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PubMed2001

Genetic and physical delineation of the region overlapping the progressive motor neuropathy (pmn) locus on mouse chromosome 13.

The mouse autosomal recessive mutation progressive motor neuropathy (pmn) results in early onset motor neuron disease with rapidly progressing hindlimb paralysis, severe muscular wasting, and death at 4--6 weeks of age. pmn is thus considered a good animal model for motor neuron diseases and the characterization of the causative gene should help in understanding the biological causes of human spinal muscular atrophies. Here we report the generation of a physical map based on a high-resolution and high-density genetic map encompassing the pmn locus on mouse chromosome 13. We have positioned the pmn locus and a cluster of markers cosegregating with it within a genetic interval of 0.30 cM, delineated by two clusters of markers. We have constructed an approximately 850-kb contig of BACs spanning the pmn critical region. This BAC contig contains the breakpoint of synteny between mouse chromosome 13 and human 1q and 7p regions and lays the foundation for identifying at the molecular level such a breakpoint region. The physical and genetic maps provided a support for the identification of five transcription units positioned in the nonrecombinant interval, and constitute invaluable tools for the identification of other candidate genes for the pmn mutation.

Alleles↗
PubMed2003

Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous and Costello syndromes.

Costello syndrome (CS) is a rare, multiple congenital anomaly syndrome with characteristic dysmorphic features, cardiac anomalies and a tendency to develop certain cancers. Phenotypically there is some overlap with other genetic disorders, notably cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome (NS), suggesting that these syndromes may be allelic. We recently identified PTPN11, which encodes the non-receptor protein tyrosine phosphatase, SHP-2, as a major NS disease gene. In this report, we screened a cohort of 27 patients, with the clinical diagnosis of CS, for PTPN11 mutations using denaturing high performance liquid chromatography analysis. No mutations of the PTPN11 gene were found in the CS patients. Common polymorphisms in introns 6 and 7 and exon 8 were identified in four individuals. With our previous exclusion of PTPN11 mutations in CFC syndrome, these data suggest distinct genetic etiologies for Noonan, CFC and Costello syndromes.

Abnormalities, Multiple↗
PubMed1992

Classical genetic analyses of responses to nicotine and ethanol in crosses derived from long- and short-sleep mice.

A classical (Mendelian) genetic analysis of responses to ethanol and nicotine was conducted in crosses derived from mouse lines which were selectively bred for differential duration of loss of the righting response (sleep-time) after ethanol. Dose-response curves for these mice, the long- and short-sleep mouse lines, as well as the derived F1, F2 and backcross (F1 x long-sleep and F1 x short-sleep) generations were generated for several measures of nicotine and ethanol sensitivity. Ethanol sensitivity was assessed using the sleep-time measure. Nicotine sensitivity was tested using a battery of behavioral and physiological tests which included measures of seizure activity, respiration rate, acoustic startle response, Y-maze activities (both crossing and rearing activities), heart rate and body temperature. The inheritance of sensitivities to both of these agents appears to be polygenic and inheritance can be explained primarily by additive genetic effects with some epistasis. Sensitivity to the ethanol sleep-time measure was genetically correlated with sensitivity to both nicotine-induced hypothermia and seizures; the correlation was greater between sleep-time and hypothermia. These data indicate that there is overlap in the genetic regulation of sensitivity to both ethanol and nicotine as measured by some, but not all, tests.

Animals↗
PubMed1993

Sequence conversion during postreplicative adenovirus overlap recombination.

Sequence conversion efficiently transfers genetic information in high yield during postreplicative adenovirus overlap recombination. This process is intrinsically nonreciprocal, depends on adenovirus-specific strand-displacement replication by both partner molecules, and requires that complementary sequences on displaced strands must exceed a minimal length to form a heteroduplex intermediate.

Adenoviridae↗
PubMed2005

The different faces of shared autoimmunity.

