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PubMed2000

Adaptation of the extended transmission/disequilibrium test to distinguish disease associations of multiple loci: the Conditional Extended Transmission/Disequilibrium Test.

Linkage and association studies in complex diseases are used to identify and fine map disease loci. The process of identifying the aetiological polymorphism, the molecular variant responsible for the linkage and association of the chromosome region with disease, is complicated by the low penetrance of the disease variant, the linkage disequilibrium between physically-linked polymorphic markers flanking the disease variant, and the possibility that more than one polymorphism in the most associated region is aetiological. It is important to be able to detect additional disease determinants in a region containing a cluster of genes, such as the major histocompatibility complex (MHC) region on chromosome 6p21. Some methods have been developed for detection of additional variants, such as the Haplotype Method, Marker Association Segregation Chi-squares (MASC) Method, and the Homozygous Parent Test. Here, the Extended Transmission/Disequilibrium Test is adapted to test for association conditional on a previously associated locus. This test is referred to as the Conditional Extended TDT (CETDT). We discuss the advantages of the CETDT compared to existing methods and, using simulated data, investigate the effect of polymorphism, inheritance, and linkage disequilibrium on the CETDT.

Genetic Diseases, Inborn↗
PubMed2001

Comparative utility of restriction fragment length polymorphism analysis and gene sequencing to the molecular epidemiological investigation of a viral outbreak.

Restriction fragment length polymorphism (RFLP) analysis and partial-genome DNA sequencing are commonly used to infer genetic relationships among pathogens. This study compares the application of both techniques to the analysis of 16 pseudorabies virus isolates collected during a 1989 outbreak. Genetic distances derived from RFLP and DNA sequence data were not significantly correlated with geographic distances between farms from which isolates were collected. RFLP-based genetic distance was, however, strongly correlated with temporal distance between isolates (days separating time of isolation). Sequence-based genetic distance was significantly correlated with temporal distance only when synonymous changes (nucleotide changes not leading to amino acid changes) were considered separately. Conversely, non-synonymous changes were correlated with the host species of origin of the viral isolate. These results indicate that selectively-neutral genetic changes most accurately reflect historical relationships, but that non-neutral changes most accurately reflect the biological environment of the viral isolate (e.g. host immune system).

Animals↗
PubMed1996

Molecular analysis of a silent polymorphism in the PDZ domain of p55, the major palmitoylated erythrocyte membrane protein.

Two independently published cDNA sequences of p55, the X-linked major palmitoylated erythrocyte membrane protein, revealed a discrepancy between G and T at position 358 (Genbank: M64925). This results in codon 85, in exon 3 in the PDZ (PSD-95, discs-large, Z0-1) domain, being either ACG or ACT. As both ACG and ACT code for threonine, this represents a silent polymorphism. Polymerase chain reaction (PCR), single-stranded conformational polymorphism (SSCP), and direct-sequencing analysis of exon 3 of the p55 gene was performed in 98 subjects of African and European origin. Of the 70 females studied, the frequency of G versus T at position 358 was 0.76:0.24, while of the 28 males, 16 had a G and 12 a T at position 358 (0.57:0.43). In subjects of African origin, the frequency of G versus T at position 358 was 0.78:0.22; in subjects of European origin the ratio was 0.63:0.37.

Blood Proteins↗
PubMed1988

Isolation and molecular characterization of a highly polymorphic centromeric tandem repeat in the family Falconidae.

An abundant tandem repeat has been cloned from genomic DNA of the merlin (Falco columbarius). The cloned sequence is 174 bp in length, and maps by in situ hybridization to the centromeric regions of several of the large chromosomes within the merlin karyotype. Complementary sequences have been identified within a variety of falcon species; these sequences are either absent or in very low copy number in the family Accipitridae. The cloned merlin repeat reveals highly polymorphic restriction patterns in the peregrine falcon (Falco peregrinus). These polymorphisms, which have been shown to be stably inherited within a family of captive peregrines, can be used to differentiate the Greenland and Argentina populations of this endangered raptor species.

Animals↗
PubMed1996

The underlying molecular mechanism of apolipoprotein E polymorphism: relationships to lipid disorders, cardiovascular disease, and Alzheimer's disease.

Apolipoprotein E (apo E) polymorphism has important clinical correlates, including disorders of lipoprotein metabolism and atherosclerosis. This article provides a detailed methodology for apo E genotyping and discusses the link between apo E genotype and type III hyperlipoproteinemia, coronary heart disease (CHD), stroke, and Alzheimer's disease (AD). Although apo E genotype appears to provide significant information concerning the genetic component of CHD and AD risk, more research is needed before genotyping can be recommended as a routine screening tool. The data so far, however, implicate apo E as a major component of the genetic basis of cardiovascular disease and AD.

