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PubMed2002

The detection of IRF-1 promoter polymorphisms and their possible contribution to T helper 1 response in chronic hepatitis C.

We described the interferon (IFN) regulatory factor-1 (IRF-1) promoter single nucleotide polymorphisms (SNPs), and the clinical and immunologic implications of these SNPs have been investigated. We successfully determined the mutation at -300 of the IRF-1 promoter by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and this mutation linked with other mutations in the promoter region. In our Japanese population, the frequency of the type -300*A/A was 11.9%, type A/G was 54.2%, and type G/G was 33.9%. We found no significant difference without IFN stimulation in the production levels of IFN-gamma and interleukin-10 (IL-10) from peripheral blood mononuclear cells (PBMC) between subjects with -300*A/A and those with other types. IFN-alpha stimulation, however, increased the levels of IFN-gamma significantly and decreased the IL-10 production level significantly only in the subject with -300*A/A type. Flow cytometric analysis showed that the Th1-type CD4(+) cell population was significantly increased by IFN-beta administration only in the patient with chronic hepatitis C with -300*A/A type. These results suggest that the IRF-1 promoter SNP types are positively involved in Th1-type response and, consequently, the -300*A/A type may be beneficial for viral elimination in chronic hepatitis C and IFN therapy.

Base Sequence↗
PubMed2002

Positional candidate gene analysis of Lim domain homeobox gene (Isl-1) on chromosome 5q11-q13 in a French morbidly obese population suggests indication for association with type 2 diabetes.

The Lim domain homeobox gene (Isl-1) is a positional candidate gene for obesity that maps on chromosome 5q11-q13, a locus linked to BMI and leptin levels in French Caucasians. Isl-1 might be involved in body weight regulation and glucose homeostasis via the activation of proglucagon gene expression, which encodes for glucagon and glucagon-like peptides. By mutation screening of 72 obese subjects, we identified three single-nucleotide polymorphisms (SNPs) in the Isl1 gene. The allele frequencies in the morbidly obese group did not differ from that of the control group. In the obese group, the -47G allele was associated with a decreased risk of type 2 diabetes (odds ratio 0.41, P = 0.019). The AG bearers displayed a higher maximal BMI than the AA bearers in the whole obese group (P = 0.026) as well as in the type 2 diabetic obese subgroup (P = 0.014). In obese families, this allele was not preferentially transmitted from heterozygous parents to their obese siblings, indicating that Isl-1 does not contribute to the linkage with obesity on 5cen-q. However, in French Caucasian morbidly obese subjects, the Isl1-47A-->G SNP may modulate the risk for type 2 diabetes and may increase body weight in diabetic morbidly obese subjects.

Adult↗
PubMed2026

Multi-locus allelic architecture underlying natural variation in leaf rolling in japonica rice.

Leaf rolling is a key component of rice canopy architecture that affects light interception, microclimate formation, and planting density. The contribution of naturally occurring allelic variation to quantitative variation in leaf rolling within cultivated rice remains poorly understood, while extreme leaf rolling caused by loss-of-function mutations often results in detrimental pleiotropic effects. Herein, we examined how multi-locus allelic variation contributes to natural variation in leaf rolling within japonica rice. Leaf rolling was quantified based on the leaf rolling index (LRI) using a panel of 201 japonica accessions. The phenotype was transformed using the Yeo-Johnson method to reduce strong right skewness and improve the distributional properties of the data, thereby facilitating subsequent regression modeling. Haplotype analyses were performed for previously reported leaf rolling-associated genes and genome-wide association study (GWAS) lead loci, leading to the identification of five loci exhibiting substantial haplotype-dependent phenotypic variation. Phenotypically defined allelic groups represented these loci were subsequently evaluated using multiple linear regression (MLR), with the first two principal components derived from genome-wide SNP data included as covariates to account for population structure. The final MLR model identified four loci (qALR1, OsYABBY1, OsSLL2, and OsSRL10) as the independent contributors to leaf rolling variation, collectively explaining 21% of the variance in the transformed phenotype after accounting for population structure. Model diagnostics and ten-fold cross-validation supported the statistical validity of the framework and indicated stable model performance across validation folds. Analysis of multi-locus allelic combinations showed 13 distinct configurations that clustered into three phenotypically differentiated groups. This reflected the cumulative dosage of high-leaf rolling alleles. Thus, the natural variation in leaf rolling in japonica rice is governed by the additive effects of multiple moderate-impact loci. The multi-locus allelic framework established here provides a statistically sound and biologically interpretable basis for dissecting polygenic canopy traits and practical guidance for developing genetic materials aimed at optimizing rice plant architecture.