The concept of shared autoimmunity comprises various forms of disease: rheumatic diseases in several members of the same family, the coincidence of autoimmune rheumatic with non-rheumatic diseases in relatives of patients, the presence of autoantibodies in healthy relatives of autoimmune disease patients, and the development of two or more autoimmune rheumatic diseases in one patient, the so-called overlap syndromes. The genetic and environmental factors that lead to these phenomena interact in a complex fashion and influence the distinct phenotypic characteristics of each patient. In a previous case series, we described 23 Mexican Mestizo patients with overlap syndromes. Interestingly, rhupus tends to develop sequentially while sclerodermatomyositis tends to appear simultaneously. The clinical course of the other overlap syndromes is rather aggressive, although clinical manifestations respond to standard treatment. The second and/or third disease appears while the first one is still active, even with adequate treatment. The distinct course of overlap syndromes may be partially explained by the interplay of environmental factors with genes that predispose to autoimmunity in general and to manifestations of specific diseases. The analyses of genes that will help understand the pathophysiology of these diseases include several MHC complex genes, cytokines, AIRE, and PDCD1 amongst others.

Autoimmune Diseases↗
PubMed1989

The distribution of the frequency of occurrence of nucleotide subsequences, based on their overlap capability.

DNA's genetic code can be represented as an alphabetic sequence composed of the four letters A, C, G, and T, which represent the four types of nucleotides--adenylic, cytidylic, guanylic, and thymidylic acid--of which DNA is composed. Now that these sequences have been identified for many genes and are available in computer-readable form, scientists can analyze these data and search for patterns in an attempt to learn more about the regulatory functions of the gene. One area of study is that of the frequency of occurrence of specific nucleotide subsequences (e.g., ACAC) within part or all of a nucleotide sequence. This paper derives the probability distribution of the frequency of occurrence of a subsequence within a nucleotide sequence, under the hypothesis that the four nucleotides occur at random and with equal probability. This distribution is nontrivial because different subsequences have different "overlap capability." For example, the subsequence AAAA can occur up to 17 times in a sequence of length 20 (which would happen if the sequence were composed solely of A's), but the subsequence ACGT cannot occur more than 5 times in a sequence of length 20. Thus, the frequency distributions are different for each type of overlap capability. It is of interest to assess and compare the degree of nonrandomness for different subsequences or among different portions of a sequence; the existence and degree of nonrandomness may be related to the type and degree of functionality of a nucleotide (sub)sequence. The frequency distributions provided here can be used to perform exact significance tests of the hypothesis of randomness. An approximate test is also described for use with long sequences; this can be used to test a more general null hypothesis of nucleotides occurring with unequal probabilities.

Algorithms↗
PubMed1998

Integrated defense system overlaps as a disease model: with examples for multiple chemical sensitivity.

The central nervous, immune, and endocrine systems communicate through multiple common messengers. Over evolutionary time, what may be termed integrated defense system(s) (IDS) have developed to coordinate these communications for specific contexts; these include the stress response, acute-phase response, nonspecific immune response, immune response to antigen, kindling, tolerance, time-dependent sensitization, neurogenic switching, and traumatic dissociation (TD). These IDSs are described and their overlap is examined. Three models of disease production are generated: damage, in which IDSs function incorrectly; inadequate/inappropriate, in which IDS response is outstripped by a changing context; and evolving/learning, in which the IDS learned response to a context is deemed pathologic. Mechanisms of multiple chemical sensitivity (MCS) are developed from several IDS disease models. Model 1A is pesticide damage to the central nervous system, overlapping with body chemical burdens, TD, and chronic zinc deficiency; model 1B is benzene disruption of interleukin-1, overlapping with childhood developmental windows and hapten-antigenic spreading; and model 1C is autoimmunity to immunoglobulin-G (IgG), overlapping with spreading to other IgG-inducers, sudden spreading of inciters, and food-contaminating chemicals. Model 2A is chemical and stress overload, including comparison with the susceptibility/sensitization/triggering/spreading model; model 2B is genetic mercury allergy, overlapping with: heavy metals/zinc displacement and childhood/gestational mercury exposures; and model 3 is MCS as evolution and learning. Remarks are offered on current MCS research. Problems with clinical measurement are suggested on the basis of IDS models. Large-sample patient self-report epidemiology is described as an alternative or addition to clinical biomarker and animal testing.

