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PubMed2003

Global patterns in peatmoss biodiversity.

DNA sequence data from the nuclear ribosomal internal transcribed spacers (ITS) and the trnL-trnF chloroplast DNA regions were used to quantify geographical partitioning of global biodiversity in peatmosses (Sphagnum), and to compare patterns of molecular diversity with patterns of species richness. Molecular diversity was estimated for boreal, tropical, Neotropical, nonboreal (tropical plus Southern Hemisphere), Old World and New World partitions, based on a total of 436 accessions. Diversity was partitioned among geographical regions in terms of combined nuclear and chloroplast sequence data and separately for the ITS and trnL-trnF data sets. Levels of variation were estimated using phylogenetic diversity (PD), which incorporates branch lengths from a phylogenetic tree, and the number of polymorphic nucleotide sites. Estimates of species richness suggest that peatmoss diversity is higher in New World than Old World regions, and that the Neotropics constitute a "hotspot" of diversity. Molecular estimates, in contrast, indicate that peatmoss biodiversity is almost evenly divided between New and Old World regions, and that the Neotropics account for only 20-35% of global peatmoss diversity. In general, levels of tropical and boreal peatmoss molecular diversity were comparable. Two species, S. sericeum from the Old World tropics and S. lapazense from Bolivia, are remarkably divergent in nucleotide sequences from all other Sphagna and together account for almost 20% of all peatmoss diversity, although they are represented by only three of the 436 accessions (0.7%). These species clearly demonstrate the nonequivalence of species biodiversity value.

Base Sequence↗
PubMed1997

Characterization of the rat neurofibromatosis 2 gene and its involvement in asbestos-induced mesothelioma.

The neurofibromatosis 2 (NF2) tumor suppressor gene was recently implicated in the genesis of human mesothelioma. To investigate the role of this tumor suppressor gene in rat asbestos-induced mesothelioma, a commonly used model for the human disease, we characterized the rat homologue of NF2 and examined rat chrysotile-induced primary mesotheliomas and cell lines derived from chrysotile- and crocidolite-induced mesotheliomas for alterations in this gene. The coding sequence obtained for the rat NF2 gene had 90% nucleotide homology with the human NF2 gene. The rat NF2 gene was ubiquitously expressed as a 4.4-kb transcript in normal rat tissues as well as in rat mesothelioma cell lines. Reverse transcription-polymerase chain reaction analysis to examine splicing of NF2 exons in mesothelioma cells indicated that the exon splicing pattern was similar in normal and neoplastic cells. To determine if mutations had occurred in the NF2 coding region in rat mesotheliomas, single-strand conformation polymorphism analysis and direct sequencing were used to screen 10 primary tumors and six tumor cell lines. No DNA sequence alterations were observed in any of the rat mesothelioma samples examined. These findings contrast with data reported previously for human mesotheliomas, in which the NF2 gene was found to be mutated in 40% of cases. Taken together, these data suggest that the role of NF2 in the development of rodent asbestos-induced mesothelioma may differ significantly from the role in the human disease.

Animals↗
PubMed1998

Positive selection driving the evolution of a gene of male reproduction, Acp26Aa, of Drosophila: II. Divergence versus polymorphism.

The evolution of the gene for a male ejaculatory protein, Acp26Aa, has been shown to be driven by positive selection when nonsibling species in the Drosophila melanogaster subgroup are compared. To know if selection has been operating in the recent past and to understand the details of its dynamics, we obtained DNA sequences of Acp26Aa and the nearby Acp26Ab gene from 39 D. melanogaster chromosomes. Together with the 10 published sequences, we analyzed 49 sequences from five populations in four continents. The southern African population is somewhat differentiated from all other populations, but its nucleotide diversity is lower at these two loci. We find the following results for Acp26Aa: (1) The R: S (replacement : silent changes) ratio is significantly higher in the between-species comparisons than in the within-species data by the McDonald and Kreitman test. Positive selection is probably responsible for the excess of amino acid replacements between species. (2) However, within-species nucleotide diversity is high. Neither the Tajima test nor the Fu and Li test indicates a reduction in nucleotide diversity due to positive selection in the recent past. (3) The newly derived nucleotides in D. melanogaster are at high frequency significantly more often than predicted by the neutral equilibrium. Since the nearby Acp26Ab gene does not show these patterns, these observations cannot be attributed to the characteristics of this chromosomal region. We suggest that positive selection is active, but may be weak, for each amino acid change in the Acp26Aa gene.

