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PubMedDate not supplied

GenePath: a system for inference of genetic networks and proposal of genetic experiments.

A genetic network is a formalism that is often used in biology to represent causalities and reason about biological phenomena related to genetic regulation. We present GenePath, a computer-based system that supports the inference of genetic networks from a set of genetic experiments. Implemented in Prolog, GenePath uses abductive inference to elucidate network constraints based on background knowledge and experimental results. Additionally, it can propose genetic experiments that may further refine the discovered network and establish relations between genes that could not be related based on the original experimental data. We illustrate GenePath's approach and utility on analysis of data on aggregation and sporulation of the soil amoeba Dictyostelium discoideum.

Animals↗

PubMed2002

Analysis of several hundred genetic polymorphisms may improve assessment of the individual genetic burden for coronary artery disease.

BACKGROUND: Single polymorphisms of different genes have been associated with coronary artery disease (CAD). The aim of this study was to evaluate the benefit of analyzing multiple genetic polymorphisms as a compound unit to assess the individual genetic burden for CAD. METHODS AND RESULTS: The study population consisted of 100 case patients with, and 100 control patients without, angiographically proven CAD. The patients were matched for age, sex, and numbers of standard cardiac risk factors. Sixteen different genetic polymorphisms were analyzed using polymerase chain reaction-based technologies. None of these polymorphisms showed a significant difference in the allele frequency between case and control patients. Eight genes with a higher allele frequency in the case group (delta allele frequency >0.05) were defined as risk alleles (RA) and subsequently tested as a compound unit. A risk stratification for 64.5% of all patients was possible when eight genes with their 16 RA were included in the analysis. With more than eight RA per individual, the odds ratio for developing CAD was 3.21 (95% CI 1.77-5.82, P<0.001). However, there was still an overlap in the number of RA in case and control patients. A computer simulation estimated that more than 200 polymorphisms were needed for a reasonable genetic discrimination for patients at risk for CAD. CONCLUSIONS: An increasing number of risk alleles are associated with an elevated risk for CAD. An analysis of multiple polymorphisms, some several hundred, each with a small impact, may allow improved assessment of the individual genetic burden for CAD. Larger studies are needed to prove this hypothesis.

Journal Article↗

PubMedDate not supplied

Genetic diversity of international bovine viral diarrhoea virus (BVDV) isolates: identification of a new BVDV-1 genetic group.

In the last decade, several studies were performed to characterise bovine viral diarrhoea virus (BVDV) isolates and define genetic groups by genotyping. Much data is now available from GenBank, predominantly sequences from the 5' untranslated region (5'-UTR). In order to find out whether genetic grouping of isolates from different countries could be harmonised, 22 new isolates from five countries were analysed in combination with published sequences. Eighteen of these isolates were typed as BVDV genotype 1 (BVDV-1), and one isolate from Argentina and three isolates from Brazil were typed as BVDV-2. BVDV-1 isolates were clustered into five previously defined genetic groups: BVDV-1a, b, d, e and f. Two isolates from Finland and one from Egypt formed a group which was tentatively labelled as BVDV-1j, since statistical support was low. By using a fragment of the Npro gene for typing, we found that these isolates fall into the same group as a deer strain, and are statistically significant. Some Swiss BVDV strains taken from GenBank were found in a new genetic group which was designated as BVDV-1k. The BVDV-2 isolates included in this study seemed to fall into two genetic groups.

Animals↗

PubMed2003

Genetic aspects and genetic epidemiology of parasomnias.

Parasomnias are undesirable phenomena associated with sleep. Many of them run in families, and genetic factors have been long suggested to be involved in their occurrence. This article reviews the present knowledge of the genetics of the major classical behavioral parasomnias as well as present results from genetic epidemiological studies. The level and type of evidence for genetic effects varies much from parasomnia to parasomnia. The genetic factors are best established in enuresis, with several linkages to chromosomal loci, but their functions are not so far known. Environmental causes and gene-environment interactions are most probably also of great importance in the origin of complex traits or disorders such as parasomnias.

Arousal↗

PubMed2003

Genetics of phytate phosphorus bioavailability: heritability and genetic correlations with growth and feed utilization traits in a randombred chicken population.

