These results do not provide confirmation of linkage on chromosome 2q in the larger white population with hand OA. They suggest that there are regional variations in the genetic cause of hand OA and that other loci not on 2q may be important in this disease.
In this paper a new form of the solution for the Laplace transform and moments of the distribution of the waiting time for two genes to coalescence is presented. The two genes are sampled from a subdivided population where migration rates between populations are constant in time. Equal subpopulation size is not assumed. For the special case of an island model with equal migration rates between islands, the Laplace transform of the coalescence time and the first and second moments are found explicitly. The new form of the solutions allows numerical calculation. The connection of how the results relate to a panmictic population when migration rates are large is illustrated using strong-migration-limit theory.
Susceptibility to the development of asthma and other atopic diseases is known to have a genetic component. To date, several studies have linked chromosome 5q31 to asthma and atopy in human beings. This region harbors a cluster of cytokine and growth factor genes, IL-4 presenting as a prime atopy candidate gene, inasmuch as it plays a pivotal role in the atopy pathway. Our approach was to identify polymorphisms within the promoter regions of IL-4 and test their association with atopic eczema. Polymorphisms were typed in a cohort of 76 small nuclear families and 25 triads with childhood atopic eczema. The genotypes were used to test for linkage in the presence of association with atopic eczema. A new polymorphism, -34C/T, was identified and studied with a known polymorphism, -590C/T. On its own, each polymorphism showed no association with atopic eczema. The 2 polymorphisms were used to generate haplotypes, and a significant result was found for the -590C/-34C haplotype. However, after Bonferroni correction for multiple testing, the association became nonsignificant. Neither polymorphism predisposes to early-onset atopic eczema by itself, but suggestive linkage was found for the -590C/-34C haplotype in this study.
Although it is clear that errors in genotyping data can lead to severe errors in linkage analysis, there is as yet no consensus strategy for identification of genotyping errors. Strategies include comparison of duplicate samples, independent calling of alleles, and Mendelian-inheritance-error checking. This study aimed to develop a better understanding of error types associated with microsatellite genotyping, as a first step toward development of a rational error-detection strategy. Two microsatellite marker sets (a commercial genomewide set and a custom-designed fine-resolution mapping set) were used to generate 118,420 and 22,500 initial genotypes and 10,088 and 8,328 duplicates, respectively. Mendelian-inheritance errors were identified by PedManager software, and concordance was determined for the duplicate samples. Concordance checking identifies only human errors, whereas Mendelian-inheritance-error checking is capable of detection of additional errors, such as mutations and null alleles. Neither strategy is able to detect all errors. Inheritance checking of the commercial marker data identified that the results contained 0.13% human errors and 0.12% other errors (0.25% total error), whereas concordance checking found 0.16% human errors. Similarly, Mendelian-inheritance-error checking of the custom-set data identified 1.37% errors, compared with 2.38% human errors identified by concordance checking. A greater variety of error types were detected by Mendelian-inheritance-error checking than by duplication of samples or by independent reanalysis of gels. These data suggest that Mendelian-inheritance-error checking is a worthwhile strategy for both types of genotyping data, whereas fine-mapping studies benefit more from concordance checking than do studies using commercial marker data. Maximization of error identification increases the likelihood of linkage when complex diseases are analyzed.
This paper studies gene trees in subdivided populations which are constructed as perfect phylogenies from the pattern of mutations in a sample of DNA sequences and presents a new recursion for the probability distribution of such gene trees. The underlying evolutionary model is the coalescent process in a subdivided population. The infinitely-many-sites model of mutation is assumed. Ancestral inference questions that are discussed are maximum likelihood estimation of migration and mutation rates; detection of population growth by likelihood techniques; determining the distribution of the time to the most recent common ancestor of a sample of sequences; determining the distribution of the age of the mutations on the gene tree; determining in which subpopulation the most recent common ancestor of all the sequences was; determining subpopulation ancestors, where they were, and times to them; and determining in which subpopulations mutations occurred. A computational technique of Griffiths and Tavaré used is a computer intensive Markov chain simulation, which simulates gene trees conditional on their topology implied by the mutation pattern in the sample of DNA sequences. The software GENETREE, which implements these ancestral inference techniques, is available.
