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At least 973 records · Page 54Linked to original sources
PubMed1989

Allelic sequence variations in the hypervariable region of a T-cell receptor beta chain: correlation with restriction fragment length polymorphism in human families and populations.

Direct sequence analysis of the human T-cell antigen receptor (TCR) V beta 1 variable gene identified a single base-pair allelic variation (C/G) located within the coding region. This change results in substitution of a histidine (CAC) for a glutamine (CAG) at position 48 of the TCR beta chain, a position predicted to be in the TCR antigen binding site. The V beta 1 polymorphism was found by DNA sequence analysis of V beta 1 genes from seven unrelated individuals; V beta 1 genes were amplified by the polymerase chain reaction, the amplified fragments were cloned into M13 phage vectors, and sequences were determined. To determine the inheritance patterns of the V beta 1 substitution and to test correlation with V beta 1 restriction fragment length polymorphism detected with Pvu II and Taq I, allele-specific oligonucleotides were constructed and used to characterize amplified DNA samples. Seventy unrelated individuals and six families were tested for both restriction fragment length polymorphism and for the V beta 1 substitution. The correlation was also tested using amplified, size-selected, Pvu II- and Taq I-digested DNA samples from heterozygotes. Pvu II allele 1 (61/70) and Taq I allele 1 (66/70) were found to be correlated with the substitution giving rise to a histidine at position 48. Because there are exceptions to the correlation, the use of specific probes to characterize allelic forms of TCR variable genes will provide important tools for studies of basic TCR genetics and disease associations.

Alleles↗
PubMed1990

Mitochondrial genotype of a unisexual salamander of hybrid origin is unrelated to either of its nuclear haplotypes.

We examined mitochondrial DNA (mtDNA), enzyme, and morphological variation among 17 unisexual Ambystoma of hybrid origin. Electrophoretic comparison of diagnostic enzymes indicates that these unisexuals are triploid with two nuclear genomes from the bisexual species Ambystoma laterale and one from Ambystoma jeffersonianum; however, according to restriction analysis, the mtDNAs of these specimens derive from a third species, Ambystoma texanum. This unusual situation is apparently due to a partially independent segregation event in an ancestor of these unisexuals. This situation highlights the potential importance of molecules with different inheritance patterns in elucidating complex cases of reticulate evolution.

Ambystoma↗
PubMed1993

Telomere-like DNA polymorphisms associated with genetic predisposition to acute myeloid leukemia in irradiated CBA mice.

There is evidence that interstitial telomere (TTAGGG)n-like sequences at chromosome 2 fragile sites play an important role in the somatic events that characterize the earliest phases of radiation-induced acute myeloid leukemia in the CBA/H mouse. Here we show that the highly inbred CBA/H colony unexpectedly contains four genotypic variants for telomere-like sequence arrays and that almost all induced myeloid leukemias derive from one of the variant subpopulations that constitutes approximately 20% of the colony. Preliminary evidence on the irregular inheritance patterns for these variant sequences is discussed together with the proposal that one form of these telomere sequence arrays either represents or is closely linked to a locus that influences chromosome 2 breakage patterns in hemopoietic cells following irradiation and, through this, susceptibility to induced myeloid leukemia.

Acute Disease↗
PubMed1996

A locus on chromosome 7 determines myocardial cell necrosis and calcification (dystrophic cardiac calcinosis) in mice.

Dystrophic cardiac calcinosis, an age-related cardiomyopathy that occurs among certain inbred strains of mice, involves myocardial injury, necrosis, and calcification. Using a complete linkage map approach and quantitative trait locus analysis, we sought to identify genetic loci determining dystrophic cardiac calcinosis in an F2 intercross of resistant C57BL/6J and susceptible C3H/HeJ inbred strains. We identified a single major locus, designated Dyscalc, located on proximal chromosome 7 in a region syntenic with human chromosomes 19q13 and 11p15. The statistical significance of Dyscalc (logarithm of odds score 14.6) was tested by analysis of permuted trait data. Analysis of BxH recombinant inbred strains confirmed the mapping position. The inheritance pattern indicated that this locus influences susceptibility of cells both to enter necrosis and to subsequently undergo calcification.