cross-validation↗
PubMed2006

MLR-tagging: informative SNP selection for unphased genotypes based on multiple linear regression.

UNLABELLED: The search for the association between complex diseases and single nucleotide polymorphisms (SNPs) or haplotypes has recently received great attention. For these studies, it is essential to use a small subset of informative SNPs accurately representing the rest of the SNPs. Informative SNP selection can achieve (1) considerable budget savings by genotyping only a limited number of SNPs and computationally inferring all other SNPs or (2) necessary reduction of the huge SNP sets (obtained, e.g. from Affymetrix) for further fine haplotype analysis. A novel informative SNP selection method for unphased genotype data based on multiple linear regression (MLR) is implemented in the software package MLR-tagging. This software can be used for informative SNP (tag) selection and genotype prediction. The stepwise tag selection algorithm (STSA) selects positions of the given number of informative SNPs based on a genotype sample population. The MLR SNP prediction algorithm predicts a complete genotype based on the values of its informative SNPs, their positions among all SNPs, and a sample of complete genotypes. An extensive experimental study on various datasets including 10 regions from HapMap shows that the MLR prediction combined with stepwise tag selection uses fewer tags than the state-of-the-art method of Halperin et al. (2005). AVAILABILITY: MLR-Tagging software package is publicly available at http://alla.cs.gsu.edu/~software/tagging/tagging.html

Algorithms↗
PubMed2005

Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study.

Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P=0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P=0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, -1.9 ms/allele, P=0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P=0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.951 of trait variance (P<0.00005). These results confirm previous heritability studies indicating that repolarization is a complex trait with a significant heritable component and demonstrate that high-resolution SNP-mapping in large population samples can detect and fine map quantitative trait loci even if locus specific heritabilities are small.

Adult↗
PubMed2006

An algorithm for model construction and its applications to pharmacogenomic studies.

A model depicts the relationship between clinical phenotypes and genotypes on a set of genetic polymorphisms. After the model is constructed and validated, it may be used to predict clinical phenotypes such as traits of complex diseases. A pharmacogenomic model is used to predict the efficacies or adverse drug reactions of a medication. The construction of a model is a challenging task. This is because a single-locus polymorphism does not contain enough information to stratify patients in general, given the complex biological mechanisms involved. An exhaustive search for the correct combination of genotypes across multiple loci is, however, computationally infeasible. We are, thus, motivated to propose a novel algorithm for the construction of models using the multiple single-nucleotide polymorphism (SNP) information in diplotype forms. This algorithm utilizes the techniques of genetic algorithms and Boolean algebra (GABA). The proposed algorithm is tested on simulated data, as well as real genotype datasets of chronic hepatitis C patients treated with interferon-combined therapy. A model for predicting the treatment efficacy is constructed and validated. The results showed that the proposed algorithm is very effective in deriving models comprising multiple SNPs.

Algorithms↗
PubMed2005

LightTyper platform for high-throughput clinical genotyping.

DNA sequence variations due to single nucleotide changes or polymorphisms (SNPs) have demonstrated an association with certain diseases as causative agents or surrogate biomarkers. Identification and genotyping of SNPs requires reliable and robust technologies. Multiple genotyping platforms are available to detect SNPs. Although many of these platforms meet the requirements of the research environment, technologies have also emerged for high-throughput clinical genotyping as well. The LightTyper is one such platform, providing SNP identification by employing melting curve analysis of fluorescently labeled probes. The LightTyper has been used to identify SNPs associated with myocardial infarction, developing and validating assays for approximately 100 SNPs in 30 candidate genes. The LightTyper is also amenable to the use of assays already developed for the LightCycler, which is widely used in clinical laboratories. The initial experience presented here suggests the potential use of the LightTyper for high-throughput clinical genotyping.

