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PubMed1998

Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group.

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.

Alleles↗
PubMed1989

Evidence for genetic heterogeneity in tuberous sclerosis.

The question of genetic heterogeneity in tuberous sclerosis (TSC) was addressed by genetic linkage studies in eight affected families using nine polymorphic markers (EFD126.3, MCT136, ABO, ABL, AK1, and MCOA12 from distal 9q, and PBGD, MCT128.1, and 1CJ52.208M from distal 11q). The data as a whole supported a TSC locus on distal 9q, the peak lod score on multipoint analysis being 3.77 at 6 cM proximal to the Abelson oncogene locus (ABL). However, analysis of two point lod scores using the HOMOG programs showed significant evidence for genetic heterogeneity (p = 0.01), linkage to ABL being unlikely in one family. After exclusion of the unlinked family, multipoint analysis gave a peak lod score of 6.1 in the vicinity of ABL. The family unlinked to ABL showed no recombinants with two chromosome 11 probes, but was too small to provide significant evidence for linkage. Genetic heterogeneity in TSC will complicate efforts to clone the causative genes and severely limit the use of linked probes for carrier detection and prenatal diagnosis.

Chromosome Mapping↗
PubMed1978

Heterogeneity in diabetes mellitus--update, 1978. Evidence for further genetic heterogeneity within juvenile-onset insulin-dependent diabetes mellitus.

The concept that idiopathic diabetes mellitus is a genetically heterogeneous group of disorders has been established by twin and HLA studied that have permitted the separation of juvenile-onset and maturity-onset diabetes. The extent of the heterogeneity within the juvenile-onset and maturity-onset types is still in question. On the basis of recent immunologic and metabolic studies we believe that further heterogeneity can be demonstrated within the juvenile-onset diabetic group. We wish to hypothesize that there are at least two distinct forms of juvenile-onset diabetes, one associated with HLA B8 and the other with BW15. The B8 type is characterized by autoimmunity, microangiopathy, and a stronger association with the HLA D locus. The BW15 type is characterized by antibody response to exogenous insulin and a stronger association with the HLA C locus. Greater understanding of the pathogenesis, natural history, and genetics of diabetes mellitus will result as the full extent of genetic heterogeneity is elucidated.

Alleles↗
PubMed2001

Triangle test statistic in discordant sib pairs: test of genetic heterogeneity of asthma and atopy in CSGA families.

The purpose of our study was to detect genetic heterogeneity (i.e., different genotype relative risks of genetic factor) between atopic and non-atopic asthma and between atopy associated or independent of asthma. Genetic heterogeneity was tested in the Caucasian Collaborative Study on the Genetics of Asthma families using the TTS (triangle test statistic) and the predivided sample test. The TTS was proposed to detect both linkage and intra-sib-pair genetic heterogeneity; such heterogeneity may exist if the sibs differ for a factor on which the penetrances of the putative linked gene depend. The TTS has been applied to asthmatic pairs discordant for atopy and atopic sib pairs discordant for asthma. To confirm genetic heterogeneity detected by the TTS, the predivided sample test was also applied among concordant and discordant sib pairs. The analyses detected a genetic factor on chromosome 8p that could be involved in atopy with different genotype relative risks according to whether asthma is present. This would suggest a pleiotropic effect of this genetic factor in asthma and atopy. Two other regions located on chromosomes 8q and 20p were detected for genetic heterogeneity with asthma and atopy, respectively, but the factor of heterogeneity could be independent from the presence of atopy or asthma, respectively. It could be a characteristic of the disease such as the severity or the presence of an environmental factor.

Adult↗
PubMed2004

Do Taq-generated RT-PCR products from RNA viruses accurately reflect viral genetic heterogeneity?

Since the first report of genetically heterogeneous, or quasispecies, populations of RNA viruses, the genetic heterogeneity of the RNA genomes of major viral pathogens has been extensively studied. These studies aim to provide insights into the evolutionary pressures that act upon viruses, in order to define windows where anti-viral therapies will be most effective, to take prognostic values from viral genetic distributions at a given time, and to aid the development of novel therapeutic compounds that may tilt viral replication towards information loss. Many methodologies are employed to analyse genetic distributions of a virus in a given sample, but all involve the generation, and subsequent analysis, of the sequence information contained in a reverse-transcription-polymerase chain reaction (RT-PCR) product. Despite the fact that the aim of these RT-PCRs is to obtain sequence information from viral genomes, their application to this task is approached without adequate consideration of this end-goal. The establishment of an RT-PCR for a specific viral target genome generally proceeds in the same fashion as one would apply to establishing a PCR to determine the presence or absence of a specific target sequence in a given sample. However, it is becoming increasingly apparent that RT-PCR products generated by amplification with the ubiquitous thermostable DNA polymerase Taq, coupled with standard cloning and sequencing methodologies, has the potential to yield inaccurate and misleading data as pertains to the information content of populations of RNA viral genomes. This review discusses varying approaches employed to analyse heterogeneous populations of hepatitis C virus RNA genomes.

