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PubMed1988

Ethical aspects of genetic disease and genetic counselling.

With the reduction in diseases due to nutritional deficiencies and infection, disorders which are wholly or partly genetic are becoming relatively more important in all branches of modern medicine. Genetic counselling has developed in recent years from just explaining to an individual or a couple the risk of them producing a handicapped child, to the possibility in many cases of better diagnosis and active intervention to reduce the risks. At the same time antenatal screening programmes have been introduced to detect women who may be carrying a fetus with a severe handicapping anomaly. The ethical aspects of these advances are considered in this article. A practical approach to the resolution of any dilemmas is proposed which concentrates on the duties incumbent on doctors and other health care workers involved with patients who have or may carry genetic disorders.

Disclosure↗

PubMed2003

Genetic Models in Applied Physiology. HXB/BXH rat recombinant inbred strain platform: a newly enhanced tool for cardiovascular, behavioral, and developmental genetics and genomics.

This review deals with the largest set of rat recombinant inbred (RI) strains and summarizes past and recent accomplishments with this platform for genetic mapping and analyses of divergent and complex traits. This strain, derived by crossing the spontaneously hypertensive rat, SHR/Ola, with a Brown Norway congenic, BN-Lx, carrying polydactyly-luxate syndrome, is referred to as HXB/BXH. The RI strain set has been used for linkage and association studies to identify quantitative trait loci for numerous cardiovascular phenotypes, including arterial pressure, stress-elicited heart rate, and pressor response, and metabolic traits, including insulin resistance, dyslipidemia and glucose handling, and left ventricular hypertrophy. The strain's utility has been enhanced with development of a new framework marker-based map and strain distribution patterns of polymorphic markers. Quantitative trait loci for behavioral traits mapped include loci for startle motor response and habituation, anxiety and locomotion traits associated with elevated plus maze, and conditioned taste aversion. The polydactyly-luxate syndrome Lx mutation has allowed the study of alleles important to limb development and malformation phenotypes as well as teratogens. The RI strains have guided development of numerous congenic strains to test locus assignments and to study the effect of genetic background. Although these strains were originally developed to aid in studies of rat genetic hypertension and morphogenetic abnormalities, this rodent platform has been shown to be equally powerful for a wide spectrum of traits and endophenotypes. These strains provide a ready and available vehicle for many physiological and pharmacological studies.

Animals↗

PubMed2005

Soft sweeps: molecular population genetics of adaptation from standing genetic variation.

A population can adapt to a rapid environmental change or habitat expansion in two ways. It may adapt either through new beneficial mutations that subsequently sweep through the population or by using alleles from the standing genetic variation. We use diffusion theory to calculate the probabilities for selective adaptations and find a large increase in the fixation probability for weak substitutions, if alleles originate from the standing genetic variation. We then determine the parameter regions where each scenario-standing variation vs. new mutations-is more likely. Adaptations from the standing genetic variation are favored if either the selective advantage is weak or the selection coefficient and the mutation rate are both high. Finally, we analyze the probability of "soft sweeps," where multiple copies of the selected allele contribute to a substitution, and discuss the consequences for the footprint of selection on linked neutral variation. We find that soft sweeps with weaker selective footprints are likely under both scenarios if the mutation rate and/or the selection coefficient is high.

Adaptation, Physiological↗

PubMed2006

Congenital long QT syndromes: clinical features, molecular genetics and genetic testing.

Congenital long QT syndrome (LQTS) is a primary electrical disease characterized by a prolonged QT interval in the surface electrocardiogram and increased predisposition to a typical polymorphic ventricular tachycardia, termed Torsade de Pointes. Most patients with LQTS are asymptomatic and are diagnosed incidentally based on an electrocardiogram. Symptomatic patients may suffer from severe cardiac events, such as syncope and/or sudden cardiac death. Autosomal dominant forms are caused by heterozygous mutations in genes encoding the components of the ion channels. The autosomal recessive form with congenital deafness is also known as Jervell and Lang-Nielsen syndrome. It is caused by homozygous mutations or certain compound heterozygous mutations. Depending on the genetic defects, there are differences in the age of onset, severity of symptoms, and number of cardiac events and event triggers. With advances in gene technology, it is now feasible to perform genetic testing for LQTS, especially for those with family history. Identification of the mutation will lead to better management of symptoms and more targeted treatment, depending on the underlying genetic defect, resulting in a reduction of mortality and cardiac events.