Acute-Phase Reaction↗
PubMed2006

Evidence for specificity of transmission of alcohol and nicotine dependence in an offspring of twins design.

Alcohol dependence (AD) and nicotine dependence (ND) have been shown to co-occur. Results from twin studies implicate the role of genetics in the etiology of both ND and AD with substantial, yet incomplete, overlap. To test for specificity of transmission of AD and ND in an offspring of twins sample we analyzed data from a study of adolescent and adult offspring of twin fathers ascertained from the Vietnam Era Twin Registry. This sample consists of 1213 twin fathers, 862 biologic or rearing mothers, and 1270 offspring. Offspring were allocated to one of four risk groups for AD based on twin fathers' zygosity and father's and cotwins AD history. Offspring DSM-IV AD and ND were measured by structured diagnostic interview. Paternal AD and ND were significantly associated with offspring AD and ND, respectively. Bivariate probit regression results suggest specificity for transmission of AD and ND. This remained constant after controlling for offspring demographics and psychopathology and maternal AD and ND. Despite the substantial genetic overlap between the two disorders, there is evidence for genetic effects specific for AD and ND.

Adolescent↗
PubMed2004

Genetic and environmental sources of covariation between generalized anxiety disorder and neuroticism.

OBJECTIVE: The authors examined the sources of covariation between generalized anxiety disorder and the personality trait of neuroticism. Because women have higher levels of neuroticism and twice the risk of lifetime generalized anxiety disorder of men, gender-specific effects were also explored. METHOD: Lifetime generalized anxiety disorder and neuroticism were assessed in more than 8,000 twins from male-male, female-female, and opposite-sex pairs through structured diagnostic interviews. Sex-limited Cholesky structural equation models were used to decompose the correlations between generalized anxiety disorder and neuroticism into genetic and environmental components, including sex-specific factors. RESULTS: Genetic correlations between generalized anxiety disorder and neuroticism were high and differed (nonsignificantly) between men and women (1.00 and 0.58, respectively). When nonsignificant gender differences were removed from the models, correlations between generalized anxiety disorder and neuroticism were estimated at 0.80 (95% confidence interval=0.52-1.00). The individual-specific environmental correlation between generalized anxiety disorder and neuroticism was estimated at 0.20 for both genders. CONCLUSIONS: There is substantial overlap between the genetic factors that influence individual variation in neuroticism and those that increase liability for generalized anxiety disorder, irrespective of gender. The life experiences that increase vulnerability to generalized anxiety disorder, however, have only modest overlap with those that contribute to an individual's level of neuroticism.

Adult↗
PubMed2003

Mutation load, functional overlap, and synthetic lethality in the evolution and treatment of cancer.

The efficacy of conventional anti-cancer drugs is puzzling in view of the ubiquitous tissue distribution and vital nature of their targets. Differences in cell cycling rates are not thought sufficient to explain chemotherapeutic selectivity. I suggest an alternative possibility based on the combinatorial effects of mutations in cancer cells. This model incorporates the concepts of synthetic-lethal interactions and mutation loads to explain the drug sensitivity of cancer cells. From this perspective, drugs that target complex processes that utilize genetically redundant or overlapping components, such as DNA replication and chromosome segregation, offer attractive target opportunities.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Craniosynostosis in two African green monkeys.

Multiple craniosynostoses were found in two infant African green monkeys. The bones of the calvariums were overlapped and fused at all the cranial sutures with resulting pressure necrosis of the cerebral cortices. The cause of the craniosynostoses is unknown, but the two infants were born within 15 days of each other and had the same father, suggesting either exposure to a teratogen or a genetic etiology. The overlapping of the cranial bones is unlike craniosynostosis in humans.

Animals↗
PubMed2005

Research agenda for preterm birth: recommendations from the March of Dimes.