The current study was undertaken to estimate variance components for phytate P bioavailability (PBA) and the genetic correlations among PBA with growth and feed utilization (or intake) traits in an unselected random mating chicken population. Pedigreed data from 901 Athens-Canadian randombred chickens hatched from 26 sires, 71 dams, and 105 grandparents were used for estimation of genetic parameters. Birds were individually housed in metabolic cages at 4 wk of age and fed a 0.35% P diet. After 3 d of acclimatization, excreta produced for 3 consecutive d were collected and feed consumed (FC) was measured. Individual 4-wk BW and BW gain (BWG) during the 3-d excreta collection period were also measured. Feed conversion ratios (FCR) were calculated. Phytate P bioavailability was estimated from the disappearance of phytate during the passage of feed through the gastrointestinal tract. The restricted maximum likelihood method with the average information matrix algorithm was used for the estimation of variance components. The heritability estimate for PBA was about 0.10. Genetic correlations between PBA and BW, BWG, and FC were moderate and negative, indicating that improving PBA utilization would moderately affect growth. The genetic correlation between PBA and FCR was negligible and suggested that selection for PBA will not adversely affect FCR. The economic implications of genetically modifying poultry to improving phytate P utilization and the subsequent elimination or reduction of the amount of phytase used in poultry diets are yet to be determined.

Animal Nutritional Physiological Phenomena↗

PubMed2025

Multivariate genetic of 2.2 million individuals demonstrate genetic influences on substance use disorders operate via behavioral disinhibition and substance-specific risk.

Ongoing efforts to identify genes involved in substance use disorders (SUDs) often focus on individual disorders despite high rates of co-occurrence with each other and other externalizing traits. Here, we investigate whether incorporating data on other externalizing traits can boost power to detect without sacrificing specificity of SUD genetic signal. We used multivariate genomic analyses and downstream biological annotation and genetic association analyses to explore this question. We found that joint analysis of SUDs and other externalizing traits resulted in increased insights into the neurobiology of broad and substance-specific SUD risk. We found no evidence of loss of specificity for SUD genetic signal but note improvements in our ability to characterize the neurobiology of broad and substance-specific SUD genetic effects. Our findings suggest that genetic risk for SUDs operates largely via pathways shared with other behaviors characterized by behavioral disinhibition, with additional substance-specific risk, and that modeling this shared disposition improves gene discovery.

Journal Article↗

PubMed2000

The genetics of phenotypic plasticity. IX. Genetic architecture, temperature, and sex differences in Drosophila melanogaster.

We examined the genetic architecture of plasticity of thorax and wing length in response to temperature in Drosophila melanogaster. Reaction norms as a function of growth temperature were analyzed in 20 isofemale lines in a natural population collected from Grande Ferrade near Bordeaux (southern France) in two different years. We found evidence for a complex genetic architecture underlying the reaction norms and differences between males and females. Reaction norms were negative quadratics. Genetic correlations were moderately high between traits within environments. Among characteristic values, the magnitudes of genetic correlations varied among traits and sexes. We hypothesized that genetic correlations among environments would decrease as temperatures became more different. This expectation was upheld for only one trait, female thorax length. For males for both traits, the correlations were large for both very similar and very different temperatures. These correlations may constrain the evolution of the shape of the reaction norms. Whether the extent of independence implies specific regulatory genes or only a specific allelic regulation of trait genes can not be decided from our results.

Animals↗

PubMedDate not supplied

Is intracytoplasmic sperm injection itself an indication to perform preimplantation genetic diagnosis (PGD)? About PGD, invasive prenatal diagnosis and genetic sonography.

Intracytoplasmic sperm injection (ICSI) provides the only sufficient treatment to overcome severe forms of male infertility. However, male infertility is linked to several genetic problems as an increased number of chromosomal aberrations, cystic fibrosis transmembrane conductance regulator gene mutations, Y-chromosome microdeletions, and androgen receptor mutations. Therefore, these couples are at a higher risk of transmitting genetic problems to their offspring compared to the general population. A proposed increased number of gonosomal aberrations in the offspring possibly results from the ICSI technique itself. This led in general to a worldwide agreement to counsel those couples to undergo invasive prenatal diagnosis in order to exclude chromosome abnormalities, especially gonosomal aberrations. In this paper the genetic risks of these couples and the possible implications of ICSI itself are discussed. Preimplantation genetic diagnosis may be considered a procedure of choice in these cases, but substantial ethical problems arise when such a screening is sought. An alternative procedure of prenatal diagnosis in these couples seems to be 'genetic sonography', i.e. high-resolution ultrasound with measurement of nuchal translucency at the end of the first trimester, and detailed fetal evaluation at 18-22 weeks of gestation.

