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PubMed1999

Distribution of haplotypes from a chromosome 21 region distinguishes multiple prehistoric human migrations.

Despite mounting genetic evidence implicating a recent origin of modern humans, the elucidation of early migratory gene-flow episodes remains incomplete. Geographic distribution of haplotypes may show traces of ancestral migrations. However, such evolutionary signatures can be erased easily by recombination and mutational perturbations. A 565-bp chromosome 21 region near the MX1 gene, which contains nine sites frequently polymorphic in human populations, has been found. It is unaffected by recombination and recurrent mutation and thus reflects only migratory history, genetic drift, and possibly selection. Geographic distribution of contemporary haplotypes implies distinctive prehistoric human migrations: one to Oceania, one to Asia and subsequently to America, and a third one predominantly to Europe. The findings with chromosome 21 are confirmed by independent evidence from a Y chromosome phylogeny. Loci of this type will help to decipher the evolutionary history of modern humans.

Animals↗
PubMed2001

Demographic history of Diadema antillarum, a keystone herbivore on Caribbean reefs.

The sea urchin Diadema antillarum was the most important herbivore on Caribbean reefs until 1983, when mass mortality reduced its populations by more than 97%. Knowledge of its past demography is essential to reconstruct reef ecology as it was before human impact, which has been implicated as having caused high pre-mortality Diadema abundance. To determine the history of its population size, we sequenced the ATPase 6 and 8 region of mitochondrial DNA from populations in the Caribbean and in the eastern Atlantic (which was not affected by the mass mortality), as well as from the eastern Pacific D. mexicanum. The Caribbean population harbours an order of magnitude more molecular diversity than those of the eastern Pacific or the eastern Atlantic and, despite the recent mass mortality, its DNA sequences bear the genetic signature of a previous population expansion. By estimating mutation rates from divergence between D. antillarum and D. mexicanum, that were separated at a known time by the Isthmus of Panama, and by using estimates of effective population size derived from mismatch distributions and a maximum likelihood coalescence algorithm, we date the expansion as having occurred no more recently than 100 000 years before the present. Thus, Diadema was abundant in the Caribbean long before humans could have affected ecological processes; the genetic data contain no evidence of a recent, anthropogenically caused, population increase.

Adenosine Triphosphatases↗
PubMed2006

The GYF domain.

GYF domains are small, versatile adaptor domains that recognize proline-rich sequences (PRS). They are present in most eukaryotic species sequenced so far, but in contrast to other PRS-recognition domains (PRD), GYF domains have not experienced the same amplification in metazoa during evolution. Mutational and structural analysis has shown the conserved signature W-X-Y-X(6-11)-GPF-X(4)-M-X(2)-W-X(3)-GYF to be the site of interaction with proline-rich peptides. In contrast, composition and length of the C-terminal half of GYF domains are not conserved. Similar to other PRD, GYF domains bind to many different PRS that converge on a minimal consensus sequence. All GYF domains analyzed so far selected for the core motif PPG, whereas amino-acid preferences adjacent to this motif vary. As a result of this analysis, two subfamilies have been identified: CD2BP2-type and SMY2-type GYF domains. The latter subfamily comprises most GYF domains and is characterized by a shorter beta(1)-beta(2) loop and an aspartate instead of the tryptophan found at position 8 in CD2BP2-type GYF domains. Recent analysis of binding specificities for GYF domains allowed identification of novel interaction partners. Thereby proteomics has contributed to a functional understanding of GYF domain-containing proteins and sets the stage for a more systematic investigation of their functions in vivo.

Amino Acid Motifs↗
PubMed1994

Identification of human immunodeficiency virus type 1 envelope genes recombinant between subtypes B and F in two epidemiologically linked individuals from Brazil.

Sequence analysis of a human immunodeficiency virus type 1 env gene PCR amplified from a Brazilian woman's peripheral blood mononuclear cell DNA (sample RJIO1) showed that it was likely to have been derived from a double recombination event between human immunodeficiency virus type 1 subtypes B and F. The major portion of the gp120 coding sequence belonged to the B lineage, but a segment of the C2 to V3 region (approximately 135 nucleotides) clearly associated with sequences of the F lineage. The subtype F-like segment had 15 noncontiguous signature nucleotides in common with Brazilian subtype F sequences that were not found, or were rare, in subtype B sequences. In contrast, this same segment had only 3 signature nucleotides shared with subtype B sequences and not present in the Brazilian subtype F sequences. Phylogenetic analysis, amino acid signature pattern analysis, and the pattern of synonymous mutations all supported the hypothesis of a recombinational origin of the RJIO1 sequence. Related recombinant genes were also detected in peripheral blood mononuclear cell DNA obtained from the woman's recent sexual partner, indicating that the recombination event probably occurred at some previous time in the chain of virus transmission. Divergent viral sequences in the V3 region were found in the male sexual partner, while a relatively homogeneous viral population was detected in the woman, consistent with her recent infection.