Animals↗
PubMed2005

Evidence for paternal transmission and heteroplasmy in the mitochondrial genome of Silene vulgaris, a gynodioecious plant.

Gynodioecy refers to the co-occurrence of females and hermaphrodites in the same population. In many gynodioecious plants, sex is determined by an epistatic interaction between mitochondrial and nuclear genes, resulting in intragenomic evolutionary conflict, should the mitochondrial genome be maternally inherited. While maternal inheritance of the mitochondrial genome is common in angiosperms, few gynodioecious species have been studied. Here, the inheritance of the mitochondrial genes atpA and coxI was studied in 318 Silene vulgaris individuals distributed among 23 crosses. While maternal inheritance was indicated in 96% of the individuals studied, one or more individuals from each of four sib groups displayed a genotype that was identical to the father, or that did not match either parent. Given evidence that inheritance is not strictly maternal, it was hypothesized that some individuals could carry a mixture of maternally and paternally derived copies of the mitochondrial genome, a condition known as heteroplasmy. Since heteroplasmy might be difficult to detect should multiple versions of the mitochondrial genome co-occur in highly unequal copy number, a method was devised to amplify low-copy number forms of atpA differentially. Evidence for heteroplasmy was found in 23 of the 99 individuals studied, including cases in which the otherwise cryptic form of atpA matched the paternal genotype. The distribution of shared nucleotide sequence polymorphism among atpA haplotypes and the results of a population survey of the joint distribution of atpA and coxI haplotypes across individuals supports the hypothesis that heteroplasmy facilitates formation of novel mitochondrial genotypes by recombination.

DNA, Mitochondrial↗
PubMed2005

Mitochondrial polymorphisms and susceptibility to type 2 diabetes-related traits in Finns.

Mitochondria play an integral role in ATP production in cells and are involved in glucose metabolism and insulin secretion, suggesting that variants in the mitochondrial genome may contribute to diabetes susceptibility. In a study of Finnish families ascertained for type 2 diabetes mellitus (T2DM), we genotyped single nucleotide polymorphisms (SNPs) based on phylogenetic networks. These SNPs defined eight major haplogroups and subdivided groups H and U, which are common in Finns. We evaluated association with both diabetes disease status and up to 14 diabetes-related traits for 762 cases, 402 non-diabetic controls, and 465 offspring of genotyped females. Haplogroup J showed a trend toward association with T2DM affected status (OR 1.69, P=0.056) that became slightly more significant after excluding cases with affected fathers (OR 1.77, P=0.045). We also genotyped non-haplogroup-tagging SNPs previously reported to show evidence for association with diabetes or related traits. Our data support previous evidence for association of T16189C with reduced ponderal index at birth and also show evidence for association with reduced birthweight but not with diabetes status. Given the multiple tests performed and the significance levels obtained, this study suggests that mitochondrial genome variants may play at most a modest role in glucose metabolism in the Finnish population. Furthermore, our data do not support a reported maternal inheritance pattern of T2DM but instead show a strong effect of recall bias.

Adenosine Triphosphate↗
PubMed1983

Interstrain mitochondrial DNA polymorphism detected in Acanthamoeba by restriction endonuclease analysis.

The genus Acanthamoeba includes pathogenic and nonpathogenic strains of amebas with unclear taxonomic and evolutionary relationships. To explore these relationships further, we have examined mitochondrial DNA fragment patterns obtained for 15 Acanthamoeba strains by use of five restriction endonucleases. The mitochondrial DNA molecules were circular, averaging 41.6 +/- 1.5 kilobase pairs. Fragments resulting from endonuclease digestion of the DNA were separated by agarose gel electrophoresis. Ten distinct families of electrophoretic patterns (digestion phenotypes) were observed. Seven phenotypes were found for seven strains considered nonpathogenic or of unknown pathogenicity. Three phenotypes were associated with pathogenic strains. One of these phenotypes included a single pathogenic strain, a second included one pathogen and one strain of unknown pathogenicity, and the third included five pathogenic strains. The latter five were of widespread geographic origin and previously were assigned to two different species. The results suggest that extensive nucleotide sequence diversity occurs among strains from a single species of Acanthamoeba, but that subgroups of strains with similar sequences also occur. Thus, restriction enzyme analysis can identify clusters of strains and may be a useful approach to classification in the genus. Improvements in classification should help clarify relationships among pathogenic and non-pathogenic strains.