INTRODUCTION: Multiple sclerosis (MS) is the most common genetic disease of the nervous system with onset usually in young adulthood. Four genome-wide searches in different Caucasian populations for MS susceptibility loci have been performed, but none reported any linkage at a level that would be regarded as significant according to current criteria. Significant linkage of MS to allelic variants of the major histocompatibility (MHC) locus on chromosome 6p21 has been established although its overall contribution to MS susceptibility has proven difficult to quantify. The objective of this review is not only to provide the reader with an update of MS genetics research, but also to provide a basic knowledge of the techniques being employed to map MS susceptibility genes. The different methodologies are discussed, and specific studies are reviewed in context. METHODS: This review is based on findings from original articles, however, the results of recent candidate gene studies are intended to update previous review articles. RESULTS: There remains no concrete non-MHC locus for MS, although there are enough findings of sufficient interest to warrant further investigation and optimism. Stratification of genome scan data based on MHC class II suggests that it interacts differentially with non-MHC loci and that it contributes moderately to disease susceptibility. Candidate gene studies have continued to return negative and ambiguous results, and follow-up fine mapping of suggestive linkages from the UK genome scan has proven unsuccessful in identifying significant linkages. Genetic analysis of crosses between mouse strains that are differentially susceptible to experimental allergic encephalomyelitis (EAE) has yielded linkages corresponding to putative MS susceptibility loci. However, recent successes in transgenic mice may provide an alternative to EAE, regarded by some as a poor model of MS. CONCLUSION: The first whole genome search for a common human disease was performed over five years ago, and it is now clear, from the lack success in this field, that the genetic complexity of these traits has been underestimated. The genome-wide searches for MS susceptibility genes have suffered from insufficient statistical power, which has probably been compounded by disease and genetic heterogeneity. Studies in isolated populations and better laboratory and clinical definitions of disease are both steps in the right direction to solving these problems. Not withstanding the negative effects of genetic heterogeneity, pooling of resources for meta-analyses may provide the increase in statistical power required for detection of loci that exert a moderate or small effect on disease predisposition.
Gene conversions and mutations affect the number of different alleles in a population as it evolves. Here these effects are studied for a sample of r individuals represented by one chromosome, each with n loci. The long-term evolution of the sample is modelled with the coalescent. Gene conversions can only occur within a chromosome between a pair of loci. Recombination is not included in the model. Mutations occur according to the infinitely many alleles model. A new expression for the expected number of alleles is derived using the Backward time approach. It is then possible to simulate the expectation for various sample paths. The new estimator is computationally inexpensive and has a lower variance than the conventional, forward time, approximation by simulation.
BACKGROUND: CA 125, known as a marker for ovarian cancer with hypothetical but hitherto uncharacterized biologic functions, was reported to be elevated in some not-well-defined benign conditions. There are no reports on fluctuations of CA 125 related to cardiac function, especially the failing heart and neurohumoral factors such as norepinephrine or atrial natriuretic peptid/e. METHODS AND RESULTS: CA 125 blood levels were determined in patients with heart failure before and after heart transplantation (HTx). In 71 patients, parallel determinations of norepinephrine, atrial natriuretic peptide, pulmonary capillary wedge pressure, and right atrial filling pressure were done. CA 125 levels also were prospectively studied in patients with heart failure with stabilization (n = 25) or worsening of the clinical status (n = 9) and after HTx (n = 25). Parallel determinations of the tumor markers CEA, CA 199, CA 153, TPS, and TPA were also done. The results were grouped according to the clinical status (New York Heart Association class) of the patients. CA 125 was significantly correlated with neurohormones and filling pressures. Follow-up investigations revealed a decrease of CA 125 levels after HTx (401 +/- 259 U/L vs 33 +/- 22 U/L, P <.001, n = 25) or stabilization (429 +/- 188 U/L vs 78 +/- 35 U/L, P <.001, n = 25) and an increase during worsening of heart failure (42 +/- 25 U/L vs 89 +/- 32 U/L, P <.01, n = 9). In 4 patients after HTx, unexpected death was preceded by rising CA 125 levels. CEA, CA 199, CA 153, TPS, or TPA did not correlate with heart failure status or clinical events. CONCLUSIONS: CA 125 is a marker of the clinical and hemodynamic status and the course of patients with heart failure before and after heart transplantation. The determination of CA 125 serum levels may be an additional tool in the management of these patients. In patients with cancer, these "nonspecific" changes must be considered when CA 125 levels are determined. Whether CA 125 has a specific biologic role in heart failure deserves further studies.