Acquired Immunodeficiency Syndrome↗
PubMed2026

FANCI promotes esophageal squamous cell carcinoma progression and cell cycle regulation and interacts with FANCD2.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor clinical outcomes, and reliable molecular biomarkers and therapeutic targets remain limited. Fanconi anemia group I protein (FANCI) is a core component of the Fanconi anemia (FA) pathway, but its expression pattern, clinical significance, and functional role in ESCC have not been comprehensively defined. This study aimed to investigate FANCI expression and prognostic value in ESCC, assess its effects on malignant cellular phenotypes and tumor growth, and explore its potential mechanistic relationship with Fanconi anemia group D2 protein (FANCD2) and cell-cycle regulation. METHODS: Multi-cohort analyses were performed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, together with ESCC single-cell RNA sequencing (RNA-seq) data. FANCI functions were assessed by bidirectional gain- and loss-of-function experiments in vitro (proliferation, colony formation, migration, invasion, apoptosis, and cell-cycle assays) and by xenograft models in vivo. Mechanistic studies included protein-protein interaction (PPI) analyses, co-immunoprecipitation (Co-IP), and immunofluorescence (IF) colocalization. RESULTS: FANCI was consistently upregulated in ESCC across bulk transcriptomic datasets and was further supported by quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry (IHC). FANCI discriminated ESCC from normal tissues in TCGA-ESCC and was independently validated in GSE53624 [area under the curve (AUC) =0.940 and 0.975, respectively]. FANCI was associated with poorer overall survival (OS) and shorter disease-free interval (DFI), and these findings were validated in an independent GEO cohort. Functionally, FANCI promoted ESCC cell proliferation, migration, and invasion, while inhibiting apoptosis; FANCI knockdown suppressed tumor growth in vivo and induced G2/M cell-cycle arrest. Mechanistically, FANCI physically interacted with FANCD2, colocalized with FANCD2 in the nucleus, and was associated with altered FANCD2 protein abundance, consistent with cell-cycle and DNA repair-related programs. Single-cell analysis indicated that FANCI was enriched in epithelial cells and associated with higher activity of malignant functional programs. In TCGA-ESCC, FANCI-high tumors showed distinct mutation profiles, a trend toward increased tumor mutation burden (TMB), and altered immune-associated signatures. CONCLUSIONS: FANCI is upregulated in ESCC and is associated with diagnostic and prognostic value. It promotes malignant phenotypes and tumor growth, potentially through a FANCI-FANCD2-linked cell-cycle/DNA repair program, supporting FANCI as a candidate biomarker and therapeutic target in ESCC.

Esophageal squamous cell carcinoma (ESCC)↗
PubMed2001

Collocation of androgen receptor gene mutations in prostate cancer.

Consistent with both the development of the normal prostate gland and prostate tumorigenesis being dependent on testicular androgens, targeting the androgen-signaling axis (i.e., androgen ablation therapy) remains the predominant treatment regime for patients with metastatic prostate cancer. Although there is a very good initial response to androgen ablation, these treatments are essentially palliative. Recent evidence suggests that treatment failure may not result from a loss of androgen signaling but, rather, from the acquisition of genetic changes that lead to aberrant activation of the androgen-signaling axis. A consistent finding is that androgen receptor (AR) gene mutations, present in metastatic prostate cancer and in human prostate cancer cell lines as well as in xenograft and other animal models, result in decreased specificity of ligand-binding and inappropriate receptor activation by estrogens, progestins, adrenal androgens, glucocorticoids and/or AR antagonists. Because a significant proportion of missense mutations in the AR gene reported in prostate cancer collocate to the signature sequence and AF-2, two discrete regions of the ligand-binding domain critical for androgen signaling, we recently proposed that collocation of mutations identified in prostate cancer would identify additional regions of the AR important in receptor function. This approach led to the identification of a four-amino acid region at the boundary of the hinge and ligand-binding domains of the receptor that forms half of a potential protein-protein binding site. AR gene mutations have also been identified that collocate to areas in the DNA-binding domain, to the NH(2)-terminal transactivation domain, and to the hinge region in prostate tumors. In nearly every case, missense mutations in the AR gene identified in prostate cancer that collocate to discrete regions of the receptor contribute to altered androgen signaling and provide a potential mechanism to explain the reemergence of tumor growth during the course of hormone ablation therapies.