Base Pair Mismatch↗
PubMed2004

Costs and benefits of genetic heterogeneity within organisms.

An increasing number of studies have recently detected within-organism genetic heterogeneity suggesting that genetically homogeneous organisms may be rare. In this review, we examine the potential costs and benefits of such intraorganismal genetic heterogeneity (IGH) on the fitness of the individual. The costs of IGH include cancerous growth, parasitism, competitive interactions and developmental instability, all of which threaten the integrity of the individual while the potential benefits are increased genetic variability, size-specific processes, and synergistic interactions between genetic variants. The particular cost or benefit of IGH in a specific case depends on the organism type and the origin of the IGH. While mosaicism easily arise by genetic changes in an individual, and will be the more common type of IGH, chimerism originates by the fusion of genetically distinct entities, and is expected to be substantially rare in most organisms. Potential conflicts and synergistic effects between different genetic lineages within an individual provide an interesting example for theoretical and empirical studies of multilevel selection.

Adaptation, Biological↗
PubMed2000

Genetic heterogeneity in ductal carcinoma of the breast.

Genetic heterogeneity in breast cancer has been observed both by cytogenetic and loss of heterozygosity (LOH) analyses; however, the frequency with which genetically heterogeneous clones arise is unknown. In this study, a panel of 115 breast carcinomas was analyzed to determine the extent of clonal divergence in tumor foci at progressive stages of tumor evolution. Intraductal, infiltrating, and metastatic tumor components were microdissected from each tumor and tested for LOH at 20 microsatellite markers on seven chromosomal arms. Of these cases, 24 (21%) demonstrated genetically divergent clones during tumor progression. Clonal divergence, inferred from discordant LOH patterns, was observed most commonly between intraductal and infiltrating tumor (18 cases), but was also demonstrated between infiltrating and metastatic tumor (11 cases). Discordant LOH was observed with markers on one chromosomal arm in 16 cases, on two in 7 cases, and on four in 1 case, and was observed most commonly with markers on 17p, 17q, and 16q. More detailed microdissection of four cases provided evidence for a specific chronology of genetic alterations occurring during the progression of each tumor. The results indicate that the different tumor components observed microscopically in breast cancer specimens often represent genetically divergent clones.

Breast Neoplasms↗
PubMed1997

Linkage disequilibrium between the dopamine transporter gene (DAT1) and bipolar disorder: extending the transmission disequilibrium test (TDT) to examine genetic heterogeneity.

Since its introduction into the statistical genetics literature, the transmission disequilibrium test (TDT) has seen widespread use in analyses of linkage and association due not only to its simplicity but also to its desirable properties relative to other within-family analytic methods. In this paper, we describe an extension to the TDT useful for examining genetic heterogeneity. This extension uses contingency table analyses such as log-linear analysis to test for differences in linkage disequilibrium across levels of one or more moderator variables. We applied these analyses to test for linkage disequilibrium between the dopamine transporter gene (DAT1) and bipolar disorder, as well as for genetic heterogeneity due to sex, diagnostic breadth, and study site. Using data from two studies (the UCSD/UBC and Cardiff data sets), we found evidence suggesting linkage disequilibrium between DAT1 and bipolar disorder, as well as heterogeneity due to diagnostic breadth and study site.

Alleles↗
PubMed1985

Strategies for elucidating the phenotypic and genetic heterogeneity of a chronic disease with a complex etiology.

Genetic heterogeneity is a consequence of the complexity of the biology of disease. Revealing genetic heterogeneity exposes the complexity of the genotype-environment interactions that are expressed by the intervening phenotypes that link genotype with the disease endpoint. Because we have not identified the genes involved in most common diseases, studies of genetic heterogeneity have primarily focused on a statistical analysis of either the discrete endpoint or the quantitative intervening phenotypes. Rapid progress in the development of sophisticated measures of the genotype and the intervening phenotypes will enhance our ability to characterize the etiology of the chronic disease. Both statistical and molecular methods will be required to understand the impact of each of the many genes that are expected to contribute to the chronic disease burden in the population at large.