Chromosome Aberrations↗

PubMed1998

Genetic and non-genetic subtypes of major depressive disorder.

BACKGROUND: We aimed to examine the hypotheses that major depression is aetiologically heterogeneous consisting of a mixture of 'genetic' and 'non-genetic' forms or, alternatively, a mixture of one form that is 'pure' depression and another that has a familial relationship with alcohol dependency or other disorders. METHOD: One hundred and eleven twin pairs (44 monozygotic, 67 dizygotic) where the proband had received treatment for DSM-IV major depression were ascertained via a hospital register. Family history information on parents and siblings was obtained from the proband, co-twin or both. Diagnoses on parents and siblings were made blind to twin zygosity or concordance and compared in the relatives of concordant versus discordant twins. RESULTS: The lifetime prevalence and age-corrected risk of depression were no different in the relatives of concordant and discordant twin pairs. There was a marginally significant increase in the rate of alcohol abuse or dependence among the relatives of concordant twins but no difference between concordant and discordant pairs in respect of other axis I diagnosis among family members. CONCLUSIONS: The results argue against genetic heterogeneity and suggest that major depression cannot usefully be divided into genetic and non-genetic forms or into 'pure' depression and depression associated with other disorders such as alcohol dependency.

Age of Onset↗

PubMed2001

Genetic and non-genetic factors affecting birth-weight and adult Body Mass Index.

Birthweight affects neonatal mortality and morbidity and has been used as a marker of foetal undernutrition in studies of prenatal effects on adult characteristics. It is potentially influenced by genetic and environmental influences on the mother, and effects of foetal genotype, which is partially derived from the maternal genotype. Interpretations of variation in birthweight and associated characteristics as being due to prenatal environment ignore other possible modes of materno-foetal transmission. Subjects were adult twins recruited through the Australian Twin Registry, aged 17 to 87 years, and the sample comprised 1820 men and 4048 women. Twins reported their own birthweight as part of a health questionnaire. Body Mass Index (BMI) was calculated from self-reports of height and weight. Correlations between co-twins' birthweights were high for both monozygotic (r = 0.77) and dizygotic (r = 0.67) pairs, leading to substantial estimates of shared environmental effects (56% of variance) with significant additive genetic (23%) and non-shared environmental (21%) components. Adult BMI was mainly influenced by genetic factors, both additive (36% of variance) and nonadditive (35%). The correlation between birthweight and BMI was positive, in that heavier babies became on average more obese adults. A bivariate model of birthweight and adult BMI showed significant positive genetic (r(g) = 0.16, p = 0.005) and environmental (r(e) = 0.08, p = 0.000011) correlations. Intra-uterine environmental or perinatal influences shared by cotwins exercise a strong influence on birthweight, but the factors which affect both birthweight and adult BMI are partly genetic and partly non-shared environmental.

Adolescent↗

PubMed2005

[Genetic factors of osteoporosis and fracture and the application of genetic information to the preventive medicine].

Osteoporosis is a common disease caused by multi-factors including genetic factor and environmental and life-style factors. The tailor-made prevention and medicine based on the individual data including genetic information for osteoporosis is expected in the post-genomic era. Genetic susceptibility of osteoporosis has been analyzed by linkage and association study. A number of studies have been shown the association between bone mass and polymorphisms in candidate gene, however, these results have been poor reproducible. Some studies have been reported the interaction between genetic factor and life-style factors on bone mass. Those results have suggested the potential application of genetic information to the prevention of osteoporosis by life-style modification. Further studies should be conducted to develop the practical tailor-made prevention.

Evidence-Based Medicine↗

PubMed1989

[The genetics of rheumatic diseases: genetic basis of the classification of multifactorial diseases].

Examination of the pattern of hereditary predisposition allows a more precise determination of pathogenetic relationships between individual clinical forms and variants of multifactorial diseases (MFD), as well as assessment of the possibilities and approaches to a genetic classification to be made. The construction of genetic classifications is based on the identification of differences in the type of inheritance, the study of the progeny in families where both parents have the same or different forms of the disease, the results of the marker adhesion test, and the genetic correlation coefficients. The study has made use of some clinical forms of rheumatic diseases, whose relationships are a subject of controversy among the clinicians, as splitting phenotypes. Segregation analysis of the selected clinical forms of rheumatic diseases and genetic correlation coefficients obtained within the framework of a quasi-continuous model provide no indication that these forms can be isolated as independent nosologic entities. Possible phenotype splitting into individual subtypes and the potentialities of a marker approach to the construction of genetic MFD classifications are demonstrated, with rheumatoid arthritis associated with HLA antigen Dr 4 taken as an example.