Ether-A-Go-Go Potassium Channels↗

PubMed2005

Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study.

The development and progression of microvascular complications have been extensively documented in a cohort of type 1 diabetic subjects enrolled in the Diabetes Control and Complications Trial (DCCT) and followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. We describe the association of genetic variation in the ACE gene in 1,365 DCCT/EDIC subjects with incident persistent microalbuminuria (n = 312) and severe nephropathy (n = 115). We studied three markers (rs1800764, insertion/deletion, and rs9896208) in the ACE gene that allowed us to capture genetic variation in the common haplotypes occurring at frequencies of >5% in Caucasians. Compared with the more frequent genotype (D/I) for the insertion/deletion polymorphism, in multivariate models, the I/I genotype conferred a lower risk for persistent microalbuminuria (hazard ratio [HR] 0.62 [95% CI 0.43-0.89], P = 0.009) and severe nephropathy (0.56 [0.32-0.96], P = 0.033). Variation at the two other markers, rs1800764 and rs9896208, were also associated with these renal outcomes. In addition, homozygosity for the common haplotype TIC (which corresponded to the T, insertion, and C alleles at the three markers, rs1800764, insertion/deletion, and rs9896208, respectively) versus the CDT/TIC haplotype pair was associated with lower risk for development of persistent microalbuminuria (HR 0.49 [0.32-0.75], P = 0.0009) and severe nephropathy (0.41 [0.22-0.78], P = 0.006). Our findings in the DCCT/EDIC cohort provide strong evidence that genetic variation at the ACE gene is associated with the development of nephropathy in patients with type 1 diabetes.

Albuminuria↗

PubMed2000

Genetic analysis of the influence of pertussis toxin on experimental allergic encephalomyelitis susceptibility: an environmental agent can override genetic checkpoints.

Pertussis toxin (PTX) is a potent ancillary adjuvant used to elicit several different autoimmune diseases, including experimental allergic encephalomyelitis (EAE). To delineate the genetics of PTX effect in EAE, we mapped EAE-modifying (eae-m) loci in cohorts of backcross mice immunized with and without PTX. In this study, we analyzed the genetic basis of EAE susceptibility and severity and the intermediate phenotypes of mononuclear cell infiltration, suppuration, and demyelination. In animals immunized with PTX, one major locus, eae9, controls disease susceptibility and severity. Eae9 also regulates the extent of mononuclear cell infiltration of the spinal cord in male mice. Without PTX, five eae-m loci were noted, including three new loci in intervals on chromosomes 8 (eae14), 10 (eae17), and 18 (eae18). Taken together, these results suggest that eae9 controls the effects of PTX in EAE susceptibility, and is capable of overriding the other genetic checkpoints in the pathogenesis of this disease.

Animals↗

PubMed2004

[Integrated population genetic and medical genetic study of two raions of the Tver oblast].

An integrated medical genetic an population genetic study has been performed in two raions (administrative districts) of the Tver oblast (region) of Russia: the Udomlya raion located in the zone affected by the Kalininskaya Nuclear Power Plant and the Ostashkov raion, which served as a control district. No significant differences has been found with respect to the genetic parameters studied. The values of these parameters in the populations of the town of Udomlya, the town of Ostashkov, the Udomlya raion, and the Ostashkov raion, respectively, are the following: random inbreeding, 0.00006, 0.00011, 0.000167, and 0.000366; endogamy index, 0.05, 0.43, 0.30, and 0.42; local inbreeding, 0.0003, 0.00045, 0.0009, and 0.0011; the degree of isolation by distance, 0.0003, 0.00045, 0.0009, and 0.0005; sigma, 2098, 1338, 1473, and 1189; the load of autosomal dominant (AD) diseases, 0.71, 0.92, 0.92, and 1.37; the load of autosomal recessive (AR) diseases, 0.68, 0.69, 0.67, and 0.82; and the load of X-linked diseases, 0.18, 0.64, 0.83, and 0.27.