Animals↗
PubMed1996

Defective subunit assembly underlies a digenic form of retinitis pigmentosa linked to mutations in peripherin/rds and rom-1.

Retinitis pigmentosa (RP) is a group of progressive retinal dystrophies that include the most common hereditary degenerative disease affecting the retina. Although most disease phenotypes appear to result from defects at single genetic loci (monogenic), at least one instance of RP appears to require a coinheritance of defects in the unlinked peripherin/rds and rom-1 alleles (digenic), which encode the polypeptide subunits of an oligomeric transmembrane protein complex present at photoreceptor outer segment disc rims. Sedimentation velocity analysis was performed upon the affected gene products expressed heterologously in COS-1 cells to examine the assembly of the subunit polypeptides. The results indicate that the missense peripherin/rds mutant, L185P, which segregates with instance of digenically inherited RP, is conditionally defective with respect to its subunit assembly. Unlike wild-type peripherin/rds, the L185P mutant does not form native-like homotetramers on its own; however, the L185P mutant can assemble with wild-type rom-1 to form a structurally normal heterotetrameric complex. These findings provide a novel molecular-based rationale for the unusual digenic disease inheritance pattern and offer insight into regions of peripherin/rds and rom-1, which contribute to subunit-subunit interactions.

Animals↗
PubMed1996

Frequency of migrants and migratory activity are genetically correlated in a bird population: evolutionary implications.

Most migratory bird populations are composed of individuals that migrate and individuals that remain resident. While the role of ecological factors in maintaining this behavioral dimorphism has received much attention, the importance of genetic constraints on the evolution of avian migration has not yet been considered. Drawing on the recorded migratory activities of 775 blackcaps (Sylvia atricapilla) from a partially migratory population in southern France, we tested two alternative genetic models about the relationship between incidence and amount of migratory activity. The amount of migratory activity could be the continuous variable "underlying" the phenotypic expression of migratory urge, or, alternatively, the expression of both traits could be controlled by two separate genetic systems. The distributions of migratory activities in five different cohorts and the inheritance pattern derived from selective breeding experiments both indicate that incidence and amount of migratory activity are two aspects of one trait. Thus, all birds without measurable activity have activity levels at the low end of a continuous distribution, below the limit of expression or detection. The phenotypic dichotomy "migrant-nonmigrant" is caused by a threshold which may not be fixed but influenced both genetically and environmentally. This finding has profound implications for the evolution of migration: the transition from migratoriness to residency should not only be driven by selection favoring resident birds but also by selection for lower migratory activity. This potential for selection on two aspects, residency and migration distance, of the same trait may enable extremely rapid evolutionary changes to occur in migratory behavior.

Animals↗
PubMed2000

George Huntington (1850-1916) and hereditary chorea.

Although Huntington's disease has existed since at least the seventeenth century, and although several physicians provided earlier descriptions of hereditary chorea, Huntington's disease was not generally recognized until the classic description by George Huntington (1850-1916) in 1872. This paper--on the sesquicentennial of Huntington's birth--reviews Huntington's original and later contributions to the description of this disorder, his professional presentations and correspondence on the topic, and his publications, as well as his background, medical training, and clinical practice. The characteristics of Huntington's disease recognized by George Huntington in 1872--i.e., the distinct clinical profile, midlife onset, and autosomal dominant inheritance pattern--made the disease ideal for investigation by genetic linkage analysis a century after Huntington's description. Subsequent breakthroughs have identified the genetic defect as an unstable expanded CAG trinucleotide repeat mutation in a novel gene on the short arm of chromosome 4. The rapidity of recent discoveries bodes well for further significant progress in understanding, and hopefully treating, this profoundly debilitating neurodegenerative disorder.

