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PubMed1998

Somatic frameshift mutations in DNA mismatch repair and proapoptosis genes in hereditary nonpolyposis colorectal cancer.

An exacerbated genomic instability at simple repeated sequences characterizes cancer of the microsatellite mutator phenotype (MMP). The majority of hereditary nonpolyposis colon cancers (HNPCCs) and about 15% of nonselected ("sporadic") gastrointestinal tumors belong to the MMP pathway of tumorigenesis. Colorectal MMP+ and MMP- tumors exhibit fundamental differences in genotype and phenotype. We have shown previously that "sporadic" MMP+ colon cancers exhibit a paradoxical low incidence of somatic mutations in the p53 tumor suppressor gene and the c-K-ras proto-oncogene. On the other hand, gastrointestinal MMP+ cancers frequently harbor frameshift mutations in genes containing mononucleotide repeats. These include the cell growth regulator gene TGFbetaRII and the proapoptotic gene BAX. We have also recently shown the frequent presence of frameshift mutations in (A)8 and (C)8 tracts within the hMSH3 and hMSH6 DNA mismatch repair genes in sporadic colon cancer of the MMP. Here, we describe the nearly identical incidence of somatic frameshift mutations in these genes in a panel of 27 HNPCC MMP+ cancers: 52% in hMSH3 and BAX and 33% in hMSH6. In contrast, no mutations in any of these genes were found in 10 MMP- cancers of HNPCC patients. These results show that the multistep model for the unfolding of the MMP also applies to HNPCC and further illustrate the importance of the escape from apoptosis in the MMP pathway for gastrointestinal cancer. They also underscore the differences in genotype between tumors with and without enhanced microsatellite instability and the similarities in genotype between tumors of the MMP regardless of their hereditary or sporadic nature.

Adult↗

PubMed1997

Transforming growth factor-beta receptor type 2 mutations and microsatellite instability in sporadic colorectal adenomas and carcinomas.

Frame-shift mutations in a run of 10 adenines (A10) of the transforming growth factor-beta receptor type 2 gene (TGF-beta RII) are commonly seen in inherited and sporadic colonic cancers that exhibit microsatellite instability. A10 mutations and instability also are commonly seen in hereditary nonpolyposis colon cancer-associated adenomas. However, instability is quite rare in sporadic adenomas, and the timing of acquisition of A10 mutations with respect to the sporadic adenoma-carcinoma sequence has not been reported. We evaluated 100 sporadic colorectal cancers and 164 sporadic adenomas for microsatellite instability with a set of 10 tetranucleotide polymerase chain reaction primer sets and for A10 frame-shift mutations. A10 mutations were significantly associated with microsatellite instability in colorectal cancers, being seen in 9 of 11 cancers with 50% or greater instability and in 0 of 89 tumors with less than 50% instability (P < 0.0001). A10 mutations were not detected in any adenomas, only three of which (1.8%) exhibited significant (30% or greater) instability. We conclude that both TGF-beta RII frame-shift mutations and microsatellite instability occur at a relatively late stage of sporadic colorectal tumorigenesis. A10 frame-shift mutations appear to be restricted to sporadic colorectal cancers with extensive microsatellite instability.

Adenoma↗

PubMed2002

Bax expression decreases significantly from primary tumor to metastasis in colorectal cancer.

PURPOSE: Bax is a proapoptotic member of the bcl-2 family. Previous studies about Bax have shown that the expression increases from normal to tumor tissue, but the clinical significance is contradictory. Our aims were to analyze the expression of Bax from normal mucosa to primary tumor and to metastases in colorectal cancer patient. We further investigated whether low Bax expression in the primary tumor or changed expression from normal mucosa to primary tumor and to metastases had biologic and clinical significance. PATIENTS AND METHODS: The study included 135 patients with primary colorectal adenocarcinoma, of whom 31 had metastases in the lymph nodes and 75 had normal mucosa. Immunohistochemistry, DNA sequencing, and microsatellite analysis were used to detect Bax expression, mutations, and microsatellite instability. RESULTS: The protein was observed in 132 of 135 tumors, all normal epithelial cells and metastases. The frequencies of weak expression were greater from well/moderately to poorly differentiated and to mucinous carcinomas. Bax expression was stronger from normal to tumor tissue, but subsequently decreased in metastases. The matched cases with lower expression in the metastases than in the primary tumor showed a more infiltrative growth pattern and more distal metastases. CONCLUSION: The association of Bax expression with tumor differentiation/histologic types and a decreased expression in the metastases, suggests that Bax expression may be involved in tumor differentiation/histologic types and metastatic progression. We also propose the novel notion that changed Bax expression in the metastases compared with the primary tumors might provide information to determine the clinicopathologic characteristics of the tumor.