Amoeba↗
PubMed2004

Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach.

Aspirin-intolerant asthma (AIA) is a subtype of bronchial asthma characterized by development of bronchoconstriction evoked by non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit the cyclooxygenase pathway, leading to enhancement of the lipoxygenase pathway. We evaluated allelic association of 370 single nucleotide polymorphisms (SNPs) of 63 candidate genes, mostly from the arachidonic acid metabolic cascade, with AIA. After two rounds of screening with 198 AIA patients, multiple SNPs in the prostaglandin E(2) receptor subtype 2 (EP2) gene were associated with AIA (P<0.05). Among the 77 SNPs identified in the EP2 gene, we selected 17 SNPs on the basis of linkage disequilibrium and allelic frequencies (minor allele frequency >0.1) for further association study. SNPs in the promoter region of the EP2 gene, uS5, uS5b, and uS7, were significantly associated with AIA (permutation P=0.039-0.001). Analysis of haplotypes constructed according to the LD pattern showed a significant association with AIA (permutation P=0.001). The most significantly associated SNP, uS5, located in the regulatory region of the EP2 gene, was in a STATs-binding consensus sequence [AIA 31.1% versus control 22.1% (permutation P=0.0016) or versus aspirin-tolerant asthma 22.2% (permutation P=0.0017)]. Although STAT1 binding was not observed in gel mobility shift assay with HeLa nuclear extract, an unidentified protein was specifically bound to the allelic sequence. In in vitro reporter assay in HCT116 cells, the site containing the uS5 allele showed reduced transcription activity. Taken together, these results suggest that uS5 allele serves as a target of a transcription repressor protein. A functional SNP of the EP2 gene associated with risk of AIA should decrease the transcription level, resulting in reduction of the PGE(2) braking mechanism of inflammation and involvement in the molecular mechanism underlying AIA.

Aspirin↗
PubMed1998

Analysis of p53 gene mutations in keloids using polymerase chain reaction-based single-strand conformational polymorphism and DNA sequencing.

BACKGROUND: Keloids are the result of a dysregulated wound healing process. They are characterized by the formation of excess scar tissue that proliferates beyond the boundaries of the original wound. Somatic mutations of p53 have been implicated as causal events in up to 50% of all human malignancies. In addition, p53 has been shown to play an important role in controlling cell proliferation and apoptosis. We hypothesize that mutations in p53 can lead to a hyperproliferative state that can result in keloid formation. OBJECTIVE: To detect p53 DNA mutations in tissues and cultured fibroblasts from skin lesions of 7 patients with keloids. DESIGN: The polymerase chain reaction followed by single-strand conformational polymorphism analysis and direct DNA sequencing were used to detect p53 gene mutations. SETTING: The Department of Dermatology, Henry Ford Hospital, Detroit, Mich. PATIENTS: Seven patients with keloids seen for routine surgical excision of their lesions. Normal DNA specimens were obtained from buccal smears and healthy skin samples from these patients. RESULTS: Mutations in the p53 were identified in all patients by polymerase chain reaction followed by single-strand conformational polymorphism analysis and subsequently confirmed by DNA sequencing. A mutation in exon 5 resulting in amino acid substitution was found in 1 of the patients in keloid tissue and cultured keloid fibroblasts (codon 156, CGC-->CCC, arginine-->proline). Frameshift mutations in exons 5 and 6 caused by the insertion or deletion of a nucleotide at different positions were found in 6 patients with keloids in both keloid tissues and cultured fibroblasts. Mutations in exon 4 resulting in amino acid substitution were found in all patients in both keloid tissues and cultured fibroblasts (all in codon 72, CGC-->CCC, arginine-->proline). No p53 mutations were detected in buccal smears or cultured fibroblasts from healthy skin samples of any of the patients. CONCLUSIONS: Focal mutations in p53 may increase cell proliferation and decrease cell death in the dysregulated growth patterns that have been clinically documented. An understanding of the pattern of all growth dysregulation related to keloids may lead to new therapeutic strategies.

Adult↗
PubMed2006

Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context.