Disease Progression↗
PubMed2002

TLR4 and LPS hyporesponsiveness in humans.

Asthma is a complex genetic disorder that is caused by a number of unique gene-gene and gene-environment interactions. The search for asthma susceptibility genes has been complicated by the broad clinical phenotype of asthma, the polygenic inheritance pattern of this disease, and the substantial role of environmental exposures in the development and progression of asthma. Inhaled environmental agents induce several biologic responses in asthmatics; including the induction of acquired and innate immunity that leads to acute and chronic forms of airway inflammation and airway remodeling. Acquired immune responses to protein antigens, such as house dust mite allergen, often induce type 2 T lymphocyte-driven responses (Th2) which appear to be important in atopic asthma. Recent studies by our group and others demonstrate that innate immunity, initiated by inhalation of bacterial and viral pathogens, organic dusts, endotoxin or lipopolysaccharide (LPS), air pollution particulate matter, and ozone, can also cause acute and chronic forms of airflow obstruction, airway inflammation, and even airway remodeling. Emerging evidence indicates that both acquired and innate immune responses in the lung may be influenced by polymorphic genes. For instance, functional polymorphisms in the IL-4 receptor gene are thought to preferentially stimulate acquired Th2 immune responses to inhaled allergens, and we have recently shown that common co-segregating mutations in TLR4 (a transmembrane receptor for LPS) are associated with diminished airway responsiveness to inhaled LPS. These observations suggest that environmental challenges can be used to narrow the phenotype of asthma and allow scientists to investigate unique gene-environment interactions that are involved in the development of biologically specific forms of asthma.

Adolescent↗
PubMed1998

Normal and increased functional asymmetries in the craniofacial area.

Normal asymmetry in the area of the craniofacial skeleton can be directional or fluctuating in nature. Directionality can in principle be found in three dimensions: anteroposterior, cranio-caudal, and asymmetries in the left-right dimension. When it comes to directional left right differences, an explanation has been difficult to find, although expressions of this type are obvious. Recent findings made in molecular genetics strongly support the genetic inheritance pattern of laterality. When functionally increased asymmetries of facial structures are concerned, it is often difficult to determine the exact contribution of each factor involved. In the light of recent experimental data, however, it seems that the influence of occlusion on the development of balanced facial structures is highly important during the early periods of life. A review of these factors is given in this article.

Dental Occlusion↗
PubMed1994

Familial nesidioblastosis: more evidence for autosomal recessive inheritance.

Severe neonatal hypoglycaemia in five Saudi Arab infants of both sexes belonging to two families of consanguineous parents is reported. All of these infants needed sub-total pancreatectomy to maintain normoglycaemia. Histopathological studies with immunohistochemistry proved diffuse nesidioblastosis of the pancreas in all five infants. Data obtained from these families and other families reported in the literature strongly suggest that familial nesidioblastosis is an autosomal recessive disorder. Knowledge of the inheritance pattern is important both for genetic counselling and for making a prompt diagnosis in subsequently affected siblings, as delay in appropriate treatment may have serious consequences.

Consanguinity↗
PubMedDate not supplied

Cohort effects in a genetically determined trait: eye colour among US whites.

BACKGROUND: While the inheritance of eye colour is likely polygenic, blue eye colour is thought to follow an inheritance pattern similar to that of a recessive trait. Consequently, age-related differences in the prevalence of blue eye colour would be unanticipated. AIM: This study explores the finding and explanation for birth cohort differences in the prevalence of blue eye colour in the US white population. SUBJECTS AND METHODS: Data from the first (1971-1975) and third (1988-1994) US National Health and Nutrition Examination Surveys (NHANES-I and NHANES-III), nationally representative surveys of the US population, were analysed. Trends in eye colour prevalence by birth cohort were analysed together with mortality rates according to eye colour. US census data (1980) were examined to explore cohort differences in ancestry and assortative mating by ancestry. RESULTS: The prevalence of blue eye colour among non-Hispanic whites in NHANES-III was 57.4% (95% CI: 50.1-64.7) for individuals born between 1899 and 1905 compared to 33.8% (95% CI: 31.3-36.5) for those born between 1936 and 1951. No association was found between survival and eye colour, nor was a cohort effect evident for primary ancestry. However, proportions reporting only one ancestry in census data declined with successive birth cohorts. CONCLUSIONS: A cohort effect in blue eye colour prevalence was found for the US white population. A secular trend of decreasing assortative mating by ancestry is the likely explanation.