Adenocarcinoma↗

PubMed2003

Single-nucleotide polymorphisms of the Trypanosoma cruzi MSH2 gene support the existence of three phylogenetic lineages presenting differences in mismatch-repair efficiency.

We have identified single-nucleotide polymorphisms (SNPs) in the mismatch-repair gene TcMSH2 from Trypanosoma cruzi. Phylogenetic inferences based on the SNPs, confirmed by RFLP analysis of 32 strains, showed three distinct haplogroups, denominated A, B, and C. Haplogroups A and C presented strong identity with the previously described T. cruzi lineages I and II, respectively. A third haplogroup (B) was composed of strains presenting hybrid characteristics. All strains from a haplogroup encoded the same specific protein isoform, called, respectively, TcMHS2a, TcMHS2b, and TcMHS2c. The classification into haplogroups A, B, and C correlated with variation in the efficiency of mismatch repair in these cells. When microsatellite loci of strains representative of each haplogroup were analyzed after being cultured in the presence of hydrogen peroxide, new microsatellite alleles were definitely seen in haplogroups B and C, while no evidence of microsatellite instability was found in haplogroup A. Also, cells from haplogroups B and C were considerably more resistant to cisplatin treatment, a characteristic known to be conferred by deficiency of mismatch repair in eukaryotic cells. Altogether, our data suggest that strains belonging to haplogroups B and C may have decreased mismatch-repair ability when compared with strains assigned to the haplogroup A lineage.

Amino Acid Substitution↗

PubMed2005

Monitoring of circulating tumour-associated DNA as a prognostic tool for oral squamous cell carcinoma.

Frequent allelic imbalances (AIs) including loss of heterozygosity and microsatellite instability on a specific chromosomal region have been identified in a variety of human malignancies. The objective of our study was to assess the possibility of prognostication and monitoring of oral squamous cell carcinoma (SCC) by microsatellite blood assay. DNA from normal and tumorous tissues and serum DNA obtained at three time points (preoperatively, postoperatively, and 4 weeks postoperatively) from 64 patients with oral SCC was examined at nine microsatellite loci. In all, 38 (59%) DNA samples from tumorous tissues and 52% from serum showed AIs in at least one locus. Patterns of AIs in the serum DNA were matched to those detected in tumour DNA. Of them, AIs were frequently detected preoperatively (44%, 28 of 64), and postoperatively (20%, 13 of 64). Moreover, among 12 cases with AIs during the postoperative period, six had no evidence of an AI 4 weeks postoperatively, and they had no recurrence and were disease free. In contrast, six patients with AI-positive DNA 4 weeks postoperatively have died with distant metastasis within 44 weeks. Thus, our results suggest that the assessment of microsatellite status in the serum DNA could be a useful predictive tool to monitor disease prognosis.

Adult↗

PubMed2003

Molecular pathology of atypical polypoid adenomyoma of the uterus.

Atypical polypoid adenomyoma (APA) is an uncommon and benign tumor of the uterus. In some patients, however, APA has been found to coexist with or to precede the development of an endometrioid adenocarcinoma similarly to complex endometrial hyperplasia. The molecular changes underlying the progression from APA to adenocarcinoma are unknown. DNA from paraffin-embedded tissue of 6 APAs was evaluated for microsatellite instability (MI), MLH-1 promoter hypermethylation, and CTNNB-1 mutations. Tissue sections were also subjected to MLH-1, MSH-2, and beta-catenin immunostaining. MI was not detected in any case. Two tumors exhibited MLH-1 promoter hypermethylation and showed focal negative MHL-1 immunostaining; 1 of these showed marked architectural complexity and cellular pleomorphism. Five cases presented beta-catenin nuclear immunoreactivity, but none of them had CTNNB-1 mutations. The results of this study suggest that APA and complex endometrial hyperplasia may share some molecular alterations. Some APAs exhibit MLH-1 promoter hypermethylation with focal lack of MLH-1 immunostaining, a molecular abnormality involved in the transition from complex atypical hyperplasia to endometrioid adenocarcinoma.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Hypermutability at a poly(A/T) tract in the human germline.