BACKGROUND: Because the risk of developing malignant tumors after heart transplantation is approximately 100-fold higher, methods for rapid diagnosis must be developed to allow early and aggressive treatment in these patients. Although tumor markers have been used frequently for surveying already detected cancer, we studied their value in screening for tumors in heart transplant patients. METHODS: The levels of the tumor markers CEA, CA19-9, CA125, CA72-4, TPA, TPS, and CYFRA 21-1 were determined prospectively in 3-month intervals in 91 heart transplant patients between 1993 and 1998. RESULTS: In eight patients a definite diagnosis of cancer was made during the marker survey (mean observation time 2.85 +/- 1.3 years), including bronchogenic carcinoma in six, renal carcinoma in one, and colon cancer in one. All patients with bronchogenic carcinoma were smokers. The markers had a sensitivity below 60% to detect cancer. Given a 2-fold cutoff level (10 ng/mL), the CEA was the only marker with sufficient specificity (93.8%, only one false-positive result). Two patients were symptom-free even though they had elevated CEA levels. In one of those patients, disseminated intractable cancer was diagnosed at first evaluation, whereas no tumor was found in the other case at first evaluation. Subsequently, by means of fluorodeoxyglucose positron emission tomography, a hypermetabolic region was found in the right upper mediastinum. Control computed tomographic scan 4 weeks after the first investigation showed disseminated intractable disease also in this patient. Another heart transplant patient with colon cancer showed a normalization of the CEA after hemicolectomy and an increase in the CEA when liver dissemination developed. There was a relationship between cardiac death and CA125 and TPS in some heart transplant patients. CONCLUSIONS: We conclude that the CEA is the only tumor marker with adequate sensitivity and specificity to detect subclinical malignancies in the follow-up of heart transplant patients. However, because of several limitations (limited diagnostic and therapeutic possibilities and enormous costs), we cannot recommend screening by tumor markers on a regular basis. Because of the elevated risk of cancer in patients who had organ transplantation, further prophylactic measures, especially smoking cessation programs, must be developed. Once a malignancy is diagnosed, tumor markers can help target clinical decisions. Additionally, nonspecific increases in CA125 and TPS levels might be related to nonmalignant circulatory disturbances and cardiac death.
Formulae for the expectation and variance of the number of segregating and homogeneous sites in a sample of two chromosomes are found. The model includes gene conversion and infinitely-many-alleles mutation in a coalescent framework. The corresponding infinitely-many-sites model limits are also found. The formulae for the expectation are extended to any sample size. Comparisons are drawn between the pure mutation model and the model where gene conversion has been added.
Based on previously published experimental studies in nude mice indicating that rTNF-alpha as well as mitomycin C are able to induce significant growth inhibition of xenotransplants of gastrointestinal and pancreatic carcinomas we have investigated the antitumor effects of rTNF-alpha (0.8 mg/kg daily for 21 days) and mitomycin C (2.4 mg/kg once weekly, day 1, 7, 14) as single drugs and in combination (0.8 + 2.4) in nude mice bearing xenografts of 4 human pancreatic carcinomas and 1 colorectal cancer. Serum CA 19-9 was measured additionally to tumor growth rate. The results demonstrate that combined treatment is more effective compared to rTNF-alpha and mitomycin C alone. Combined therapy resulted in a significant inhibition of tumor growth in 3 of 5 xenografts and in decrease of tumor volume to less than 50% of the initial values in 2 of 5 tumors. The results support the concept that combinations of cytokines with cytostatics might be of value for treatment of gastrointestinal and pancreatic cancer in vivo.
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Ten xenotransplants of human gastrointestinal carcinomas (eight human pancreatic carcinomas) were assayed for their sensitivity to human rIFN-gamma and human rTNF-alpha in nude mice. Both substances demonstrated a dose and route dependent antitumoral activity in principle. However, the extent of response varied distinctly between the tested xenografts. rTNF-alpha was clearly superior to rIFN-gamma at systemic application of comparable doses (0.8 mg/kg/d). Intramural administration of both cytokines could cause cytotoxic effects and was significantly more effective than systemic administration that predominantly resulted in antiproliferation. Growth inhibition of rIFN-gamma or rTNF-alpha alone could be clearly enhanced by combining both cytokines. In addition, the results suggest: the possibility to enhance the effects of rIFN-gamma alone also by combination with nIL 2, as well as a decrease of the effects of rTNF-alpha with time of therapy.
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In order to investigate whether combinations of monoclonal antibodies (MAbs) allow a more sensitive and valid localisation of tumors by immunoscintigraphy compared to the application of single MAbs we injected 3.7 MBq/animal of various 131I-labelled MAbs (anti-CA 19-9, -CA 125, -CEA, BW 494/32, 431/31) or equivalent combinations thereof into NuNu-Balb-C mice bearing xenografts of human gastrointestinal tumors. In addition, "dose response curves" were calculated in order to evaluate the results for different total doses. As parameters we mainly used quality of the scans, fractional uptake of injected dose and tumor/blood or tumor/organ ratios. The results do not support the concept that "cocktails" of MAbs improve the results of immunoscintigraphy. In contrast, a single MAb should be used for clinical immunoscintigraphy, preferably the most appropriate one according to the results of serum determinations of the corresponding tumor-associated antigens or of immunohistochemistry. Cocktails or consecutive applications of different MAbs for immunoscintigraphy should be restricted to cases without dominant tumor-associated antigen and corresponding MAb, respectively, and to patients in whom a first trial with a first single MAb failed.
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