We questioned the significance of haplotype structure in gene regulation by testing whether individual single nucleotide polymorphisms (SNPs) within a gene promoter region [interleukin-1-beta (IL1B)] might affect promoter function and, if so, whether function was dependent on haplotype context. We sequenced genomic DNA from 25 individuals of diverse ethnicity, focusing on exons and upstream flanking regions of genes of the cluster. We identified four IL1B promoter region SNPs that were active in transient transfection reporter gene assays. To substantiate allelic differences found in reporter gene assays, we also examined nuclear protein binding to promoter sequence oligonucleotides containing different alleles of the SNPs. The effect of individual SNPs on reporter gene transcription varied according to which alleles of the three other SNPs were present in the promoter construct. The SNP patterns that influenced function reflected common haplotypes that occur in the population, suggesting functionally significant interactions between SNPs according to haplotype context. Of the haplotypes that include the four functional IL1B promoter SNPs (-3737, -1464, -511, -31), the four haplotypes that showed different contextual effects on SNP function accounted for >98% of the estimated haplotypes in Caucasian and African-American populations. This finding underlines the importance of understanding the haplotype structure of populations used for genetic studies and may be especially important in the functional analysis of genetic variation across gene regulatory regions.

Black or African American↗
PubMed2005

High sequence diversity and evidence of balancing selection in the Pvmsp3alpha gene of Plasmodium vivax in the Venezuelan Amazon.

The genetic diversity of a defined Plasmodium vivax population from the Venezuelan Amazon was evaluated by direct sequencing of the gene encoding the P. vivax merozoite surface protein-3alpha, Pvmsp3alpha. Three allele sizes (1.9, 1.4 and 1.1kb) were amplified from 58 isolates with frequencies of 59.3%, 21.9% and 18.8%, respectively. 27 Pvmsp3alpha nucleotide sequences were determined, with nine distinct haplotypes observed. The genetic diversity (h) at this single locus was 0.774. The P. vivax population in this region exhibits significant diversity in contrast to the genetically restricted diversity of the sympatric P. falciparum population. Despite sharing vector and human hosts, different control strategies may be required for these two species in this region. Substitution patterns in the conserved C-terminus of Pvmsp3alpha showed a significant departure from neutrality, suggesting these polymorphisms are being maintained by frequency-dependent selection as the result of an effective immune response from the host. Our findings support the use of Pvmsp3alpha genotyping as a tool for monitoring interventions aimed at control of P. vivax.

Alleles↗
PubMed2003

Using haplotype blocks to map human complex trait loci.

Understanding of linkage disequilibrium (LD) in human populations could facilitate the discovery of genes that influence complex human diseases. The "HapMap" project is now underway to characterize patterns of LD in the human genome. A pilot study showed "haplotype blocks" in 51 regions scattered throughout the genome. These intriguing results raise important questions about the nature of recombination, and highlight practical issues of marker collection, the influence of statistical modelling on apparent block structure, and the levels of genotyping necessary for studies of common diseases. Knowledge of local disequilibrium patterns may help identify common polymorphisms involved in complex disease, but completely new analytical methods and experimental designs will be required to identify important rare variants.

Chromosome Mapping↗
PubMed1998

Species-wide homogeneity of nuclear ribosomal ITS2 sequences in the spider mite Tetranychus urticae contrasts with extensive mitochondrial COI polymorphism.

We compared patterns of intraspecific polymorphism of two markers with contrasted modes of evolution, nuclear ribosomal DNA (rDNA) and mitochondrial DNA (mtDNA), in the phytophagous mite Tetranychus urticae Koch. The second internal transcribed spacer (ITS2) of rDNA and a fragment in the mtDNA gene coding for Cytochrome Oxidase I (COI), were PCR-amplified and sequenced in samples of various geographical origins distributed worldwide. The 15 COI haplotypes found fell into two major phylogenetic lineages differing by an average of 5% nucleotide divergence. Samples from the Mediterranean basin were represented in both lineages, and showed no phylogeographical structure. The other samples, from temperate regions of the northern hemisphere, were clustered in one of the lineages and displayed little variation, indicating a recent colonization of this region. In contrast, no variation at all was found at the ITS2 in this species. We sequenced both COI and ITS2 in four other species of the genus Tetranychus and found that, despite the absence of intraspecific polymorphism, ITS appears to evolve 2.5 times faster than COI. We argue that rDNA homogeneity over the species range of T. urticae results from the high colonization potential of this species, preventing long-term differentiation. Preliminary data on two other mite species (Amphitetranychus viennensis Zacher and Mononychellus progresivus Doreste) with stricter ecological requirements and more restricted colonization potential revealed substantial and concordant geographical differentiation for both ITS2 and COI.