Classification↗

PubMed1988

Possible genetic etiology of damselfish neurofibromatosis: genetic differentiation of bicolor damselfish (Pomacentrus partitus) populations.

Variable prevalence rates of damselfish neurofibromatosis (DNF) between Florida Keys reefs have previously been used as evidence against a genetic etiology of DNF in favor of an infectious etiology. Such a conclusion also presumes a genetically homogeneous population, that is, panmixia, throughout the reef system population. In order to address this issue, we conducted a survey of allozyme variation in two closely situated populations of the bicolor damselfish (Pomacentrus partitus) within the Florida Keys. The results suggest that gene flow between these two populations is restricted. Data analyses show significant heterogeneity in allelic frequencies at two enzyme-coding loci (ACO1 and ADH) and a relatively high estimate of genetic distance between samples from Little Grecian Rocks Reef and Grecian Rocks Reef. These preliminary findings are consistent with the hypothesis that the etiology of DNF is genetic. It is of some interest that these results are in contrast to previous studies of genetic differentiation among widely separated populations of coral reef fishes. Sufficient allozyme variation was detected (12 out of 23 loci were polymorphic) to allow for a subsequent rigorous assessment of panmixia in these populations at risk for DNF.

Animals↗

PubMed1996

Differential genetic mediation of sensitivity to morphine in genetic models of opiate antinociception: influence of nociceptive assay.

Several genetic mouse models of opiate sensitivity have been identified or produced in an attempt to investigate mechanisms underlying individual variation in responses to opiate drugs like morphine. The major models in use presently are the DBA/2 (DBA) versus C57BL/6 (C57) inbred strains, the recombinantly inbred CXBK strain, and mouse lines selectively bred for high- and low-magnitude antinociception after swim stress (HA and LA lines, respectively) or levorphanol administration (HAR and LAR lines, respectively). The hot-plate test, an assay of acute, thermal nociception, was used in the selection of the HA/LA and HAR/LAR lines, and has largely been used to characterize the differential opiate sensitivity of the DBA (high) and C57 (low) strains and the deficient sensitivity of the CXBK strain. There exist, however, many other nociceptive assays used with murine subjects; the most common are the tail-flick/withdrawal test, the acetic acid abdominal constriction test and the formalin test. In the present experiment, baseline nociceptive sensitivities and morphine antinociceptive dose-response relationships (0.1-10 mg/kg i.p. or s.c.) were investigated in mice of all four genetic models and in all four major nociceptive assays, with identical parameters. Results indicate a high degree of dissociation between different genetic models, which suggests that these strains differ in their nociceptive and antinociceptive sensitivities due to the effects of very different genetic and physiological mechanisms. In addition, the present findings suggest that morphine inhibits different modalities of nociception via separate mechanisms that can be genetically dissociated and independently altered. Strikingly, in HA/LA and HAR/LAR mice, we find that an inverse relationship exists with respect to morphine antinociceptive sensitivity in the hot-plate and acetic acid abdominal constriction tests, respectively.

Analgesia↗

PubMed2004

On the neutrality of molecular genetic markers: pedigree analysis of genetic variation in fragmented populations.

Many studies employ molecular markers to infer ecological and evolutionary processes, assuming that variation found at genetic loci offers a reliable representation of stochastic events in natural populations. Increasingly, evidence emerges that molecular markers might not always be selectively neutral. However, only a few studies have analysed how deviations from neutrality could affect estimates of genetic variation, using populations with known genealogy. We monitored changes in allozyme variation over eight generations in captive metapopulations of the butterfly Bicyclus anynana. Population demography was recorded by individually marking 35 000 butterflies and constructing pedigrees. We designed a computer program that simulated the inheritance of founder allozyme alleles in butterfly pedigrees. We thus tested whether the observed transmission of allozyme alleles could be explained by random genetic drift alone, or whether there was evidence for positive or negative selection. This analysis showed that in the smallest metapopulations the loss of allozyme variation exceeded the neutral rate. Possibly, linkage disequilibria between deleterious mutations and marker alleles resulted in background selection and a faster erosion of allozyme variation. In larger metapopulations, one locus (MDH) showed a significant heterozygote excess and smaller than expected loss in heterozygosity, observations consistent with (associative) overdominance. This study demonstrates that the neutrality of molecular markers cannot always be assumed, particularly in small populations with a high mutation load.