Androgens↗
PubMed2006

Metastasis predictive signature profiles pre-exist in normal tissues.

Previous studies from our laboratory have demonstrated that metastatic propensity is significantly influenced by the genetic background upon which tumors arise. We have also established that human gene expression profiles predictive of metastasis are not only present in mouse tumors with both high and low metastatic capacity, but also correlate with genetic background. These results suggest that human metastasis-predictive gene expression signatures may be significantly driven by genetic background, rather than acquired somatic mutations. To test this hypothesis, gene expression profiling was performed on inbred mouse strains with significantly different metastatic efficiencies. Analysis of previously described human metastasis signature gene expression patterns in normal tissues permitted accurate categorization of high or low metastatic mouse genotypes. Furthermore, prospective identification of animals at high risk of metastasis was achieved by using mass spectrometry to characterize salivary peptide polymorphisms in a genetically heterogeneous population. These results strongly support the role of constitutional genetic variation in modulation of metastatic efficiency and suggest that predictive signature profiles could be developed from normal tissues in humans. The ability to identify those individuals at high risk of disseminated disease at the time of clinical manifestation of a primary cancer could have a significant impact on cancer management.

Animals↗
PubMed2005

Detection of the BRAF V600E mutation in melanocytic lesions using the ligase detection reaction.

BACKGROUND: BRAF is a member of the RAF kinase family, and it promotes signaling through the RAS-MAP kinase signal transduction cascade. Research has shown that a majority of melanomas and nevi exhibit an activating V600E (T1799A) mutation in BRAF exon 15. Additional studies of BRAF have demonstrated that the T1799A mutation is absent in uveal melanomas and Spitz nevi. METHODS: The ligase detection reaction (LDR) is a sensitive technique that can identify specific DNA mutations occurring at very low frequency within heterogeneous clinical samples, and it has previously been used to analyze mutations in paraffin-embedded tissue specimens. RESULTS: The LDR can readily detect mutations in DNA extracted from non-microdissected paraffin-embedded sections of common nevi, dysplastic nevi, and melanomas. In addition, this method demonstrated the absence of the V600E (T1799A) mutation within Spitz nevi. CONCLUSION: The LDR is a highly sensitive and specific test for detecting mutations in formalin-fixed tissue. The LDR can be easily adapted to detect any mutation associated with a cutaneous disorder. The absence of the BRAF V600E mutation in Spitz's nevi may serve as a molecular signature to distinguish these lesions from common nevi, dysplastic nevi, and some types of malignant melanoma.

Base Sequence↗
PubMed1997

The Bloom's syndrome gene product is a 3'-5' DNA helicase.

Bloom's syndrome (BS) is an autosomal recessive condition characterized by short stature, immunodeficiency, and a greatly elevated frequency of many types of cancer. The gene mutated in BS, BLM, encodes a protein containing seven "signature" motifs conserved in a wide range of DNA and RNA helicases. BLM is most closely related to the subfamily of DEXH box-containing DNA helicases of which the prototypical member is Escherichia coli RecQ. To analyze its biochemical properties, we have overexpressed an oligohistidine-tagged version of the BLM gene product in Saccharomyces cerevisiae and purified the protein to apparent homogeneity using nickel chelate affinity chromatography. The recombinant BLM protein possesses an ATPase activity that is strongly stimulated by either single- or double-stranded DNA. Moreover, BLM exhibits ATP- and Mg2+-dependent DNA helicase activity that displays 3'-5' directionality. Because many of the mutations in BS individuals are predicted to truncate the BLM protein and thus eliminate the "helicase" motifs or map to conserved positions within these motifs, our data strongly suggest that these mutations will disable the 3'-5' helicase function of the BLM protein.

Adenosine Triphosphatases↗
PubMed2007

The distal fallopian tube: a new model for pelvic serous carcinogenesis.