Poly(A/T) tracts are abundant simple sequence repeats (SSRs) within the human genome. They constitute part of the coding sequence of a variety of genes, encoding polylysine stretches that are important for protein function. Assessment of poly(A/T) tract stability is also used to identify microsatellite unstable colorectal cancers, which are characteristic of tumours defective in DNA mismatch repair. Despite their importance, little is known about the stability of poly(A/T) SSRs in the human germline. We have determined the stability of a paradigm poly(A/T) tract, BAT-40, by study of population allele frequencies, mutation frequency in families and mutation frequency in sperm DNA. We show that the locus is polymorphic, with a level of heterozygosity of 59.7%. Germline mutation was observed in 13 of 187 germline transmissions (7.0%) in 10 families suggesting BAT-40 is unstable in the germline. Further evidence for germline instability at BAT-40 was provided by small pool PCR analysis of matched blood and sperm DNA templates, revealing a significantly elevated frequency of mutation in the germline (P < 0.001). These findings provide insight into poly(A/T) tract stability in the germline. They also have relevance to the study of gene expression and to determination of microsatellite instability in tumours.

AT Rich Sequence↗

PubMed1999

[Microsatellite instability: a potential tool for the study of life sciences].

Microsatellites are simply repeated nucleotide sequences scattered throughout the human genome. They are highly polymorphic among human population and inherited in a stable manner. The microsatellite instability (MI) is highly polymorphic, which is associated with the defects in DNA mismatch repair genes. MI has been widely used by scientists to study the tumorigenesis. On the basis of their findings, a "mutator that mutates the other mutator" model for tumorigenesis has been proposed. MI is also a potential tool for the study of genetics, aging and other life sciences.

Base Pair Mismatch↗

PubMed2004

Morphologically similar epithelial and stromal cells in primary bilateral breast tumors display different genetic profiles: implications for treatment.

The morphologic features of primary bilateral breast carcinoma have been well elucidated, but it is not known whether tumors at two sides share a common genetic profile and undergo the same clinical course. To address this issue, morphologically comparable epithelial and stromal cells in 18 paired primary bilateral breast tumors were microdissected and subjected to comparisons for the frequency and pattern of loss of heterozygosity (LOH) and microsatellite instability (MI), as well as the profiles of comparative genomic hybridization. Of 18 paired bilateral epithelial samples assessed with 10 DNA markers at five chromosomes, 78 altered loci were found; of these, 23 (29.5%) displayed concurrent and 55 (70.5%) showed independent LOH, MI, or both. Of 18 paired bilateral stromal samples assessed with the same markers, 70 altered loci were seen; of these, 9 (12.9%) displayed concurrent and 61 (87.1%) showed independent LOH, MI, or both. Collectively, all the markers and 30 (83.3%) of 36 paired bilateral epithelial and stromal cells displayed significantly more (P < 0.01) independent than concurrent LOH, MI, or both. In contrast, the epithelial cells of a pulmonary small cell carcinoma metastasized to both breasts displayed concurrent LOH at each of the four altered loci. Of seven selected cases for comparative genomic hybridization, six (86%) displayed chromosomal changes, but none showed an identical pattern and frequency of changes in both breasts. The significantly higher rate of independent genetic alterations in morphologically comparable cells of paired bilateral primary breast tumors supports the notion that the development and clinical course of tumors in two sides differ substantially; consequently, different interventions might be needed for the optimal management of bilateral breast tumors.

Adolescent↗

PubMedDate not supplied

Dynamics of genetic instability in sporadic and familial colorectal cancer.

Genetic instability is a defining feature of human cancer. In colorectal cancer, two specific types of genetic instabilities have been identified: microsatellite instability (MIN) leads to a 1000-fold increase in the rate of subtle DNA changes, whereas chromosomal instability (CIN) enhances the rate at which gross chromosomal changes occur during cell division. In this paper, we develop a mathematical model for the dynamics of colon cancer initiation. We outline the processes and rate constants that determine the fraction of colon cancers where MIN or CIN mutations precede the inactivation of the first tumor suppressor gene. For a wide range of parameter values, we find support for the radical hypothesis that genetic instability initiates colonic tumorigenesis. We compare sporadic and hereditary forms of colorectal cancer.