Consanguinity↗

PubMed1995

Attitudes toward genetic testing among the general population and relatives of patients with a severe genetic disease: a survey from Finland.

In the present study we explore the attitudes of the Finnish population toward genetic testing by conducting a questionnaire study of a stratified sample of the population as well as of family members of patients with a severe hereditary disease, aspartylglucosaminuria (AGU). The questionnaire evaluated attitudes toward gene tests in general and also respondents' preparedness to undergo gene tests for predictive testing, carrier detection, prenatal diagnosis, and selective abortion, in theoretical situations. The results of the study indicate that both the Finnish population in general and family members of AGU patients have a favorable attitude toward genetic testing. However, a commonly expressed reason against testing was that test results might lead to discrimination in employment or insurance policies. Based on the responses, we predict that future genetic testing programs will most probably be met with a high acceptance rate by the Finnish population.

Adolescent↗

PubMed1995

A strategy for constructing high-resolution genetic maps of the human genome: a genetic map of chromosome 17p, ordered with meiotic breakpoint-mapping panels.

Genetic linkage analyses with genotypic data obtained from four CEPH reference families initially assigned 24 new PCR-based markers to chromosome 17 and located the markers at specific intervals of an existing genetic map of chromosome 17p. Each marker was additionally genotyped with an ordered set of obligate, phase-known recombinant chromosomes. The breakpoint-mapping panels for each family consisted of two parents, one sib with a nonrecombinant chromosome, and one or more sibs with obligate recombinant chromosomes. The relative order of markers was determined by sorting segregation patterns of new markers and ordered anchor markers and by minimizing double-recombination events. Consistency of segregation patterns with multiple flanking loci constituted support for order. A genetic map of chromosome 17p was completed with 39 markers in 23 clusters, with an average space of 3 cM between clusters. The collection of informative genotypes was highly efficient, requiring fivefold fewer genotypes than would be collected with all the CEPH families. Given the availability of large numbers of highly informative PCR-based markers, meiotic breakpoint mapping should facilitate construction of a human genomic map with 1-cM resolution.

Base Sequence↗

PubMed1981

Quantitative genetics of skeletal nonmetric traits in the rhesus macaques on Cayo Santiago. II. Phenotypic, genetic, and environmental correlations between traits.

The general lack of phenotypic correlation among skeletal nonmetric traits has been interpreted as indicating a lack of genetic correlation among these traits. Nonmetric traits scored on animals in the skeletal collection of rhesus macaques from Cayo Santiago are used to calculate phenotypic, genetic, and environmental correlations between traits. The results show that even when phenotypic correlations are low, there may be large, significant genetic correlations among these traits. The genetic correlation pattern suggests that genes which affect nonmetric trait variation act primarily at a local level in the cranium, even though there are genes with pleiotropic effects on skeletal nonmetric traits throughout the cranium. Environmental and phenotypic correlations do not show this neighborhood pattern of correlation.

Animals↗

PubMed1983

Genetic disorders presenting as "schizophrenia". Karl Bonhoeffer's early view of the psychoses in the light of medical genetics.

There is overwhelming empirical evidence for the influence of genetic factors in the etiology of schizophrenic psychoses. An appreciable and still increasing number of exogenous factors have been known for decades that are capable of inducing psychoses that present as "schizophrenia" or are more or less similar to it. In this article, genetic disorders--chromosomal abnormalities and Mendelian diseases--are summarized that may be associated with such psychoses. These disorders frequently but not necessarily exhibit additional physical symptoms. Although the majority of schizophrenic psychoses can so far not be explained by exogenous factors or well-defined genetic disorders, the proportion of these etiologies among all cases may be higher than presumed so far, because they evade detection. Data from the literature are discussed in the light of Karl Bonhoeffer's early concept of exogenous reaction types and modern medical genetics.