Preterm birth (PTB) is a common, serious, and costly health problem affecting nearly 1 in 8 births in the United States. Burdens from PTB are especially severe for the very preterm infant (<32 weeks' gestation), comprising 2% of all US births. Successful prevention needs to include newly focused and adequately funded research, incorporating new technologies and recognition that genetic, environmental, social, and behavioral factors interact in complex pathogeneses and multiple pathways leading to PTB. The March of Dimes Scientific Advisory Committee created this prioritized research agenda, which is aimed at garnering serious attention and expanding resources to make major inroads into the prevention of PTB, targeting six major, overlapping categories: epidemiology, genetics, disparities, inflammation, biologic stress, and clinical trials. Analogous to other common, complex disorders, progress in prevention will require incorporating multipronged risk reduction strategies that are based on sound scientific discovery, as well as on effective translation into clinical care.

Charities↗
PubMed2005

A combined genetics and genomics approach to unravelling molecular pathways in coeliac disease.

Coeliac disease (CD) is a complex, inflammatory disorder of the small intestine induced by gluten. It is common and has a prevalence of approximately 1:200 in Western populations. A major known susceptibility locus for CD is the HLA -DQ locus. However, the genetic contribution of this region is limited to approximately 40%, so non-HLA genes must also be involved in the disease aetiology. Genetic studies have so far identified multiple loci that may potentially be involved in disease aetiology, although the majority of these loci are expected to point to genes with a small effect. A major CD locus on chromosome 19 was recently identified in the Dutch population. Interestingly, there is some marked overlap when comparing genetic linkage studies conducted in different autoimmune disorders, suggesting that common pathways contribute to these diseases. This knowledge may eventually help in identifying some of the disease genes. To identify the true disease-causing genes, linkage analysis needs to be followed by genetic association. Because of the nature of the probable mutations, it is to be expected that the investigation of gene expression data can assist in selecting candidate genes from linkage regions. Furthermore, expression data will point to the molecular pathways involved in the disease pathogenesis.

Celiac Disease↗
PubMed1996

Promoters for synthesis of the pre-C and pregenomic mRNAs of human hepatitis B virus are genetically distinct and differentially regulated.

Two similar, yet functionally distinct genomic RNAs are transcribed from the DNA genome of the human hepatitis B virus. The pre-C RNAs encode the precore protein which is proteolytically processed to yield e antigen. The pregenomic RNAs encode both the nucleocapsid protein and reverse transcriptase and serve as the templates for viral DNA replication. To determine whether synthesis of these two RNAs is directed from a single or a closely spaced pair of promoters, we introduced point and insertion mutations into the basal elements of the promoter that directs their synthesis. Transcription from these mutants was examined both in cell-free transcription systems derived from hepatoma (HepG2) and nonliver (HeLa) cell lines and by transient transfection of hepatoma cell lines (Huh7 and HepG2). The data from these experiments indicated that synthesis of the pre-C and pregenomic RNAs is directed by two distinct promoters and that the basal elements of these two promoters partially overlap, yet are genetically separable, with each consisting of its own transcriptional initiator and a TATA box-like sequence situated approximately 25 to 30 bp upstream of its sites of initiation. A 15-bp insertion was found to be sufficient to physically separate these two promoters. Furthermore, these two promoters can be differentially regulated, with the transcriptional activator Sp1 specifically activating transcription from the pregenomic promoter and the hepatocyte nuclear factor 4 specifically repressing transcription from the pre-C promoter. Thus, we conclude that the promoters used in synthesis of the pre-C and pregenomic mRNAs are genetically distinct and separately regulated.

Base Sequence↗
PubMed1996

Linguistic complexity of protein sequences as compared to texts of human languages.