Alleles↗
PubMed1991

Immunogenetics of the human major histocompatibility complex.

The biologic significance of the human major histocompatibility complex (MHC), also referred to as HLA, is well known through its influence on transplant immunity and its association with many diseases. This article attempts to summarize recent progress in the field of HLA polymorphisms. Topics discussed include the genetic basis of HLA, methods to determine HLA polymorphisms, and definitions of HLA Class I and II polymorphisms.

Genes, MHC Class I↗
PubMed2004

Genetic polymorphism of MJD1 alleles and molecular analysis of SCA3 patients from Rio de Janeiro, Brazil.

Spinocerebellar ataxia type 3 is the most common form of autosomal dominant cerebellar ataxia. It is a severe progressive neurological disorder caused by an expansion of an exonic CAG repeat of the MJD1 gene. The repeated sequence is polymorphic among both normal individuals and patients. In general, expanded alleles are paternally inherited and the disorder exhibits anticipation. We performed a PCR-based study to determine polymorphisms of the number of CAG repeats of the MJD1 gene in an anonymous sample of normal Brazilian individuals. We also analyzed DNA samples from 9 patients with ataxia. We identified 29 different allele sizes ranging from 12 to 40 CAG repeats, with heterozygosity of 79%. The distribution of allele sizes showed two major peaks of 16 (7%) and 26 (10.1%) CAG repeats. When grouping normal alleles by size, we observed that the distribution varies between males and females, and a significant deviation from the Hardy-Weinberg equilibrium was observed with an excess of normal large alleles among males. We also detected expanded alleles with 68-73 CAG repeats in 3 out of 9 ataxic patients.

Adolescent↗
PubMed1988

[Molecular cytogenetic research on the polymorphism of segments of the constitutive heterochromatin in human chromosomes].

Cloned alpha-satellite DNA sequences were used to evaluate the specificity and possible variability of repetitive DNA in constitutive heterochromatin of human chromosomes. Five probes of high specificity to individual chromosomes (chromosomes 3, 11, 17, 18 and X) were hybridized in situ to metaphase chromosomes of different individuals. The stable position of alpha-satellite DNA sequences in definite heterochromatic regions of particular chromosomes was found. Therefore, the chromosome-specific alpha-satellite DNA sequences may be used as molecular markers for heterochromatic regions of certain human chromosomes. The significant interindividual differences in relative copy number of alpha-satellite DNA have been detected. The homologous chromosomes of many individuals were characterized by cytologically visible heteromorphisms, as shown by intensity of hybridization with chromosome-specific alpha-satellite DNA sequences. A special analysis of hybridization between homologues with morphological differences gives evidence for a high resolution power of in situ hybridization technique for evaluation of chromosome heteromorphisms. The approaches for detection of heteromorphisms in cases without morphological differences between homologues are discussed. The results obtained indicate that constitutive heterochromatin of human chromosomes is variable for amount of alpha-satellite DNA sequences. In situ hybridization of cloned satellite DNA sequences may be used as novel general approach to analysis of chromosome heteromorphisms in man.

Chromosome Aberrations↗
PubMed1994

Molecular analysis of esterase D polymorphism.

We have analyzed the esterase D (EsD) polymorphism at the nucleic acid level. Two common alleles, EsD1 and EsD2, are characterized by the substitution of one amino acid (Gly-to-Glu), which is caused by the point mutation of one nucleotide (G-to-A). Individuals exhibiting the EsD1 and EsD 2 phenotypes are homozygotes for EsD 1 and EsD 2 cDNAs, respectively. Individuals showing the EsD 2-1 phenotype have two kinds of cDNAs, viz., EsD 1 and EsD 2. The point mutation difference between the cDNAs of the EsD1 and EsD2 alleles results in a different SspI digestion site. A restriction fragment length polymorphism caused by this difference with respect to the SspI digestion site makes it possible to determine the EsD phenotype using DNA samples extracted from forensic materials with no EsD enzymatic activity.

Amino Acid Sequence↗
PubMed1993

Molecular variation in Plasmodium falciparum: polymorphic antigens of asexual erythrocytic stages.

Numerous polymorphic antigens of the asexual erythrocytic stages of P. falciparum are now well characterized. Diversity in some of these antigens, including MSA-1, MSA-2 and the S-antigen is associated with changes in the repeat sequences which are frequently a prominent structural feature of malaria antigens. It is not known whether the variation in repeats causes allelic gene products to adopt different conformations but variation in and around the repeats in SPAM, a newly characterized secreted antigen, preserve the unusual alanine-heptad repeats which we assume generate a helical bundle in this protein. Mutations in non-repetitive regions of the S-antigen and in AMA-1, an antigen lacking repeats, are strongly biased towards those which alter the amino acid sequence. This and other evidence indicates the operation of biological selection but the role of immune responses as a selection pressure operating on these diverse antigens remains to be established.