Anemia, Sickle Cell↗
PubMed1998

Typing methods to approach Pneumocystis carinii genetic heterogeneity.

The study of the genetic heterogeneity of P. carinii is complicated by the lack of an in vitro culture system, as well as by the likely occurrence of co-infections with several special forms or types in a single host. Karyotyping and multilocus enzyme electrophoresis are useful for studies at the evolutionary level. However, these methods require a large number of cells, which prevents their use for the special form infecting humans. DNA sequence analysis of genomic regions is useful to study P. carinii diversity, both at the evolutionary and epidemiological levels. To type the special form specific to humans, several methods are currently used to detect polymorphism in PCR products of polymorphic regions of the genome: DNA sequencing, type-specific hybridisations, and single-strand conformation polymorphism. All these methods still need evaluation. The frequency of potential co-infections in humans determined by these various methods is different. The differences could be due to methodological problems or to real variations between patient populations, geographical locations and/or prophylaxis regimens. In the future, elucidating the population structure of P. carinii and the frequency of potential co-infections is going to be crucial for a better understanding of its epidemiology, and thus for a better prevention of P. carinii pneumonia in humans.

DNA, Fungal↗
PubMed2006

Determination of molecular types and genetic heterogeneity of Cryptococcus neoformans and C. gattii in Malaysia.

The molecular types and genetic heterogeneity of Cryptococcus neoformans and C. gattii clinical isolates in Malaysia were determined in this study. Of 44 C. neoformans collected between 1980 and 2003, 42 (95.5%) were molecular type VNI, 2 (4.5%) were molecular type VNII. Of 17 C.gattii isolates, 13 (76.5%) were molecular type VGI, and 4 (23.5%) were molecular type VGII. A difference was noted when comparing the molecular types of cryptococcal isolates in the earlier and recent cases of cryptococcosis. While both molecular types VNI and VGI were equally predominant in the earlier cases of cryptococcosis, VNI was the most predominant molecular type isolated from the recent cases. VNII was a new molecular type, isolated from 5.1% of the recent cases. All the bird dropping isolates were molecular type VNI. The genetic heterogeneity of the two predominant molecular types, i.e., VNI, VGI clinical isolates and bird dropping isolates of C. neoformans were further determined by polymerase chain reaction (PCR) fingerprinting method, using (GTG)5 as single primer. Two clusters of cryptococcal isolates were distinguished at 68.5% of similarity, with cluster I consisting of VNI isolates and cluster II consisting of VGI isolates. Each cluster was further subdivided into three subtypes at >/=80% of similarity. Fourteen bird dropping isolates were grouped into a subtype within VN1, sharing 82.7% of similarity with the clinical isolates. A higher degree of similarities, ranging from 93.4-97.6% was noted between 3 bird dropping isolates with the clinical isolates in another subtype. This study demonstrated the existence of various molecular types of C. neoformans isolates in Malaysia and the genetic heterogeneity within the predominant molecular types. The study also provides evidence for genetic relatedness of clinical isolates with bird dropping isolates in the environment.

Cryptococcosis↗
PubMed1971

Genetic heterogeneity in Streptococcus mutans.

The genetic homogeneity among eight cariogenic strains of Streptococcus mutans was assessed by deoxyribonucleic acid (DNA)-DNA reassociation experiments. DNA species were extracted from strains GS5, Ingbritt, 10449, FAl, BHT, E49, SLl, and KlR. Labeled DNA ((14)C-DNA) was extracted from strains 10449, FAl, and SLl. Denatured (14)C-DNA fragments were allowed to reassociate, i.e., form hybrid duplexes, with denatured DNA immobilized on membrane filters incubated in 0.45 m NaCl-0.045 m sodium citrate at 67 or 75 C. At 67 C, 10449 (14)C-DNA reassociated extensively only with GS5 and Ingbritt DNA. FAl (14)C-DNA hybridized extensively only with BHT DNA, and SLl (14)C-DNA reassociated with KlR and E49 DNA. DNA which hybridized extensively at 67 C also reassociated to a high degree at 75 C. Thermal elution of (14)C-FAl-BHT duplexes showed that the hybrid duplexes were thermostable. The results indicate that S. mutans is a genetically heterogeneous species. The strains studied can be divided into three (possibly four) genetic groups, and these groups closely parallel antigenic groups.

Carbon Isotopes↗
PubMedDate not supplied

[Genetical heterogeneity of phenylketonuria].