Animals↗

PubMed1999

Clinical impact of molecular genetic diagnosis, genetic counseling, and management of hereditary cancer. Part I: Studies of cancer in families.

Hereditary cancer represents approximately 5-10% of the total cancer burden and may account for 60,000 to 120,000 new cancer occurrences this year in the United States. New developments in molecular genetics and the cloning of cancer-prone genes have intensely fueled interest in dealing with hereditary forms of cancer. The authors provide an algorithm that depicts the process for the identification, study, and DNA-based genetic counseling of families being investigated under a research proposal at the Hereditary Cancer Institute of Creighton University School of Medicine. They have studied 56 hereditary nonpolyposis colorectal carcinoma families; in 18 of them, associated genomic mutations have been identified in affected members. DNA-based genetic counseling has been provided for seven of these families. The authors have also evaluated 131 hereditary breast-ovarian carcinoma families. BRCA1 and BRCA2 mutation searches have been performed for 76 of these families; BRCA1 mutations were found in 38 families and BRCA2 mutations in 9. The study of cancer-prone families is a powerful approach to cancer control, particularly when the germ-line mutation is identified in the family and individuals at high risk can be tested, once they provide informed consent, and receive DNA-based genetic counseling. Discovery of the germ-line mutation for cancer proneness provides an unparalleled opportunity to predict patients' life-time risk for cancer of specific anatomic sites, inclusive of a pattern of multiple primaries. Surveillance and management protocols, when melded to the particular syndrome's natural history, can be life-saving.

Clinical Protocols↗

PubMed1999

Clinical impact of molecular genetic diagnosis, genetic counseling, and management of hereditary cancer. Part II: Hereditary nonpolyposis colorectal carcinoma as a model.

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is the most common hereditary form of colorectal carcinoma (CRC) and may account for 5-10% of the total CRC burden. The discovery of DNA mismatch repair (MMR) genes, inclusive of hMSH2, hMLH1, hPMS2, and hMSH6, has enabled the identification of who has and who does not have inordinately increased susceptibility to CRC as well as a litany of extracolonic cancers. Mutation testing has focused on hMSH2 and hMLH1, the most common mutations in HNPCC. The protocol for DNA testing and DNA-based genetic counseling is described in Part I of this study. One hundred ninety-nine bloodline relatives were tested and counseled from five hMLH1 and two hMSH2 families. Their major reason for seeking genetic counseling and DNA testing was to inform their children and other loved ones of their mutation status. Those who sought counseling overestimated their risk for inheriting the mutation and showed a high rate of interest in prophylactic surgery, and many were greatly concerned about insurance discrimination. Knowledge about HNPCC, its molecular genetic diagnosis, surveillance and management opportunities, and genetic counseling implications are still emerging, all in the face of a greater need for physician education regarding all facets of hereditary cancer.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Genetic heterogeneity in northeastern India: reflection of Tribe-Caste continuum in the genetic structure.

We critically examined the gene frequency data for 11 genetic markers commonly available in the literature for 22 populations of northeastern India in the light of their geographic, linguistic, and ethnic affiliations. The markers investigated were three blood groups (A1A2BO, MNS, and Rh), four serum proteins (KM, Gc, Hp, and Tf), and four enzyme systems (AP, AK, EsD, and Hb). The neighbor-joining tree and multidimensional scaling of the distance matrix suggest relatively high genetic differentiation among the Mongoloid groups, with probably diverse origins when compared to the Caucasoid Indo-European populations, which had probably come from relatively more homogeneous backgrounds. Broadly speaking, the pattern of population affinities conforms to the ethno-historic, linguistic, and geographic backgrounds. An interesting and important feature that emerges from this analysis is the reflection of the effect of the sociological process of a Tribe-Caste continuum on genetic structure. While on one end we have the cluster of Caucasoid caste populations, the other end consists of Mongoloid tribal groups. In between are the populations which were originally tribes but now have become semi-Hinduized caste groups, viz., Rajbanshi, Chutiya, and Ahom. These groups have currently assumed caste status and speak Indo-European languages. Therefore, one may infer that what appears to be a purely sociological phenomenon of a Tribe-Caste continuum may well reflect in their genetic structure.

Blood Group Antigens↗