PURPOSE OF REVIEW: Research over the past 50 years has yielded little concrete information on the source of pelvic serous cancer in women, creating a knowledge gap that has adversely influenced our ability to identify, remove or prevent the earliest stages of the most lethal form of ovarian cancer. RECENT FINDINGS: The distal fallopian tube is emerging as an established source of many early serous carcinomas in women with BRCA mutations (BRCA+). Protocols examining the fimbrial (SEE-FIM) end have revealed a noninvasive but potentially lethal form of tubal carcinoma, designated tubal intraepithelial carcinoma. Tubal intraepithelial carcinoma is present in many women with presumed ovarian or peritoneal serous cancer. A candidate precursor to tubal intraepithelial carcinoma, entitled the 'p53 signature', suggests that molecular events associated with serous cancer (p53 mutations) may be detected in benign mucosa. SUMMARY: A fully characterized precursor lesion is a first and necessary step to pelvic serous cancer prevention. The emerging data offer compelling evidence for a model of 'fimbrial-ovarian' serous neoplasia, and call attention to the distal fallopian tube as an important source for this disease, the study of which could clarify pathways to cancer in both organs and generate novel strategies for cancer prevention.

Adenocarcinoma, Mucinous↗
PubMed2026

Identification of ultrasound-associated gene candidates in myeloid cells and construction of a prognostic risk model for acute myeloid leukemia.

BACKGROUND: Incorporating ultrasound (US) treatment sensitivity analysis may improve the treatment of acute myeloid leukemia (AML). METHODS: This study integrated single-cell and bulk datasets for analysis. Differential expression analysis between US-treated and control samples was performed using limma package. The AUCell package was used to calculate US-associated scores in the single-cell dataset. Differentially expressed genes (DEGs) between the specific groups were identified, followed by intersection analysis with previously identified DEGs. Univariate regression, Least Absolute Shrinkage and Selection Operator (LASSO) analysis (using the glmnet package), and stepwise multivariate regression (using the MASS package) were used to refine the candidate genes and to construct a risk model. The model genes were validated using in vitro experiments. Enrichment analysis was conducted using gene set enrichment analysis (GSEA), and immune infiltration was evaluate by single-sample GSEA (ssGSEA) and ESTIMATE algorithms. The correlations between RiskScores and drug sensitivity were analyzed by oncoPredict package. Finally, tumor mutational burden (TMB) and genomic mutations were compared between the risk groups. RESULTS: Nine prognostic signatures (SPINK2, HNRNPAB, SH3BGRL3, CLEC11A, ITGA4, RPL39L, MX1, HEXIM1, and MAP4K4) were identified. Particularly, low expression of SPINK2 attenuated the activity and invasion of AML cells. High-risk group had higher immune cell infiltration. Eight drugs were predicted to be correlated with the RiskScore model. DNMT3A and RUNX1 showed higher mutation frequencies in the high-risk group, whereas KIT and MUC16 showed higher mutation frequencies in the low-risk group. CONCLUSION: The RiskScore model established in this study provides a theoretical basis for clinically screening responsive populations and optimizing treatment strategies.

Humans↗
PubMed2005

Recognition sequence 2 (residues 60-71) plays a role in oligomerization and exchange dynamics of alphaB-crystallin.

Previously, using the peptide scan method, we have determined that residues 42-57 and 60-71 in alphaB-crystallin (TSLSPFYLRPPSFLRA, named recognition sequence 1 or RS-1, and WFDTGLSEMRLE, named recognition sequence 2 or RS-2) are involved in interaction with alphaA-crystallin. To understand the significance of the RS-2 region in interactions between alphaA- and alphaB-crystallins, W60R, F61N, and S66G mutants of alphaB-crystallin were made and tested for their ability to interact with alphaA-crystallin. W60R and S66G mutations increased the oligomeric size of alphaB-crystallin by 1.6- and 2.7-fold respectively, whereas the F61N mutation had no effect. The tryptophan fluorescence intensity of alphaBS66G was 1.5-fold higher than that for the wild type. The intrinsic fluorescence of alphaBF61N was marginally lower than that of alphaB, whereas the fluorescence intensity of alphaBW60R decreased by 40% compared with that of alphaB. The relative availability of hydrophobic sites in the mutants was in the following order: alphaBS66G >> alphaB = alphaBF61N = alphaBW60R. The far-UV CD profiles for the wild type and alphaB-crystallin mutants indicated no significant changes in their secondary structures, except for alphaBS66G, which showed an increase in alpha-helical content. The near-UV CD profiles of alphaBW60R and alphaBF61N were nearly similar to that of wild type alphaB. On the other hand, alphaBS66G beyond 270 nm exhibited a signature completely different from that of wild type alphaB. Mutations did not alter the chaperone-like activity of these proteins. The W60R mutation did not affect the rate of subunit exchange between alphaB- and alphaA-crystallins. On the other hand, the S66G mutation increased the subunit exchange rate by 100%, whereas the F61N mutation decreased the rate of subunit exchange between alphaB- and alphaA-crystallins by 36%. Our results establish the importance of residues 60-71 in oligomerization of alphaB-crystallin and subunit interaction between alphaB- and alphaA-crystallins.