Animals↗
PubMed1999

Identity by descent genome segmentation based on single nucleotide polymorphism distributions.

In the course of our efforts to build extended regions of human genomic sequence by assembling individual BAC sequences, we have encountered several instances where a region of the genome has been sequenced independently using reagents derived from two different individuals. Comparing these sequences allows us to analyze the frequency and distribution of single nucleotide polymorphisms (SNPs) in the human genome. The observed transition/transversion frequencies are consistent with a biological origin for the sequence discrepancies, and this suggests that the data produced by large sequencing centers are accurate enough to be used as the basis for SNP analysis. The observed distribution of single nucleotide polymorphisms in the human genome is not uniform. An apparent duplication in the human genome extending over more than 130 kb between chromosomes 1p34 and 16p13 is reported. Independently derived sequences covering these regions are more than 99.9% identical, indicating that this duplication event must have occurred quite recently. FISH mapping results reported by the relevant laboratories indicate that the human population may be polymorphic for this duplication. We present a population genetic theory for the expected distribution of SNPs and derive an algorithm for probabilistically segmenting genomic sequence into regions that are identical by descent (IBD) between two individuals based on this theory and the observed locations of polymorphisms. Based on these methods and a random mating model for the human population, estimates are made for the mutation rate in the human genome.

Algorithms↗
PubMed2006

Individual single tube genotyping and DNA pooling by allele-specific PCR to uncover associations of polymorphisms with complex diseases.

BACKGROUND: The genotyping for the study of the SNPs in different complex diseases require a great number of patients. In this sense, the determination of allele frequencies and genotypes requires a rapid and economical procedure. METHODS: The genotype has been carried out by allele-specific PCR in single tube with the discrimination of the products of PCR by its T(m). For this purpose a GC tail was added to 5' extreme of the specific primer. The allele frequencies were also calculated by DNA pooling and QRT-PCR using allele-specific primers. RESULTS: The use of the genotyping in single tube through allele-specific PCR and melting curves has led us to the accurate genotype of three polymorphisms of vdr (cdx-2), osteoprotegerin (A-163G) and ppar-gamma (C-681G) genes in 225 postmenopausal women to be associated to osteoporosis. Only the cdx-2 polymorphism was associated with a reduced bone mineral density (BMD). These data were similar to those obtained when the allele frequencies were calculated using QRT-PCR in DNA pools. CONCLUSIONS: Individual genotyping with allele-specific PCR in single tube and melting curve analysis is a fast, trustworthy and economic method to study any SNP. We propose the following approach to determine the possible association of SNPs with complex and multifactorial diseases like osteoporosis, in which hundreds of individuals should be analyzed: construct control and problem groups, make DNA pools, and calculate pooled allelic frequencies. Genotyping each individual further permits to determine the genotypic distribution when differences in allelic frequencies are observed, thus allowing more complex statistical analyses (including other variables like age, weight, etc.).

CDX2 Transcription Factor↗
PubMed2005

Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study.

Mutations in the WNK1 gene cause Gordon's syndrome, a rare Mendelian form of hypertension. We assessed whether common WNK1 variants might also contribute to essential hypertension (EH), a multifactorial disorder affecting > 25% of the adult population worldwide. A panel of 19 single nucleotide polymorphisms (SNPs) spanning the gene was selected from public databases and was genotyped in 100 white European families to determine the pattern of linkage disequilibrium, haplotype structure and tagging SNPs for the WNK1 locus. Eight tagging SNPs were identified with 90% power to predict common WNK1 haplotypes and SNPs. Family-based association tests were used to test for association with EH and severity of hypertension in 712 severely hypertensive families from the MRC British Genetics of Hypertension study resource. No association was found between WNK1 polymorphisms or haplotypes with hypertension; however, one SNP rs1468326, located 3 kb from the WNK1 promoter, was found to be nominally associated with severity of hypertension, with both systolic blood pressure (BP) (Z = +2.24, P = 0.025) and diastolic BP (Z = +1.99, P = 0.046). We also found nominal support for association of one common WNK1 haplotype with increased systolic BP (Z = +1.91, P = 0.053). This is the first study to perform haplotype association analysis of the WNK1 gene with EH. This finding of association between a SNP near the promoter region and the severity of hypertension suggests that increased expression of WNK1 might contribute to BP variability and susceptibility to EH similar to the mechanism of hypertension observed in Gordon's syndrome.