Adenomatous Polyposis Coli↗

PubMed1998

Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process.

Primary responses to the hapten phenyloxazolone and chronic responses to environmental antigens occurring in Peyer's patches were analyzed in two different mismatch repair-deficient backgrounds. Paradoxically, whereas primary responses were found normal in MSH2- and only slightly diminished in PMS2-deficient mice, mutations in Peyer's patch B cells from both k.o. animals were reduced three times, the subset of Peyer's patch B cells with highly mutated sequences being specifically missing in the mismatch repair-deficient context. Strikingly, germinal center B cells from Peyer's patches of k.o. animals showed microsatellite instability at an unprecedented level. We thus propose that the amount of DNA damages generated prevents these cells from recycling in germinal centers and that mismatch repair deficiency is only the indirect cause of the lower mutation incidence observed.

Adenosine Triphosphatases↗

PubMed2026

DHX9 Inhibition Enhances Paclitaxel Sensitivity by Inducing Mitotic Failure in Ovarian and Endometrial Cancers.

Recurrent high-grade serous ovarian carcinoma (HGSOC) and endometrial cancer remain major clinical challenges with limited effective treatment options. DExH-box helicase 9 (DHX9), a DNA/RNA helicase essential for genomic stability, has not yet been explored as a therapeutic target in gynecologic cancers. In this study, we show that a selective DHX9 inhibitor (DHX9i) suppresses proliferation in a subset of HGSOC and endometrial cancer cell lines by inducing DNA damage, chromosomal instability, and mitotic failure. This effect was independent of microsatellite instability status and prior resistance to platinum or PARP inhibitors. Genomic analysis indicated that DHX9i resistance was unlikely to be driven by single-gene mutations but was instead associated with copy-number alterations in mitotic spindle and microtubule-regulating genes in both HGSOC and endometrial cancer. Transcriptomic profiling further revealed consistent alterations in microtubule- and spindle-associated pathways in DHX9i-resistant models following DHX9i treatment. Mechanistically, DHX9i induced mitotic defects in DHX9i-sensitive models, whereas resistant lines maintained mitotic integrity. Given the convergence of resistance-associated features on microtubule-related pathways, we combined DHX9i with the microtubule-stabilizing agent paclitaxel to enhance mitotic stress. This combination triggered mitotic disruption and enhanced cytotoxicity in DHX9i-resistant cells. In vivo, the combination led to sustained tumor regression and prolonged survival in both DHX9i-sensitive and DHX9i-resistant models without notable toxicity. Overall, our findings define genomic, transcriptomic, and phenotypic characteristics associated with differential responses to DHX9i and support the clinical evaluation of the DHX9i-paclitaxel combination as a therapeutic strategy in recurrent gynecologic cancers.

Female↗

PubMed2002

Spectral karyotype analysis of colon cancer cell lines of the tumor suppressor and mutator pathway.

BACKGROUND AND AIMS: Microsatellite instability (MSI) is characterized by the size variation of microsatellites in tumor DNA as compared to matching normal DNA due to defects in the mismatch repair system. To examine the chromosomal differences in microsatellite-stable (MSS) and -unstable (MSI) tumors in detail, we analyzed MSS (Caco-2, Colo-205, SW948) and MSI (HCT-15, HCT-116, LoVo) cell lines by spectral karyotyping (SKY). METHODS: SKY is a sensitive method to detect chromosome aberrations by visualizing each chromosome in a different color. Metaphases were hybridized with a SKY probe mixture. Images were visualized with the SpectraCube system and analyzed with the SKYview imaging software. RESULTS: The average number of chromosomes was 49 in LoVo, 45 in HCT-116, 46 in HCT-15, 71 in Colo-205, 89 in Caco-2 and 66 in SW-948. Three aberrant chromosomes were detected in LoVo, three in HCT-116, two in HCT-15, seventeen in Colo-205, fourteen in Caco-2 and nine in SW948. CONCLUSION: The karyotypes of MSS colon cancer cells displayed complex numerical and structural aberrations. In contrast the chromosomes of MSI colon cancer cells were mostly unaltered but displayed a few isolated numerical and structural aberrations. We speculate that these isolated aberrations may be specifically involved in the pathogenesis of MSI tumors.