Adult↗
PubMed2005

Fanconi anemia: current management.

Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder, characterized by congenital anomalies, defective hematopoiesis and a high risk of developing acute myeloid leukemia and certain solid tumors. All racial and ethnic groups are at risk, and at least 11 complementation groups have been identified and the genes defective in eight of these have been identified (FANCA, C, D2, E, F, G, L and BRCA2). FA-A is the most common complementation group, accounting for approximately 65% of all affected individuals. The gold-standard screening test for FA is based on the characteristic hypersensitivity of FA cells to the crosslinking agents, such as mitomicin C or diepoxybutane. Recent progress has been made in identifying the genes bearing pathogenetically relevant mutations, but slower progress has been made in defining the precise functions of the proteins in normal cells, in part because that the proteins are multifunctional. Molecular studies have established that a common pathway exist, both between the FA proteins and other proteins involved in DNA repair such as NBS1, ATM, BRCA1 and BRCA2. Stem cell transplantation (SCT) is the only option for establishing normal hematopoiesis. To reduce undue toxicities due to inherent hypersensitivity, nonmyeloablative conditioning for transplants has been advocated. This review summarizes the general clinical and hematologic features and the current management of FA. Fanconi anemia (FA) is the commonest type of inherited bone marrow failure syndrome with the birth incidence of around three per million. The inheritance pattern is autosomal recessive with the estimated heterozygote frequency being one in 300 in Europe and the US.

DNA Repair↗
PubMedDate not supplied

Merging genetic and environmental effects in the Iowa Adoption Studies: focus on depression.

BACKGROUND: It is generally acknowledged that the vast majority of serious mental disorders have significant genetic contributions that manifest complex inheritance patterns. Despite this, few gene polymorphisms have been unambiguously identified as risk factors for behavioral illness and the mechanisms through which these select polymorphisms affect human behavior is completely unclear. One of the major reasons for this lack of progress is the phenomenon of gene-environment (GxE) interactions. METHODS: We review prior evidence of GxE interactions for major depressive disorder (MDD) in the Iowa Adoption Studies. RESULTS: The results demonstrate the usefulness of these cohorts to direct G effects for MDD. CONCLUSIONS: We conclude that further use of the adoption paradigm will generate critical insight into the effects of candidate genes for a variety of complex human behavioral illnesses.

Adoption↗
PubMed2002

The specificity of family history of alcohol and drug abuse in cocaine abusers.