Circular Dichroism↗
PubMed2004

Nucleotide variability at the acetyl coenzyme A carboxylase gene and the signature of herbicide selection in the grass weed Alopecurus myosuroides (Huds.).

Acetyl coenzyme A carboxylase (ACCase) is the target of highly effective herbicides. We investigated the nucleotide variability of the ACCase gene in a sample of 18 black-grass (Alopecurus myosuroides [Huds.]) populations to search for the signature of herbicide selection. Sequencing 3,396 bp encompassing ACCase herbicide-binding domain in 86 individuals revealed 92 polymorphisms, which formed 72 haplotypes. The ratio of nonsynonymous versus synonymous substitutions was very low, in agreement with ACCase being a vital metabolic enzyme. Within black grass, most nonsynonymous substitutions were related to resistance to ACCase-inhibiting herbicides. Differentiation between populations was strong, in contrast to expectations for an allogamous, annual plant. Significant H tests revealed recent hitchhiking events within populations. These results were consistent with recent and local positive selection. We propose that, although they have only been used since at most 15 black-grass generations, ACCase-inhibiting herbicides have exerted a positive selection targeting resistant haplotypes that has been strong enough to have a marked effect upon ACCase nucleotide diversity. A minimum-spanning network of nonrecombinant haplotypes revealed multiple, independent apparitions of resistance-associated mutations. This study provides the first evidence for the signature of ongoing, recent, pesticide selection upon variation at the gene encoding the targeted enzyme in natural plant populations.

Acetyl-CoA Carboxylase↗
PubMed2002

Conformational changes in hemoglobin S (betaE6V) imposed by mutation of the beta Glu7-beta Lys132 salt bridge and detected by UV resonance Raman spectroscopy.

The impact upon molecular structure of an additional point mutation adjacent to the existing E6V mutation in sickle cell hemoglobin was probed spectroscopically. The UV resonance Raman results show that the conformational consequences of mutating the salt bridge pair, betaGlu(7)-betaLys(132), are dependent on which residue of the pair is modified. The betaK132A mutants exhibit the spectroscopic signatures of the R --> T state transition in both the "hinge" and "switch" regions of the alpha(1)beta(2) interface. Both singly and doubly mutated hemoglobin (Hb) betaepsilon7Alpha exhibit the switch region signature for the R --> T quaternary state transition but not the hinge signature. The absence of this hinge region-associated quaternary change is the likely origin of the observed increased oxygen binding affinity for the Hb betaepsilon7Alpha mutants. The observed large decrease in the W3 alpha14beta15 band intensity for doubly mutated Hb betaepsilon7Alpha is attributed to an enhanced separation in the A helix-E helix tertiary contact of the beta subunits. The results for the Hb A betaGlu(7)-betaLys(132) salt bridge mutants demonstrate that attaining the T state conformation at the hinge region of the alpha(1)beta(2) dimer interface can be achieved through different intraglobin pathways; these pathways are subject to subtle mutagenic manipulation at sites well removed from the dimer interface.

Dimerization↗
PubMed2025

LCORL and STC2 Variants Increase Body Size and Growth Rate in Cattle and Other Animals.

Natural variants can significantly improve growth traits in livestock and serve as safe targets for gene editing, thus being applied in animal molecular design breeding. However, such safe and large-effect mutations are severely lacking. Using ancestral recombination graphs, we investigated recent selection signatures in beef cattle breeds, pinpointing sweep-driving variants in the LCORL and STC2 loci with notable effects on body size and growth rate. The ACT-to-A frameshift mutation in LCORL occurs mainly in central-European cattle, and stimulates growth. Remarkably, convergent truncating mutations were also found in commercial breeds of sheep, goats, pigs, horses, dogs, rabbits, and chickens. In the STC2 gene, we identified a missense mutation (A60P) located within the conserved region across vertebrates. We validated the two natural mutations in gene-edited mouse models, where both variants in homozygous carriers significantly increase the average weight by 11%. Our findings provide insights into a seemingly recurring gene target of body size enhancing truncating mutations across domesticated species, and offer valuable targets for gene editing-based breeding in animals.