Adult↗
PubMed2004

The - 564 A/G polymorphism in the promoter region of the proteinase 3 gene associated with Wegener's granulomatosis does not increase the promoter activity.

Proteinase 3 is the major autoantigen in patients with Wegener's granulomatosis. Earlier studies have shown that circulating leucocytes from patients with Wegener's granulomatosis show elevated proteinase 3 surface expression and mRNA levels. Wegener's granulomatosis patients also have increased levels of proteinase 3 in plasma. A single nucleotide polymorphism (SNP) (-564 A/G SNP) in the promoter region has been associated with disease. This SNP introduces a new potential Sp1 transcription factor binding site that may be responsible for the observed up-regulated expression of proteinase 3. To investigate this a 740 base pair long region of the promoter was cloned from genomic DNA. The disease-associated -564 A/G, as well as a control -621 A/G exchange, were introduced by polymerase chain reaction mutagenesis and cloned into a luciferase reporter vector. Endogenous expression levels of proteinase 3 mRNA and promoter activity of the cloned constructs were measured in three myeloid cell lines, HL-60, U937 and NB-4, and in epithelial HeLa cells. The results demonstrate a good correlation between the endogenous proteinase 3 mRNA expression and the promoter activity, as judged by luciferase activity. However, no significant differences in activity between the wild-type, polymorphic and the mutated control variant were found. In conclusion, the -564 A/G polymorphism is not responsible for the increased expression levels seen in myeloid cells from patients with Wegener's granulomatosis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2004

Influence of LRP5 polymorphisms on normal variation in BMD.

UNLABELLED: Genetic studies based on cohorts with rare and extreme bone phenotypes have shown that the LRP5 gene is an important genetic modulator of BMD. Using family-based and case-control approaches, this study examines the role of the LRP5 gene in determining normal population variation of BMD and describes significant association and suggestive linkage between LRP5 gene polymorphisms and BMD in >900 individuals with a broad range of BMD. INTRODUCTION: Osteoporosis is a common, highly heritable condition determined by complex interactions of genetic and environmental etiologies. Genetic factors alone can account for 50-80% of the interindividual variation in BMD. Mutations in the LRP5 gene on chromosome 11q12-13 have been associated with rare syndromes characterized by extremely low or high BMD, but little is known about the contribution of this gene to the development of osteoporosis and determination of BMD in a normal population. MATERIALS AND METHODS: To examine the entire spectrum of low to high BMD, 152 osteoporotic probands, their families (597 individuals), and 160 women with elevated BMD (T score > 2.5) were recruited. BMD at the lumbar spine, femoral neck, and hip were measured in each subject using DXA. RESULTS: PAGE sequencing of the LRP5 gene revealed 10 single nucleotide polymorphisms (SNPs), 8 of which had allele frequencies of >5%, in exons 8, 9, 10, 15, and 18 and in introns 6, 7, and 21. Within families, a strong association was observed between an SNP at nucleotide C171346A in intron 21 and total hip BMD (p < 1 x 10(-5) in men only, p = 0.0019 in both men and women). This association was also observed in comparisons of osteoporotic probands and unrelated elevated BMD in women (p = 0.03), along with associations with markers in exons 8 (C135242T, p = 0.007) and 9 (C141759T, p = 0.02). Haplotypes composed of two to three of the SNPs G121513A, C135242T, G138351A, and C141759T were strongly associated with BMD when comparing osteoporotic probands and high BMD cases (p < 0.003). An SNP at nucleotide C165215T in exon 18 was linked to BMD at the lumbar spine, femoral neck, and total hip (parametric LOD scores = 2.8, 2.5, and 2.2 and nonparametric LOD scores = 0.3, 1.1, and 2.2, respectively) but was not genetically associated with BMD variation. CONCLUSION: These results show that common LRP5 polymorphisms contribute to the determination of BMD in the general population.