Amino Acid Sequence↗
PubMed1981

Hippocampal polymorph neurons are the cells of origin for ipsilateral association and commissural afferents to the dentate gyrus.

Neurons in the polymorph layer of the hippocampal dentate hilus were found to be the cells of origin for ipsilateral association and commissural projections to the dentate gyrus. Both afferent systems terminate in the proximal one-third of the stratum moleculare. The polymorph layer is the primary target for noradrenergic, serotonergic and cholinergic input to the hippocampal dentate region. It is hypothesized that one or all of these afferent groups affect hippocampal function through synaptic modification of the defined polymorph afferent system.

Afferent Pathways↗
PubMed1981

Hippocampal polymorph neurons are the cells of origin for ipsilateral association and commissural afferents to the dentate gyrus.

Neurons in the polymorph layer of the hippocampal dentate hilus were found to be the cells of origin for ipsilateral association and commissural projections to the dentate gyrus. Both afferent systems terminate in the proximal one-third of the stratum moleculare. The polymorph layer is the primary target for noradrenergic, serotonergic and cholinergic input to the hippocampal dentate region. It is hypothesized that one or all of these afferent groups affect hippocampal function through synaptic modification of the defined polymorph afferent system.

Afferent Pathways↗
PubMed2006

Irinotecan cytotoxicity does not necessarily depend on the UGT1A1 polymorphism but on fluoropyrimidine: a molecular case report.

We have previously demonstrated that the combined use of doxifluridine and irinotecan shows a different molecular mechanism than that of the protracted venous infusion of 5-FU and irinotecan. In this analysis, there is a suggestion that doxifluridine may enhance irinotecan and enable us to decrease the dose of irinotecan without losing the strong effect by using doxifluridine instead of 5-FU. We present a colon cancer patient with the UGT1A1 polymorphism (UGT1A1 *28) as a known high risk for irinotecan, who was treated with a combination of doxifluridine and irinotecan for peritoneal dissemination resulting in stable disease for 2 years without adverse reactions, although the patient initially developed severe adverse effects to the combination of the protracted venous infusion of 5-FU and irinotecan. Even with the same ratios of fluoropyrimidine and irinotecan combinations, replacing 5-FU with doxifluridine or capecitabine could provide new strategies to obtain not only convenience but also better efficacy and safety at the molecular level.

Aged↗
PubMed1994

Molecular genetic basis of allelic polymorphism in malate dehydrogenase (mdh) in natural populations of Escherichia coli and Salmonella enterica.

Nucleotide sequences of the mdh gene encoding the metabolic enzyme malate dehydrogenase (MDH) were determined for 44 strains representing the major lineages of Escherichia coli and the eight subspecies of Salmonella enterica. Sequence diversity was four times greater in S. enterica than in E. coli, and in both species the rate of amino acid substitution was lower in the NAD(+)-binding domain than in the catalytic domain. Divergence of the mdh genes of the two species apparently has not involved excess nonsynonymous substitutions resulting from the fixation of adaptive amino acid mutations. Allozyme analysis detected 57% of the distinctive amino acid sequences. Statistical tests of the distribution of polymorphic synonymous nucleotide sites identified four possible intragenic recombination events, one involving a single allele of E. coli and three involving alleles of the three subspecies of S. enterica. But recombination at mdh has not occurred with sufficient frequency to obscure the phylogenetic relationships among strains indicated by multilocus enzyme electrophoresis, total DNA hybridization, and sequence analysis of the gapA and putP genes. These findings provide further evidence that the effective (realized) rates of horizontal transfer and recombination for metabolic enzyme and other housekeeping genes are generally low in these species, in contrast to those for loci encoding or mediating the structure of cell-surface and other macromolecules for which recombinants may be subject to strong balancing, directional, or diversifying selection.

Adaptation, Physiological↗
PubMed1995

The eighth component of human complement: molecular basis of C8A (C81) polymorphism.

Using an exon-specific polymerase chain reaction (PCR) followed by direct DNA sequence analysis we have analyzed the polymorphism of the alpha-chain of the eighth component of human complement (C8) at the DNA level. We found that two common alleles, C8A*A and C8A*B, are characterized by the substitution of a single amino acid (Gln to Lys), which is caused by a point mutation of a single nucleotide (C to A) in exon 3 at position 187 of the mature C8 alpha cDNA sequence. Based on this mutation, an allele-specific PCR was designed detecting the two alleles of C8A. We applied this method to type the C8A polymorphism using DNA samples from a Chinese Han population. The comparison with the data of protein typing of the same samples proved that the described method is efficient and reliable for the identification of C8A genotypes and may be valuable for further application in population studies and forensic science.

Alleles↗