Analysis of an IFN-gamma gene (IFNG) polymorphism in multiple sclerosis in Europe: effect of population structure on association with disease.

An intronic dinucleotide polymorphism in the IFN-gamma gene (IFNG) was used as a marker for testing association with multiple sclerosis (MS). Disease association was analyzed in case-control sets sampled from four geographically separate European populations (Germany, Northern Italy, Sardinia, and Sweden). Only in the Swedish was a weak disease association of the IFNG allele pattern found, mainly due to a higher frequency of IFNG allele I1 in MS patients.

Helicobacter pylori infection and polymorphisms in the tumor necrosis factor region.

Twin studies evidence that genetic factors of the host influence the acquisition and the clinical outcome of Helicobacter pylori infections in addition to bacterial and environmental factors. In the tumor necrosis factor (TNF) alpha-gene, allelic frequencies of the polymorphic microsatellite TNFa and the promoter polymorphism TNF-308 were studied for 209 H. pylori+ patients and compared to 184 H.

Protein binding to simple repetitive sequences depends on DNA secondary structure(s).

Simple repetitive DNA sequences are ubiquitous constituents of eukaryotic chromosomes. The properties of simple repeats generate increased interest as expansions of certain trinucleotide blocks cause human diseases. We studied protein binding and structural features of (gaa x ttc)n tracts e.

DNA analyses support the hypothesis that infanticide is adaptive in langur monkeys.

Although the killing of dependent infants by adult males is a widespread phenomenon among primates, its causes and consequences still remain hotly debated. According to the sexual selection hypothesis, infanticidal males will gain a reproductive advantage provided that only unrelated infants are killed and that the males increase their chances of siring the next infants. Alternatively, the social pathology hypothesis interprets infanticide as a result of crowded living conditions and, thus, as not providing any advantage.

Telomeric lengths and telomerase activity in liposarcomas.

To assess the role of telomerase in the development of liposarcomas, we measured telomerase activity in 36 malignant and seven benign lipomatous neoplasias from 34 patients. A sensitive polymerase chain reaction-based telomerase assay (the telomeric repeat amplification protocol) was applied. Shortening or elongation of telomeric repeat fragment lengths, as measured by using hybridization with a telomere-specific oligonucleotide probe, was correlated with the presence of telomerase activity.

Polymerase chain reaction-single strand conformation polymorphism or how to detect reliably and efficiently each sequence variation in many samples and many genes.

A simple and fast method with high reliability is necessary for the identification of mutations, polymorphisms and sequence variants (MPSV) within many genes and many samples, e.g. to clarify the genetic background of individuals with multifactorial diseases.

[Promoting remyelination as a future therapeutic principle in multiple sclerosis?].

Multiple sclerosis (MS), the most common neurological autoimmune disorder diagnosed in young adults, is characterised by the repeated occurrence of demyelinating lesions within the central nervous system (CNS). Promotion of remyelination in the brain and spinal cord constitutes a potential strategy for therapeutic intervention in MS and other demyelinating diseases. Three different principles are known to promote remyelination in the CNS of different animal models: Application of growth factors, transplantation of myelin-forming cells and intravenous immunoglobulin (IVIg) therapy.

Amplification of microsatellites adapted from human systems in faecal DNA of wild Hanuman langurs (Presbytis entellus).

Microsatellite systems originally established for human DNA were utilized for paternity testing from faecal DNA in a natural population of Hanuman langurs (Presbytis entellus). Thirty-two primer pairs were applied to amplify DNA obtained from langur faeces. Twenty-two of these primer pairs yielded specific amplification products and 11 loci were polymorphic.

On telomere shortening in soft-tissue tumors.

Purpose: Specific simple DNA repeats occur at the telomeric ends of mammalian chromosomes. Loss of (G + C)-rich repeats can result in genetic instability, associated with tumorigenesis. So far, data on telomere shortening have not been available for different types of soft-tissue tumors.

An association between NIDDM and a GAA trinucleotide repeat polymorphism in the X25/frataxin (Friedreich's ataxia) gene.

Friedreich's ataxia is the most common hereditary ataxia and is frequently associated with disturbances of glucose metabolism. This autosomal recessive disease is caused by the decreased expression of a mitochondrial protein, frataxin, encoded by the X25 gene. Homozygous expansion of a GAA repeat in the first intron of X25 inhibits frataxin expression and is associated with clinical disease.

Friedreich's ataxia. Revision of the phenotype according to molecular genetics.

Friedreich's ataxia is an autosomal recessively inherited neurodegenerative disorder caused by expansions of an unstable GAA trinucleotide repeat in the STM7/X25 gene on chromosome 9q. We studied the (GAA)n polymorphism in 178 healthy controls and 102 patients with idiopathic ataxia. The repeat size ranged from 7 to 29 (GAA)n motifs on normal chromosomes and from 66 to 1360 trinucleotide repetitions in Friedreich's ataxia patients.

Human PEX1 is mutated in complementation group 1 of the peroxisome biogenesis disorders.