Diagnosis, Differential↗

PubMed1983

Genetic instability associated with the aroC321 allele in Salmonella typhimurium involves genetic duplication.

Strains of Salmonella typhimurium that contain the aroC321 allele require phenylalanine, tyrosine, and tryptophan for growth but revert to tryptophan-prototrophy at high frequencies (about 10(-4) per cell plated). The Trp+ derivatives remain auxotrophic for phenylalanine and tyrosine and are genetically unstable, in that they readily give rise to cells that require all three aromatic amino acids. On the basis of growth characteristics and genetic instability, it has been proposed that reversion to tryptophan-prototrophy in aroC321 strains occurs by genetic duplication. This paper provides genetic evidence in support of that hypothesis. The data indicate, moreover, that the tryptophan prototrophs contain a duplication that extends at least from glpT to xyl, a region of greater than 30% of the Salmonella chromosome. The aroC locus is found within the duplicated region, and aroC321/aroC321 merodiploids apparently grow as tryptophan prototrophs because of a gene-dosage effect.

Chromosome Mapping↗

PubMed1982

Evolutionary genetics of birds. V. Genetic distances within Mimidae (mimic thrushes) and vireonidae (Vireos).

Genetic distances (D's) between five species within each of the families Mimidae and Vireonidae were estimated from frequencies of protein electromorphs at 23 loci. For three mimid species in the genus Toxostoma, D equals 0.084 (range, 0.069-0.104); and among three mimid genera, D equals 0.223 (0.167-0.278). These distances typify values previously reported in other birds at comparable levels of taxonomic recognition. In sharp contrast, the mean genetic distance among five congeneric species of Vireonidae is far higher, D = 0.360 (0.027-0.578). One possible explanation for these results is that Vireo species are considerably older, on the average, than are species of Toxostoma or than are members of several other avain genera assayed to date. Conventional thought about the origin and relative age of the Vireonidae appears compatible with this explanation. Although genetic distances in the Vireonidae are large by "avian standards," they remain modest or even small in comparison with distances between many nonavian vertebrate congeners. Results for the Mimidae and the Vireonidae are directly contrasted with genetic distances in well-known genera of Amphibia and Reptilia.

Animals↗

PubMed1989

Genetic and non-genetic control of myocardial calcium.

Some aspects of the genetic and non-genetic control of the amount and rate of calcium cycled during steady-state activation of papillary muscles from right ventricular rabbit myocardium are presented. Genetic reorganization of the intracellular structure of the myocardium is achieved by producing right ventricular pressure overload and thyrotoxic hypertrophy. The mechanical performance of the pressure overload heart is slowed while time to peak tension is increased. These changes are associated with an increase in myothermal economy. In thyrotoxic hypertrophy the rate of mechanical performance is increased while time to peak tension is decreased. These alterations are associated with a decrease in myothermal economy. Tension-independent heat is used as an index of calcium cycling. In pressure overload hearts the amount and rate of calcium cycling is decreased. In contrast in thyrotoxic hypertrophy the amount of calcium cycled is unchanged while the rate is increased. In the pressure overload hearts there is a decrease in sarcoplasmic reticular (SR) Ca++ ATPase, whereas in the thyrotoxic preparations the message is increased. The change in the rate of calcium uptake in pressure overload and thyrotoxic hearts is correlated with a change in the amount of SR Ca++ ATPase mRNA. Calcium cycling was also altered by non-genetic inotropic intervention. Isoproterenol (1 microM) increases the amount of calcium cycled during each contraction relaxation cycle and the rate at which it is removed. These alterations are associated with an increase in force and a foreshortened twitch. Incubating the papillary muscle in high calcium (11 mM) also increases the force and the amount of calcium released into the cytosol. Under these circumstances the rate of uptake is not significantly increased and, accordingly, the isometric twitch is not foreshortened. In the presence of verapamil (14 microM) the peak twitch force is decreased and the isometric myogram is foreshortened. These changes are associated with a decrease in the amount of calcium released during activation and the rate at which it is removed.