Adolescent↗
PubMed2005

Association of the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase gene with schizophrenia in the Chinese Han population.

Several independent linkage studies have demonstrated that the 1q22 region is likely to harbor candidate schizophrenia susceptibility genes. Recently, some genetic variants within CAPON have been reported as exhibiting significant linkage disequilibrium to schizophrenia in Canadian familial-schizophrenia pedigrees. We examined nine single nucleotide polymorphisms (SNPs), which span an approximately 236-kb region of CAPON, in 664 schizophrenia cases and 941 controls in the Chinese Han population. We detected a significant difference in allele distributions of SNP rs348624 (P = 0.000017). Moreover, the overall frequency of haplotypes constructed from three SNPs including rs348624 showed significant difference between cases and controls (P = 0.000025). Our findings indicate that CAPON gene may be a candidate susceptibility gene for schizophrenia in Chinese Han population, and also provide further support for the potential importance of NMDAR-mediated glutamatergic transmission in the etiology of schizophrenia.

Adaptor Proteins, Signal Transducing↗
PubMed2000

A simple procedure for the analysis of single nucleotide polymorphisms facilitates map-based cloning in Arabidopsis.

We developed a modified allele-specific PCR procedure for assaying single nucleotide polymorphisms (SNPs) and used the procedure (called SNAP for single-nucleotide amplified polymorphisms) to generate 62 Arabidopsis mapping markers. SNAP primers contain a single base pair mismatch within three nucleotides from the 3' end of one allele (the specific allele) and in addition have a 3' mismatch with the nonspecific allele. A computer program called SNAPER was used to facilitate the design of primers that generate at least a 1,000-fold difference in the quantity of the amplification products from the specific and nonspecific SNP alleles. Because SNAP markers can be readily assayed by electrophoresis on standard agarose gels and because a public database of over 25,000 SNPs is available between the Arabidopsis Columbia and Landsberg erecta ecotypes, the SNAP method greatly facilitates the map-based cloning of Arabidopsis genes defined by a mutant phenotype.

Alleles↗
PubMed2003

Allelic variation of the inducible costimulator (ICOS) gene: detection of polymorphisms, analysis of the promoter region, and extended haplotype estimation.

The human chromosome region 2q33 including the three costimulatory molecules CD28, CTLA-4 and ICOS, has been subject to much attention due to its linkage to a number of autoimmune diseases. The search for the causal relationship of this linkage has revealed several polymorphisms, but no variations in the amino acid sequences, except for one polymorphism in the leader sequence of CTLA-4. In the present study, we examined the ICOS gene of an unrelated group of healthy donors from the Danish population. We were able to report 16 intronic SNP, one intronic G-insert and two repeat regions in intron 4, consistent with the [T]n and the [GT]n regions reported in a Japanese study. Putative haplotypes for the established SNP and repeat polymorphisms have been estimated by computational analysis. Sequencing of approximately 3500 bp of the upstream region of ICOS revealed an additional eight SNP of which two resided in putative NF-kB and Sp1 sites. In accordance with previous studies we detected no variations in the coding regions except for a rare polymorphism that was found in one donor in the last codon of exon 5, which lead to a heterozygous genotype, but no amino acid change. This suggests that regulation of transcription rather than protein structure could be a possible mechanism in the explanation of linkage.

5' Flanking Region↗
PubMed2001

An efficient procedure for genotyping single nucleotide polymorphisms.