Human peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal-recessive disease caused by mutations in PEX genes that encode peroxins, proteins required for peroxisome biogenesis. These lethal diseases include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum's disease (IRD), three phenotypes now thought to represent a continuum of clinical features that are most severe in ZS, milder in NALD and least severe in IRD2. At least eleven PBD complementation groups have been identified by somatic-cell hybridization analysis compared to the eighteen PEX complementation groups that have been found in yeast.

On simple repetitive DNA sequences and complex diseases.

Simple repetitive DNA sequences are abundantly interspersed in eukaryote genomes and therefore useful in genome research and genetic fingerprinting in plants, fungi and animals, including man. Recently, simple repeats were also identified in some prokaryotic genomes. Hence the same probes can be applied for multilocus DNA fingerprinting in medically relevant bacteria.

Differential stability of the (GAA)n tract in the Friedreich ataxia (STM7) gene.

Friedreich ataxia (FA) is an autosomal recessive, neurodegenerative disorder characterized by polypurine trinucleotide expansion. The (GAA)n motif is located in intron 18 of the STM7 gene (previously considered as intron 1 of the X25 gene) on chromosome 9q13. We studied the distribution profile of the polymorphic (GAA)n repetitive tract in 178 healthy individuals.

Extensive gene flow in human populations as revealed by protein and microsatellite DNA markers.

Population genetic studies are mainly based on the description of genetic variability and on interpopulational comparisons using genetic distance measures. The evolutionary dynamics of the populations are inferred from these parameters and accurate estimates of gene flow may be critical. The present study reevaluates the role of gene flow in human populations by different statistical methods from a number of microsatellite and protein polymorphism data.

Genetic predisposition to multiple sclerosis as revealed by immunoprinting.

This study was designed to examine the immunogenetic background predisposing to multiple sclerosis (MS). Three hundred fifty-eight clinically well-characterized MS patients from Germany were investigated and compared to 395 healthy control subjects. Each individual was genotyped for 22 polymorphic markers located within or close to immunorelevant candidate genes including HLA-DRB1*, T-cell receptor (TCR), cell interaction molecules, cytokines, and cytokine receptor genes.

Coding versus intron variability: extremely polymorphic HLA-DRB1 exons are flanked by specific composite microsatellites, even in distant populations.

Although microsatellite typing is the dominant method in genome research and indirect gene diagnosis, precise relationships of exonic and adjacent simple repeat polymorphisms are not known. We investigated exon 2 sequences of HLA-DRB1 genes and their neighbouring (GT)n(GA)m repeats including the intervening single copy spacer. DRB1 is the most polymorphic protein-coding locus in man and all vertebrates investigated.

Multilocus fingerprinting and single locus analyses in the great tit for paternity determination.

In order to arrive at detailed information about the occurrence of alternative reproductive tactics in the great tit (Parus major) we examined parental lineages by multilocus fingerprinting in 51 great tit broods containing 429 nestlings. In 45% of the broods at least one nestling was found to stem from copulations with males other than the social mate of the female. Single broods contained up to 62% extra-pair young (EPY).

Immunoprinting reveals different genetic bases for (auto)immuno diseases.

The genetic basis of complex (auto)immune diseases has been studied for an ovine nematode infection, human rheumatoid arthritis (RA), early onset pauciarticular arthritis (EOPA) and multiple sclerosis (MS). Immunoprinting combines the powerful simplicity of polymerase chain reaction (PCR)-based amplification of discrete, highly informative microsatellite loci with the principle of genetic associations. This approach has allowed us to define novel genetic risk factors in adult RA patient categories whereas EOPA forms in juveniles display other prominent genetic contributions.

Immunoprinting excludes many potential susceptibility genes as predisposing to early onset pauciarticular juvenile chronic arthritis except HLA class II and TNF.

DNA profiles (immunoprints) were generated for 120 patients suffering from early onset pauciarticular chronic arthritis (EOPA-JCA) and > 500 healthy controls utilizing highly polymorphic microsatellites in the vicinity of immunorelevant genes. Six T cell receptor (TCR) markers for the CD3D, TCRDVAJ, TEA, TCRBV6S1, BV6S3, BV6S7 and BV13S2 genes were analysed. Furthermore markers for the cell surface molecule CD40L, for cytokine genes (IL-1A, IL-2, IFN-alpha, FGF-alpha, TNF-alpha), the chromosomal region of the IRF2 and the cytokine receptor gene IL5RA were studied as well as two polymorphisms within the promotor region of the TNF-alpha gene.

Indirect gene diagnoses for complex (multifactorial) diseases--a review.

The analysis of multifactorial diseases requires the efficient investigation of large numbers of (gene) loci and patient (family) samples. Since simple repetitive DNA markers are dispersed all over the chromosomes, molecular techniques employing these tools render most conventional screening procedures obsolete. Examples of tumors, autoimmune diseases and infections are presented to validate concepts of indirect gene diagnoses via simple, tandemly arranged, repetitive DNA sequences.

Indirect DNA/gene diagnoses via electrophoresis--an obsolete principle?

In principle, gene defects can be investigated directly or indirectly via informative polymorphisms in their vicinity. But because many defects are not yet defined molecularly, these inherited diseases can only be diagnosed indirectly via analysis of informative family situations. Since (multiple) mutation analyses, e.