A notion and a measure of linguistic complexity introduced earlier (Trifonov, 1990) were originally used for analysis of nucleotide sequences. This measure was shown to reflect multiplicity of codes (messages) of different natures superimposed in the sequences. Unlike human language texts, genetic texts are 'read' by cellular mechanisms in several different ways, each time using a different selection of the characters of the same text while skipping others (Trifonov, 1989). Human texts are read in one way only, sequentially and involving all characters (one code). The conceptual significance and essence of the idea on the multiplicity of overlapping codes in genetic sequences, as opposed to human languages, is discussed. The linguistic complexity technique allows a calculation to be made of the structural complexity of any linear sequence of characters irrespective of whether the text is cognized or presently undeciphered. The texts (sequences) are compared exclusively from the point of view of their structural complexity with no reference to the meaning of the texts which is beyond the scope of this article. Results of such a comparison of protein sequences with various texts, written in English, Italian and Welsh are presented. The human texts are found to be structurally simpler than genetic (protein) texts, reflecting, apparently, a difference in the reading modes: single code versus many codes.

Amino Acid Sequence↗
PubMed1993

Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes.

Recent advances in molecular genetics have led to a better understanding of mitochondrially inherited diseases. Mitochondrial encephalomyopathy overlap syndrome is one such group of diseases in which ocular abnormalities are frequently manifest. The authors describe the clinical, molecular genetic, and pathologic findings of two patients with the mitochondrial encephalomyopathy overlap syndrome. The patients shared a similar clinical course with features overlapping the three traditionally distinct clinical phenotypes (the Kearns-Sayre syndrome; the syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke [MELAS], and the syndrome of myoclonus, epilepsy, and ragged red fibers [MERRF]). The patients had identical mitochondrial DNA mutations (at nucleotide position 3243) and had similar ultrastructural abnormalities, including abundant enlarged mitochondria with "whorled" and "tubular" cristae. These abnormal mitochondria appeared to be preferentially distributed in cells with high metabolic activity (retinal pigment epithelium, corneal endothelium, and extraocular muscles).

Abnormalities, Multiple↗
PubMed1989

The Malmö polymorphism of factor IX: establishing the genotypes by rapid analysis of DNA.

A DNA polymorphism in the coding region of coagulation factor IX--potentially valuable for carrier detection, prenatal diagnosis, and population studies--was described in 1985. It had been discovered with monoclonal antibodies that distinguish between threonine and alanine as the 148th residue of the peptide. Its use as a diagnostic tool has been limited because threonine-containing factor IX (Malmö A) is dominant to alanine-containing factor IX (Malmö B) in immunoassays of plasma; therefore, detection of Malmö heterozygotes is not possible in all instances. A DNA method for recognizing all heterozygotes has been developed, but it also has limitations. We report the development of another DNA procedure based on amplification of the relevant DNA with the polymerase chain reaction (PCR). This method is quick, avoids the use of isotopes and x-ray film, and specifically identifies all the Malmö genotypes: hemizygotes, homozygotes, and heterozygotes. The procedure can be performed satisfactorily on small samples of blood (less than 1 mL) as suggested by Kogan et al (N Engl J Med 317:985, 1987). The method described is applicable to any genetic polymorphism that overlaps a restriction enzyme recognition site.

Base Sequence↗
PubMed1993

NUP2, a novel yeast nucleoporin, has functional overlap with other proteins of the nuclear pore complex.

We have isolated a new gene, NUP2, that encodes a constituent of the yeast-nuclear pore complex (NPC). The NUP2 protein sequence shares a central repetitive domain with NSP1 and NUP1, the two previously characterized yeast nucleoporins. Like NUP1 and NSP1, NUP2 localizes to discrete spots in the nuclear envelope, as determined by indirect immunofluorescence. Although the sequence similarity among these three nucleoporins suggests that they have a similar role in the nuclear pore complex, NUP2, in contrast to NSP1 and NUP1, is not required for growth. Some combinations of mutant alleles of NUP1, NSP1, and NUP2 display "synthetic lethal" relationships that provide evidence for functional interaction between these NPC components. This genetic evidence of overlapping function suggests that the nucleoporins act in concert, perhaps participating in the same step of the recognition or transit of macromolecules through the NPC.

Amino Acid Sequence↗