Analysis of single nucleotide polymorphisms (SNPs) has been and will be increasingly utilized in various genetic disciplines, particularly in studying genetic determinants of complex diseases. Such studies will be facilitated by rapid, simple, low cost and high throughput methodologies for SNP genotyping. One such method is reported here, named tetra-primer ARMS-PCR, which employs two primer pairs to amplify, respectively, the two different alleles of a SNP in a single PCR reaction. A computer program for designing primers was developed. Tetra-primer ARMS-PCR was combined with microplate array diagonal gel electrophoresis, gaining the advantage of high throughput for gel-based resolution of tetra-primer ARMS-PCR products. The technique was applied to analyse a number of SNPs and the results were completely consistent with those from an independent method, restriction fragment length polymorphism analysis.

DNA↗
PubMedDate not supplied

Association of IL-13, RANTES, and leukotriene C4 synthase gene promoter polymorphisms with asthma and/or atopy in African Americans.

PURPOSE: IL-13, RANTES (Regulated on Activation, Normal T cells Expressed and Secreted), and cysteinyl leukotrienes are asthma and atopy mediators. Two RANTES -403(G to A) and -28(C to G), an -1055 IL-13(C to T), and a -444(A to C) leukotriene C4 synthase (LTC4S) single nucleotide polymorphisms (SNPs) have been shown in Caucasians and Asians as asthma and atopy risk factors. We studied these SNPs in African Americans with asthma and/or atopy. METHODS: We studied 61 patients with asthma and/or atopy and 129 to 157 newborn controls for the -403 RANTES, -28 RANTES, and -1055 IL-13 SNPs, as well as 47 patients and 60 newborn controls for the -444 LTC4S SNP. RESULTS: The two groups did not significantly differ at the genotypes of the -403 and -28 RANTES SNP. On the other hand, the mutant TT genotype for the -1055 IL-13 SNP was detected in 19.7% of patients versus 12.7% in controls (P < 0.04, OR 2.9, 95% CI 1.0-8.0), and the mutant T allele in 58.3% versus 36.6% in controls (P < 0.02, OR 2.4, 95% CI 1.1-5.2). In a similar fashion, for the -444 LTC4S SNP, the mutant AC genotype was detected in 19.1% versus 10.0% in controls (P > 0.28); mutant C allele had an OR of 2.1 (95% CI 0.7-6.3). CONCLUSION: African American asthmatics/atopics had higher frequency of the TT mutant gene for the -1055 IL-13 SNP and of its mutant T allele. Regarding the -444 LTC4S SNP, there was a definite difference, although not statistically significant, with an OR of 2.1 for the mutant AC genotype in patients. If these findings become reproduced by larger studies, it may suggest that IL-13 and LTC4S SNPs can be used as predictive markers for asthma/atopy in African Americans.

Adolescent↗
PubMed2006

Genome-wide allelic imbalance analysis of pediatric gliomas by single nucleotide polymorphic allele array.

Using single nucleotide polymorphic (SNP) allele arrays, we analyzed 28 pediatric gliomas consisting of 14 high-grade gliomas and 14 low-grade gliomas. Most of the low-grade gliomas had no detectable loss of heterozygosity (LOH) in any of the 11,562 SNP loci; exceptions were two gangliogliomas (3q and 9p), one astrocytoma (6q), and two subependymal giant cell astrocytomas (16p and 21q). On the other hand, all high-grade gliomas had various degrees of LOH affecting 52 to 2,168 SNP loci on various chromosomes. LOH occurred most frequently in regions located at 4q (54%), 6q (46%), 9p (38%), 10q (38%), 11p (38%), 12 (38%), 13q (69%), 14q (54%), 17 (38%), 18p (46%), and 19q (38%). We also detected amplifications of epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor alpha (PDGFRalpha) in a few of the 13 cases of glioblastoma multiforme analyzed. Interestingly, the amplified EGFR and PDGFRalpha were located within regions of LOH. SNP loci with LOH and copy number changes were validated by sequencing and quantitative PCR, respectively. Our results indicate that, in some pediatric glioblastoma multiforme, one allele each of EGFR and PDGFRalpha was lost but the remaining allele was amplified. This may represent a new molecular mechanism underlying tumor progression.

Alleles↗