Animals↗
PubMed2006

A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity.

Childhood absence epilepsy (CAE) is considered to exhibit a complex non-Mendelian pattern of inheritance. So far, only few CAE susceptibility genes have been identified. In a previous study of our group, an association between the GABA(A) receptor beta3 subunit (GABRB3) gene and CAE was shown. To further investigate this association, we screened 45 CAE patients of the first study for mutations in the 10 exons, the exon-intron boundaries and the regulatory sequences of GABRB3. Although we found no functionally relevant mutation, we did identify 13 single nucleotide polymorphisms (SNPs) in the GABRB3 gene region from the exon 1a promoter to the beginning of intron 3. Using these SNPs we defined four haplotypes for the respective GABRB3 gene region. A transmission disequilibrium test in the same 45 CAE patients and their parents indicated a significant association of this region and CAE (P=0.007075). Reporter gene assays in NT2 cells using exon 1a promoter constructs indicated that the disease-associated haplotype 2 promoter causes a significantly lower transcriptional activity than the haplotype 1 promoter that is over-represented in the controls. In silico analysis suggested that an exchange from T (haplotype 1) to C (haplotype 2) within this promoter impairs binding of the neuron-specific transcriptional activator N-Oct-3. Electrophoretic mobility shift assays demonstrated that the respective polymorphism reduces the nuclear protein binding affinity, thus explaining the results of the reporter gene assays. Reduced expression of the GABRB3 gene could therefore be one potential cause for the development of CAE, pathogenetically relevant in our patient group.

Adolescent↗
PubMed1994

Fluctuation of hepatitis C virus quasispecies in persistent infection and interferon treatment revealed by single-strand conformation polymorphism analysis.

Hepatitis C virus (HCV) populations in vivo consist of heterogeneous mixtures of genetically different but closely related variants defined as a 'quasispecies'. The longitudinal fluctuation of HCV quasispecies populations in chronic hepatitis C has not been elucidated. Serial plasma samples were obtained from four patients with chronic hepatitis C (two patients without any treatment and two patients treated with interferon), and cDNA fragments containing the 5'-terminal region of the E2 gene of HCV were amplified from plasma RNA using PCR. Since conventional cloning of PCR products detects only a small part of the entire population, PCR products of each sample were separated by electrophoresis using single-strand conformation polymorphism (SSCP) analysis, which can distinguish DNA fragments of the same size as different electrophoretic bands depending on their sequence-specific conformation. Separated DNA fragments were recovered from SSCP bands in gels and their nucleotide sequences determined. SSCP electrophoresis separated PCR products into bands with different mobility. Sequence analysis of these bands confirmed that HCV populations in each patient are composed of quasispecies with different E2-hypervariable regions (HVR), which are known to contain antibody epitopes. Different patterns of variation in the HVR of quasispecies were observed in individual patients with different clinical features over time during chronic infection. Following interferon treatment, some quasispecies disappeared during the treatment and reappeared after the end of the treatment, whereas other quasispecies in the same patient remained during the treatment suggesting that the sensitivity to interferon is different among quasispecies.

Base Sequence↗
PubMed2004

Nucleotide variation of seven genes in Drosophila kikkawai.

We examined levels and patterns of nucleotide variation in 21 strains of Drosophila kikkawai from Miyako island, Japan for the partial regions of the following seven nuclear genes: Adh, Ddc, esc, ksr, Pgi, su(f), and Tpi. The nucleotide variation at total sites (pi(t)) ranged from 0.0013 in the ksr, to 0.0173 in the Adh. The nucleotide divergence at total sites (K(t)) between D. kikkawai and D. lini ranged from 0.0286 in the Tpi to 0.0687 in the su(f). The levels of nucleotide polymorphism and divergence were heterogeneous among the investigated gene regions. The HKA test, which tests imbalance between the intra and interspecific nucleotide variation, showed that the intraspecific nucleotide variation in the Pgi region was much lower than the interspecific variation, while intraspecific variation in the Tpi region was only slightly lower than interspecific variation. The MK test showed an excess of low frequency replacement polymorphic changes in the Adh region, suggesting that most replacement mutations are deleterious. Fay and Wu's test detected an excess of newly arisen variants in the Ddc region. In total, four of the seven gene regions showed significant deviation from the neutrality.

Alcohol Dehydrogenase↗
PubMed2004

The role of haplotypes in candidate gene studies.