Chromosome Banding↗

PubMed2004

[Recognising hereditary non-polyposis colorectal cancer without a clear family history].

In 3 patients, 2 men aged 46 and 51 years and a woman aged 54 years, with colorectal cancer there was insufficient information on the basis of the family history to diagnose 'hereditary non-polyposis colorectal cancer' (HNPCC). Further investigation showed microsatellite instability in the tumour material, an indicator for a mutation in DNA-'mismatch repair' (MMR-) genes. Immunohistochemical study of lymphocytes showed an absence of the gene products MSH2 and MSH6. Study of the MMR genes revealed a pathogenic germ-line mutation in MSH2. All three patients were satisfied with genetic testing of the MMR-genes as this gave their children and their family members the opportunity to clarify genetic status. HNPCC is a clinical diagnosis, based on family history. As family history taking is often incomplete, the diagnosis is regularly not considered. The following individual criteria can help to recognize a patient at risk for HNPCC: (a) colorectal cancer diagnosed below 50 years of age, (b) second colorectal cancer, (c) a combination of colorectal and endometrial cancer.

Base Pair Mismatch↗

PubMed2003

Early-age-at-onset colorectal cancer and microsatellite instability as markers of hereditary nonpolyposis colorectal cancer.

PURPOSE: Early-age-at-onset colorectal cancer and microsatellite instability are characteristic features of hereditary nonpolyposis colorectal cancer. Our aim was therefore to investigate whether these features might be useful markers in screening for hereditary nonpolyposis colorectal cancer and mismatch repair gene mutations. METHODS: From 1,132 consecutive patients who underwent surgery for colorectal cancer at our department between 1980 and 1999, we selected all patients 40 years of age or younger (study group, n = 59) and a subset of patients 40 years of age or older (control group, n = 60) who were matched for gender and pathologic TNM stage. Patients for whom a complete family cancer history or microsatellite status was unavailable were excluded from the study. Family cancer histories, retrieved from archival charts, were reassessed. Microsatellite status was investigated with the five microsatellites from the Bethesda recommended panel (BAT-26, BAT-25, D2S123, D5S346, and D17S250). On the basis of the number of altered microsatellites (> or = 2, 1, or 0), tumors were considered as having high or low instability or microsatellite stability, respectively. Mutation analysis for MLH1 and MSH2 genes was performed only in cases of high instability. DNA was investigated for mutations by single-strand conformational polymorphism and sequencing analysis. RESULTS: Data from 95 patients (study group: n = 37, 18 males, mean age 35 years; control group: n = 58, 29 males, mean age 62 years) were available for analysis. Four patients (study group, n = 3; control group, n = 1) fulfilled the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. Of the 37 study group tumors, 12 (32.4 percent) showed high-frequency microsatellite instability, and 25 had microsatellite stability, whereas among the 58 control group tumors, 4 (7 percent) showed high-frequency microsatellite instability, and 54 had microsatellite stability (P < 0.002). Mismatch repair gene mutation analysis was performed in 12 cases (study group, n = 7; control group, n = 5). We found four mutations (MSH2 119delG, MLH1 ex9 684insT, MSH2 Gln239Stop, and MLH1 del0.8 Kb) in the study group patients and none in the control group. Of four hereditary nonpolyposis colorectal cancer patients who underwent mismatch repair gene mutation analysis, one had a mutation. CONCLUSIONS: Early-age-at-onset colorectal cancer is significantly correlated with high-frequency microsatellite instability tumor status and is a useful criterion to identify hereditary nonpolyposis colorectal cancer patients. Moreover, when used in association with high-frequency microsatellite instability status, it is effective in selecting patients for mismatch repair gene mutation analysis.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Identification of a second MutL DNA mismatch repair complex (hPMS1 and hMLH1) in human epithelial cells.