Animals↗

PubMed1988

Repeated electroconvulsive shock normalizes blood glucose levels in genetically obese mice (C57BL/6J ob/ob) but not in genetically diabetic mice (C57BL/KsJ db/db).

There are several conflicting reports on the effect of electroconvulsive shock (ECS) on diabetes in humans. The present study investigated the effect of repeated ECS on blood glucose levels in genetically obese mice, which are considered an animal model for non-insulin dependent (maturity onset) diabetes. These mice were compared with genetically diabetic mice which are thought to be an animal model for insulin-dependent (juvenile-type) diabetes. A marked decrease in blood glucose concentrations was observed in obese mice after the first ECS which lasted for 14 days after the last ECS. No effect was seen in genetically diabetic mice. The neural mechanisms by which ECS normalizes blood glucose in genetically obese mice are discussed.

Animals↗

PubMed2006

Congenital heart diseases in small animals: part II. Potential genetic aetiologies based on human genetic studies.

Comparative genetics provides veterinary researchers and clinicians with invaluable information for the understanding the possible genetic aetiologies and the disease process in congenital heart defects (CHDs) of dogs and cats. Although, the demand on this type of research has increased in the veterinary field, to date no fundamental genetic studies have been reported in the veterinary literature. In this second part of a two-part review, the general features and pathogenesis of major CHDs in humans and small animals are discussed. In addition, the known genetic aetiologies in human CHDs have been considered in parallel to CHDs in small animals.

Animals↗

PubMed1997

Rules and guidelines for genetic nomenclature in mice: excerpted version. Committee on Standardized Genetic Nomenclature for Mice.

The unique identification of genes and mouse strains is critical to their identification in research and in the scientific literature. Rules for genetic nomenclature in mice have existed since the 1940s. The latest complete revision of the rules was approved by the International Committee on Standardized Genetic Nomenclature for Mice in November, 1993. Minor revisions have occurred since. The complete, current rules are available on-line from The Jackson Laboratory's Mouse Genome Database (MGD), URL: http:(+)+www.informatics.jax.org. A printed version appeared in Mouse Genome 92 (2), June, 1994, and in Genetic Variants and Strains of the Laboratory Mouse, 3rd edition (Committee on Standardized Genetic Nomenclature for Mice, 1996a,b,c). The excerpted version below gives the general guidelines for naming and symbolizing mouse genes, transgenes and transgenic strains, targeted mutations and DNA markers. More detailed guidelines, including revisions as they are made, may be found at the MGD Web site given above. Subparagraphs are numbered as in the complete guidelines so that the user can refer easily from this excerpted version to the full text. Textual references to paragraphs not included here may be found in the full text as well.

Animals↗

PubMed1997

Genetic and environmental influences on parent-son relationships: evidence for increasing genetic influence during adolescence.

Genetic and environmental influences on self-reported parent-child relationships were examined in a sample of 824 individual male twins and their parents. Cross-sectional comparisons of twin similarity at ages 11 and 17 were undertaken to identify developmental changes in the contribution of genetic and environmental factors to family relationships. Significant genetic influences were found on perceptions of parent-son conflict, regard, involvement, and overall support. Heritabilities were significantly higher in older twins, suggesting increased genetic influence with age. Age differences were present primarily in the father-son relationship. These results provide support for the proposal of S. Scarr and K. McCartney (1983) that the importance of active gene-environment correlations increases during adolescence. Older adolescents may have more choice and impact on the nature of the relationships they have with their parents.

Adolescent↗