Animals↗
PubMed1998

Models for haplotype evolution in a nonstationary population.

Haplotype mapping has emerged in the past few years as a powerful tool for the fine mapping of disease genes. It is typically carried out on a sample of affected individuals from a population isolate. If the chromosome neighborhood of a disease gene is saturated with markers, then each new mutation in the population or existing mutation introduced by a population founder exhibits a unique haplotype signature at the time of its introduction. Partial disruption of these signatures by recombination can be visualized in affects and provide important clues to the location of the disease gene. The current paper models haplotype evolution with the intention of clarifying the most favorable circumstances for haplotype mapping. Comparisons with linkage mapping are stressed. For dominant diseases, both deterministic and stochastic models are suggested. Numerical examples based on Finnish population parameters illustrate the general theory in the presence of the complications of selection, mutation, and slow, exponential growth of the isolate.

Biological Evolution↗
PubMed2003

Patterns of intra- and interhost nonsynonymous variation reveal strong purifying selection in dengue virus.

Considerable uncertainty surrounds the evolutionary rates of and selection pressures acting on arthropod-borne RNA viruses (arboviruses). In particular, it is unclear why arboviruses such as dengue virus show substantial genetic variation within individual humans and mosquitoes yet low long-term rates of amino acid substitution. To address this question, I compared patterns of nonsynonymous variation in populations of dengue virus sampled at different levels of evolutionary divergence. Although nonsynonymous variation was abundant in viral populations within individual humans, there was a marked reduction in the frequency of nonsynonymous mutations in interhost comparisons. Moreover, intrahost genetic variation corresponded to a random pattern of mutation, and most of the sites that exhibited nonsynonymous variation within hosts were invariant at deeper phylogenetic levels. This loss of long-term nonsynonymous variation is the signature of extensive purifying selection such that more than 90% of all nonsynonymous mutations are deleterious. Consequently, although arboviruses are able to successfully adapt to diverse cell types, they are characterized by a high rate of deleterious mutation.

Dengue Virus↗
PubMed1994

Can we predict solar ultraviolet radiation as the causal event in human tumours by analysing the mutation spectra of the p53 gene?

The tumour suppressor gene, p53, has proved to be one of the genes most often modified in human cancers. These alterations consist mainly of point mutations located in the evolutionarily conserved sequences which render the protein inactive for its normal biological functions. In fact the p53 gene presents nearly 300 potential mutation sites whose analysis should enable the correlation of specific mutation spectra with different causal agents in cancer development. In this study we have analysed the mutation spectrum of the p53 gene in skin tumours from normal individuals and repair-deficient xeroderma pigmentosum (XP) patients in comparison with mutations found in internal cancers. Point mutations are mainly GC-->AT transitions in skin tumours (74% in non-XP, 87% in XP), and also to a lesser extent in internal tumours (47%) where, however, they are mainly located at CpG (63%) sequences probably due to the deamination of the unstable 5-MeC. Moreover, mutations are targeted at py-py sequences in over 90% of skin tumours whereas the distribution of mutations in internal malignancies is proportional to the frequency of py-py sites (61%) and other sequences (39%) at mutable sites. Indeed, in XP skin tumours 100% of the mutations are targeted at py-py sequences and 55% of these are tandem CC-->TT transitions considered as a signature of UV-induced lesions. In skin tumours from normal individuals, 14% of the p53 mutations are double mutations and as in XP skin tumours all these are CC-->TT transitions. In contrast, internal tumours rarely contain tandem mutations (0.8%), and of these only 2/14 were CC-->TT transitions. Finally, nearly all (95%) of the mutations in XP are located on the non-transcribed strand while internal or non-XP skin tumours do not show this strand bias. Hence, the mutation spectrum analysed in XP skin tumours also demonstrates for the first time the existence of preferential repair in humans. In conclusion, the specificity of UV-induced p53 mutation spectra in skin tumours shows that this gene is a particularly appropriate candidate for the correlation of mutation spectra with specific damaging agents.

DNA↗