Data on genetic nature of phenylketonuria molecular mechanisms of its pathogenesis and approaches to treatment and prophylaxis of the disease are reviewed. Genetic heterogeneity of phenylketonuria, dependent on polylocus control of phenylalanine hydroxylase complex, is considered in detail. A possibility is discussed of the existence of the genetically different forms of phenylketonuria. Data on the molecular structure of phenylalanine hydroxylase and cooperative nature of its active site are discussed. Variations in pathogenesis of different forms of the phenylketonuria, theoretical and practical significance of these investigations are considered.

Animals↗
PubMed1986

Detecting linkage for genetically heterogeneous diseases and detecting heterogeneity with linkage data.

Interest in searching for genetic linkage between diseases and marker loci has been greatly increased by the recent introduction of DNA polymorphisms. However, even for the most well-behaved Mendelian disorders, those with clear-cut mode of inheritance, complete penetrance, and no phenocopies, genetic heterogeneity may exist; that is, in the population there may be more than one locus that can determine the disease, and these loci may not be linked. In such cases, two questions arise: (1) What sample size is necessary to detect linkage for a genetically heterogeneous disease? (2) What sample size is necessary to detect heterogeneity given linkage between a disease and a marker locus? We have answered these questions for the most important types of matings under specified conditions: linkage phase known or unknown, number of alleles involved in the cross at the marker locus, and different numbers of affected and unaffected children. In general, the presence of heterogeneity increases the recombination value at which lod scores peak, by an amount that increases with the degree of heterogeneity. There is a corresponding increase in the number of families necessary to establish linkage. For the specific case of backcrosses between disease and marker loci with two alleles, linkage can be detected at recombination fractions up to 20% with reasonable numbers of families, even if only half the families carry the disease locus linked to the marker. The task is easier if more than two informative children are available or if phase is known. For recessive diseases, highly polymorphic markers with four different alleles in the parents greatly reduce the number of families required.

Alleles↗
PubMed1984

Detection of genetic heterogeneity among pedigrees through complex segregation analysis: an application to hypercholesterolemia.

Several methods for investigating genetic heterogeneity for extreme levels of a quantitative trait with hypothesized multiple genetic etiologies require a priori stratification of families and/or identification of distinct phenotypes among affected individuals. We present a statistical approach for detecting genetic heterogeneity that does not rely on either a priori stratification or discrete disease phenotypes. Complex segregation analysis was applied to total serum cholesterol measurements in 709 relatives of 98 healthy index cases selected from 3,666 school children surveyed for lipid levels in Rochester, Minnesota. Thirty-three of the index cases and 109 relatives had hypercholesterolemia (cholesterol levels greater than the 95th percentile for their age and sex). Through application of the mixed genetic model and then estimation of conditional probabilities for having the mutant allele at the major locus, genetic heterogeneity for hypercholesterolemia was indicated. In three of 70 pedigrees with one or more hypercholesterolemics, there is strong evidence for segregation at a major locus. In the remaining pedigrees, only polygene variation and/or environmental variation are associated with cholesterol variability. Grandparents in the three pedigrees that were segregating at the major locus had the highest rates of death due to coronary heart disease. This study establishes that the mixed model has the potential to identify pedigrees with different genetic etiologies for variability in quantitative traits.

Adult↗
PubMed2001

Indication of linkage and genetic heterogeneity of asthma according to age at onset on chromosome 7q in 107 French EGEA families.

It is generally believed that an early age at the onset of disease is associated with a stronger genetic component. Our aim here was to investigate both linkage and genetic heterogeneity of asthma, the latter corresponding to different genotype relative risks of a putative linked gene according to age at onset of asthma. This analysis was conducted in 107 French EGEA families with at least two asthmatic siblings, considering 157 markers that were part of our previous genome screen, using the TTS (the Triangle Test Statistic) which has been developed to detect both linkage and intra-sibpair genetic heterogeneity. This test has been applied to 38 asthmatic sib-pairs discordant for age at the onset of asthma. To confirm the existence of genetic heterogeneity, we also used the predivided sample test (PST) which compares the IBD (identity by descent) distribution of marker alleles between asthmatic sib-pairs concordant (67) and discordant (38) for the age at onset. The cutoff point used for the age at onset was 4 years, the median age at onset in our sample of asthmatic sibs. Linkage and genetic heterogeneity for a region located on chromosome 7q (at 109 cM from pter) were indicated by both tests, TTS (P=0.005, P>0.5 after correction for multiple testing) and PST (P=0.0001, 0.015 after correction). These results suggest a genetic factor on 7q involved in asthma with genotype relative risks differing according to age at onset of disease.

Age of Onset↗