This study addresses the issue of whether the increased rates of substance-related problems for family members of cocaine abusers are specific for each substance. The present analysis examined the prevalence of problems due to alcohol or drug use separately for mothers, fathers, sisters, and brothers using the Family History Assessment Module. The probands were 343 out-of-treatment subjects with DSM-III-R cocaine disorders who did or did not have additional alcohol and opiate disorders. After accounting for age, race, gender, and antisocial personality, family history of alcohol-related problems had an odds ratio of 1.6 (p <.05) if a participant was alcoholic in addition to abusing cocaine. Specifically, a significantly greater proportion of participants' sisters (p <.001) and brothers (p <.05) had alcohol-related problems if the participant had a history of alcoholism. Among probands who reported opiate abuse or dependence, 38% had relatives with drug-related problems, while participants without opiate abuse or dependence had less than 31% of relatives with drug-related problems (p <.05). However, this association with opiate abuse or dependence and family history of drug-related problems was non-significant after controlling for participants' age, race, gender, treatment status, and antisocial personality diagnosis (odds ratio = 1.4, 95% C.I. = 0.8-2.4). Associations between participants' alcoholism and first-degree relatives' drug-related problems (and vice versa) showed that participants' history of opiate addiction did improve prediction of first-degree relatives' alcohol-related problems, except for participants' brothers. Additional familial risks for alcoholism were seen among siblings of drug abusers who also reported abuse of or dependence on alcohol even after controlling for relatives' ages. Furthermore, parental prevalence of alcohol-related problems were greater when participants had opiate addiction in addition to cocaine addiction. This seems to indicate that opiate addiction in addition to cocaine addiction has particularly strong inheritance patterns. In contrast, parental prevalence of drug-related problems was not greater when participants had alcohol addiction in addition to cocaine addiction. Thus, the cross-substance parent-child familial risk is limited to the dually diagnosed illicit drug.

Adult↗
PubMed1997

Trinucleotide repetition and fragile X syndrome.

Insufficiently appreciated as a cause of learning disability and other behavioral problems, fragile X syndrome accounts for almost 10% of inherited mental retardation. Identification of the specific mutation as a dramatic trinucleotide expansion inaugurates an era of accurate diagnosis, and goes far toward explaining the syndrome's inheritance patterns, in which risk varies as the disease descends through a family.

Amino Acid Sequence↗
PubMed2001

Genes for left-handedness: how to search for the needle in the haystack?

Although several genes that determine left-right asymmetry for structural syndromes such as situs inversus have been characterised in recent years (Supp, Witte, Potter, & Brueckner, 1997), there has been little progress in determining which genes or loci predispose to left-right handedness in humans. Linkage analysis has been used widely for the localisation of genes followed by their positional cloning. The complex genetics of handedness is one of the greatest problems for standard linkage analysis. Several genetic models have been proposed for the inheritance of handedness in humans. On the basis of these models, left-handedness can be considered a common single gene trait with a high gene frequency and a non-mendelian inheritance pattern. We report here a possible strategy, using these genetic models, that can be applied for the identification for genes determining handedness in humans.

Journal Article↗
PubMed1984

Linkage analysis of the murine interferon-alpha locus on chromosome 4.

Southern blot analysis with a murine interferon-alpha2 (MuIFN-alpha2) cDNA probe revealed restriction fragment polymorphism of EcoRI- and HindIII-digested C57BL/6 and BALB/cDNA. The inheritance pattern of this polymorphism was examined using DNA from each of the seven recombinant inbred strains derived from C57BL/6 and BALB/c; the strain distribution pattern suggests linkage of INF-alpha genes to two histocompatibility loci on chromosome 4. Southern blot analysis of DNA from six bilinear congenic strains carrying different fragments of the BALB/c chromosome 4 on a C57BL/6 background showed linkage of IFN-alpha genes to the histocompatibility locus H-15. It can therefore be concluded that the IFN-alpha gene cluster is situated on chromosome 4 near the H-15 locus, between loci Mup-1 and b.

Animals↗
PubMed1998

Simple, robust linkage tests for affected sibs.

Parametric-linkage analysis applied to large pedigrees with many affected individuals has helped in the identification of highly penetrant genes; but, for diseases lacking a clear Mendelian inheritance pattern or caused by several genes of low to moderate penetrance, a more robust strategy is nonparametric analysis applied to small sets of affected relatives, such as affected sib pairs. Here we show that the robustness of affected-sib-pair tests is related to the shape of the constraint set for the sibs' identity-by-descent (IBD) probabilities. We also derive a set of constraints for the IBD probabilities of affected sib triples and use common features of the shapes of the two constrain sets to introduce new nonparametric tests (called "minmax" tests) that are more robust than those in current use. Asymptotic-power computations support the robustness of the proposed minmax tests.

Automation↗