Human geneticists working on systems for which it is possible to make a strong case for a set of candidate genes face the problem of whether it is necessary to consider the variation in those genes as phased haplotypes, or whether the one-SNP-at-a-time approach might perform as well. There are three reasons why the phased haplotype route should be an improvement. First, the protein products of the candidate genes occur in polypeptide chains whose folding and other properties may depend on particular combinations of amino acids. Second, population genetic principles show us that variation in populations is inherently structured into haplotypes. Third, the statistical power of association tests with phased data is likely to be improved because of the reduction in dimension. However, in reality it takes a great deal of extra work to obtain valid haplotype phase information, and inferred phase information may simply compound the errors. In addition, if the causal connection between SNPs and a phenotype is truly driven by just a single SNP, then the haplotype-based approach may perform worse than the one-SNP-at-a-time approach. Here we examine some of the factors that affect haplotype patterns in genes, how haplotypes may be inferred, and how haplotypes have been useful in the context of testing association between candidate genes and complex traits.

Genetic Predisposition to Disease↗
PubMed2005

Dynamic model based algorithms for screening and genotyping over 100 K SNPs on oligonucleotide microarrays.

MOTIVATION: A high density of single nucleotide polymorphism (SNP) coverage on the genome is desirable and often an essential requirement for population genetics studies. Region-specific or chromosome-specific linkage studies also benefit from the availability of as many high quality SNPs as possible. The availability of millions of SNPs from both Perlegen and the public domain and the development of an efficient microarray-based assay for genotyping SNPs has brought up some interesting analytical challenges. Effective methods for the selection of optimal subsets of SNPs spanning the genome and methods for accurately calling genotypes from probe hybridization patterns have enabled the development of a new microarray-based system for robustly genotyping over 100,000 SNPs per sample. RESULTS: We introduce a new dynamic model-based algorithm (DM) for screening over 3 million SNPs and genotyping over 100,000 SNPs. The model is based on four possible underlying states: Null, A, AB and B for each probe quartet. We calculate a probe-level log likelihood for each model and then select between the four competing models with an SNP-level statistical aggregation across multiple probe quartets to provide a high-quality genotype call along with a quality measure of the call. We assess performance with HapMap reference genotypes, informative Mendelian inheritance relationship in families, and consistency between DM and another genotype classification method. At a call rate of 95.91% the concordance with reference genotypes from the HapMap Project is 99.81% based on over 1.5 million genotypes, the Mendelian error rate is 0.018% based on 10 trios, and the consistency between DM and MPAM is 99.90% at a comparable rate of 97.18%. We also develop methods for SNP selection and optimal probe selection. AVAILABILITY: The DM algorithm is available in Affymetrix's Genotyping Tools software package and in Affymetrix's GDAS software package. See http://www.affymetrix.com for further information. 10 K and 100 K mapping array data are available on the Affymetrix website.

Algorithms↗
PubMed2003

Human inter-individual DNA sequence variation in candidate genes, drug targets, the importance of haplotypes and pharmacogenomics.

The identification of genes predisposing to human diseases is of paramount importance for understanding the molecular basis of the disease and individually different drug response, and will establish new routes to diagnosis and therapeutic advances of immense medical benefit. A key step common to all strategies for disease gene identification is the systematic analysis of candidate gene sequences to identify specific sequence variations associated with disease or any other phenotype of pharmaceutical relevance. In this article, current concepts and approaches to haplotype-based candidate gene analysis are reviewed. Moreover, a comprehensive summary of recent studies and data on the amount, nature, pattern and structure of genetic variation in candidate genes is given. These data demonstrate altogether remarkable gene sequence and haplotype diversity. Numerous individually different forms of a gene may exist. This presents challenges to the traditional views of the concept of "a" gene with far-reaching implications on the functional analysis of candidate gene variation, on the establishment of "sequence"-"structure"-"function" and complex haplotype/genotype-phenotype relationships, on the identification, evaluation and prioritization of drug targets and the concept of a "personalized medicine" in general. Moreover, present and future approaches to the identification of candidate and disease genes will be addressed. These include whole genome-based approaches such as integrative genomics as well as functional genomics-based approaches to analyze and model complex biological and medical processes. The analysis of whole complex systems in particular will provide the basis to make "maximally informed" guesses on candidate genes and address complex variability patterns in genes as well as complex genotype-phenotype relationships comprehensively at an advanced level.

Base Sequence↗