Deficiencies of MutL DNA mismatch repair-complex proteins (hMLH1, hPMS2, and hPMS1) typically result in microsatellite instability in human cancers. We examined the association patterns of MutL proteins in human epithelial cancer cell lines with (HCT-116, N87, SNU-1, and SNU-638) and without microsatellite instability (HeLa, AGS, KATO-III, and SNU-16). The analysis of hMLH1, hPMS2, and hPMS1 was performed using Northern blot, Western blot, and co-immunoprecipitation studies. Our data provide evidence that MutL proteins form two different complexes, MutL-alpha (hPMS2 and hMLH1) and MutL-beta (hPMS1 and hMLH1). Gastric and colorectal cancer cells lines with microsatellite instability lacked detectable hMLH1. Decreased levels of hMLH1 protein were associated with markedly reduced levels of hPMS2 and hPMS1 proteins, but the RNA levels of hPMS1 and hPMS2 were normal. In this study, we describe the association of hPMS1 with hMLH1 as a heterodimer, in human cells. Furthermore, normal levels of hMLH1 protein appear to be important in maintaining normal levels of hPMS1 and hPMS2 proteins.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Genetic analysis of multiple synchronous lesions of the colon adenoma-carcinoma sequence.

The colorectal adenoma-carcinoma sequence represents a well-known paradigm for the sequential development of cancer driven by the accumulation of genomic defects. Although the colorectal adenoma-carcinoma sequence is well investigated, studies about tumours of different dignity co-existent in the same patient are seldom. In order to address the distribution of genetic alterations in different lesions of the same patient, we coincidently investigated carcinomas, adenomas and aberrant crypt foci in patients with sporadic colon cancer. By utilizing polymerase chain reaction, single-strand conformation polymorphism, heteroduplex-analysis, restriction fragment length polymorphism, protein truncation test and sequencing techniques we looked for mutations and microsatellite instability of APC, H-ras, K-ras, p53, DCC and the DNA repair genes hMLH1/hMSH2. In accordance with the suggested adenoma-carcinoma sequence of the colon, four patients reflected the progressive accumulation of genetic defects in synchronously appearing tumours during carcinogenesis. However, two patients with non-hereditary malignomas presented different genetic instabilities in different but synchronously appearing tumours suggesting non-clonal growth under almost identical conditions of the environment. Thus, sporadically manifesting multiple lesions of the colon were not necessarily driven by similar genetic mechanisms. Premalignant lesions may transform into malignant tumours starting from different types of genetic instability, which indicates independent and simultaneous tumorigenesis within the same organ.

Adenocarcinoma↗

PubMed2000

Evolutionary dynamics of microsatellite DNA.

Within the past decade microsatellites have developed into one of the most popular genetic markers. Despite the widespread use of microsatellite analysis, an integral picture of the mutational dynamics of microsatellite DNA is just beginning to emerge. Here, I review both generally agreed and controversial results about the mutational dynamics of microsatellite DNA. Microsatellites are short DNA sequence stretches in which a motif of one to six bases is tandemly repeated. It has been known for some time that these sequences can differ in repeat number among individuals. With the advent of polymerase chain reaction (PCR) technology this property of microsatellite DNA was converted into a highly versatile genetic marker (Litt and Luty 1989; Tautz 1989; Weber and May 1989). Polymerase chain reaction products of different length can be amplified with primers flanking the variable microsatellite region. Due to the availability of high-throughput capillary sequencers or mass spectrography the sizing of alleles is no longer a bottleneck in microsatellite analysis. The almost random distribution of microsatellites and their high level of polymorphism greatly facilitated the construction of genetic maps (Dietrich et al. 1994; Dib et al. 1996) and enabled subsequent positional cloning of several genes. Almost at the same time, microsatellites were established as the marker of choice for the identification of individuals and paternity testing. The high sensitivity of PCR-based microsatellite analysis was not only of great benefit for forensics, but opened completely new research areas, such as the analysis of samples with limited DNA amounts (e.g., many social insects) or degraded DNA (e.g., feces, museum material) (Schlötterer and Pemberton 1998). More recently, microsatellite analysis has also been employed in population genetics (Goldstein and Schlötterer 1999). Compared with allozymes, microsatellites offer the advantage that, in principle, several thousand potentially polymorphic markers are available. Nevertheless, the application of microsatellites to population genetic questions requires a more detailed understanding of the mutation processes of microsatellite DNA as the evolutionary time frames covered in population genetics are often too long to allow novel microsatellite mutations to be ignored. Additional interest in the evolution of microsatellite DNA comes from the discovery that trinucleotide repeats, a special class of microsatellites, are involved in human neurodegenerative diseases (e.g., fragile X and Huntington's disease). A detailed understanding of the processes underlying microsatellite instability is therefore an important contribution toward a better understanding of these human neurodegenerative diseases.

Animals↗