Letteratura scientifica selezionata sul tema "Les Mutations"
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Articoli di riviste sul tema "Les Mutations"
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Tarlock, Katherine, Todd M. Cooper, Todd A. Alonzo, Robert Gerbing, Jessica Pollard, Richard Aplenc, E. Anders Kolb, Alan S. Gamis e Soheil Meshinchi. "Mutational Concordance from Diagnosis and Relapse in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group". Blood 128, n. 22 (2 dicembre 2016): 2846. http://dx.doi.org/10.1182/blood.v128.22.2846.2846.
Testo completoAbstract (sommario):
Abstract The range of genomic drivers of leukemogenesis and clonal nature of the disease illustrate the heterogeneity of the mutational spectrum in AML. Genomic interrogation of the evolution of AML has begun to highlight the scope of somatic changes that occur between diagnosis and relapse. A total of 1,214 patients were treated on the Children's Oncology Group trials AAML03P1 and AAML0531, of which 398 had relapse after initial remission. Of this cohort, 201 patients had matching diagnostic and relapse specimens for molecular profiling for the most common somatic mutations in pediatric AML (FLT3/ITD, FLT3/ALM, NPM1, CEBPA, WT1, NRAS, and KIT). Sequencing techniques included PCR with Sanger sequencing for detection of point mutations and indels and fragment length analysis for FLT3/ITD. In the cohort, FLT3/ITD was detected in 31/201 (15%) cases at diagnosis. Of the cases with diagnostic ITD, 22 (71%) relapsed with FLT3/ITD. Conversely, of the 28 cases with FLT3/ITD detected at relapse, 6 (21%) did not have detectable ITD at diagnosis. Overall, there were 37 patients (18%) with FLT3/ITD mutations detected at either time point. Of the 37 patients, 22 (59%) demonstrated stability of the mutation from diagnosis to relapse. Discordant mutation status was observed in 15 patients (41%). Among the discordant patients, 9 had FLT3/ITD detected at diagnosis only. Conversely, 6 patients were ITD-positive at relapse only, demonstrating disease evolution with continued mutational acquisition (Table 1). In every discordant case, ultra sensitive PCR analysis confirmed absence of an ITD. The median ITD allelic ratio (AR) for patients with concordant status was 0.47 (range 0.03-2.67) vs. 0.24 (range 0.04-0.47) for those with disappearance of the ITD at relapse, suggesting an association of diagnostic AR with mutation stability. NPM1 mutations were detected in 8 patients at diagnosis and 100% concordance was observed in the cohort. CEBPA mutations were detected in 6 patients at diagnosis, and in 5 cases remained at relapse. One patient had a CEBPA mutation detected at diagnosis only. FLT3/ALM mutations were detected in 7 patients at either time point. Seven patients had an ALM at diagnosis, however concordance was observed in 2 cases, whereas 4 patients had detection at diagnosis only. There were 22 patients (11%) with NRAS mutations detected at either time point. Diagnostic NRAS mutations were detected in 18 patients, while only 3 (17%) had the identical mutation detected at relapse, as one patient had a distinct mutational sequence present at relapse. NRAS mutations were detected at diagnosis only in 13 patients (59%), where as 5 patients (23%) had a mutation detected at relapse only. NRAS was the most discordant mutations analyzed, with only 3/22 patients (14%) demonstrating stability of the mutation from diagnosis to relapse (Table 1). WT1 exon 17 indels were observed in 24 patients (12%) at either time point. Nineteen patients had diagnostic mutations, with 18 patients demonstrating stability at relapse. Five patients had mutations detected at relapse only. Overall, concordance was observed in 18 patients (75%). Only 1 alteration was detected at diagnosis in all patients, however 6 patients with concordant WT1 status had multiple indels detected at relapse, demonstrating continued mutational acquisition. KIT mutations (missense and indels) in exons 8 (n=11) and 17 (n=7) were detected in 17 patients. Mutational concordance was observed in 7 patients. Eight patients had mutations detected at diagnosis only, while 2 patients had mutations detected at relapse only (Table 1). We demonstrate the complexity of the evolving somatic landscape from diagnosis to relapse in pediatric AML. The stability of NPM1 mutations, considered an early leukemogenic event, is in contrast to the discordant NRAS and KIT mutations. There was evolution of FLT3/ITD status, and we observed overall higher ARs in the concordant cohort, perhaps suggesting mutations in this cohort served as stronger leukemic drivers. Further investigation on the biologic implications and clonal prevalence is critical to determine a mutation's significance in leukemogenesis, timing of acquisition, and if appropriate for therapeutic targeting and disease monitoring. Table 1 Mutational concordance from diagnosis to relapse. Legend: Discordant D+/R-: Discordant status with diagnostic only positive Discordant D-/R+: Discordant status with relapse only positive Table 1. Mutational concordance from diagnosis to relapse. / Legend:. / Discordant D+/R-: Discordant status with diagnostic only positive. / Discordant D-/R+: Discordant status with relapse only positive Disclosures No relevant conflicts of interest to declare.
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GARCÍA-DORADO, A., C. LÓPEZ-FANJUL e A. CABALLERO. "Properties of spontaneous mutations affecting quantitative traits". Genetical Research 74, n. 3 (dicembre 1999): 341–50. http://dx.doi.org/10.1017/s0016672399004206.
Testo completoAbstract (sommario):
Recent mutation accumulation results from invertebrate species suggest that mild deleterious mutation is far less frequent than previously thought, implying smaller expressed mutational loads. Although the rate (λ) and effect (s) of very slight deleterious mutation remain unknown, most mutational fitness decline would come from moderately deleterious mutation (s ≈ 0·2, λ ≈ 0·03), and this situation would not qualitatively change in harsh environments. Estimates of the average coefficient of dominance (h¯) of non-severe deleterious mutations are controversial. The typical value of h¯ = 0·4 can be questioned, and a lower estimate (about 0·1) is suggested. Estimated mutational parameters are remarkably alike for morphological and fitness component traits (excluding lethals), indicating low mutation rates and moderate mutational effects, with a distribution generally showing strong negative asymmetry and little leptokurtosis. New mutations showed considerable genotype–environment interaction. However, the mutational variance of fitness-component traits due to non-severe detrimental mutations did not increase with environmental harshness. For morphological traits, a class of predominantly additive mutations with no detectable effect on fitness and relatively small effect on the trait was identified. This should be close to that responsible for standing variation in natural populations.
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Watters, M. K., e D. R. Stadler. "Spontaneous mutation during the sexual cycle of Neurospora crassa." Genetics 139, n. 1 (1 gennaio 1995): 137–45. http://dx.doi.org/10.1093/genetics/139.1.137.
Testo completoAbstract (sommario):
Abstract The DNA sequences of 42 spontaneous mutations of the mtr gene in Neurospora crassa have been determined. The mutants were selected among sexual spores to represent mutations arising in the sexual cycle. Three sexual-cycle-specific mutational classes are described: hotspot mutants, spontaneous repeat-induced point mutation (RIPs) and mutations occurring during a mutagenic phase of the sexual cycle. Together, these three sexual-cycle-specific mutational classes account for 50% of the mutations in the sexual-cycle mutational spectrum. One third of all mutations occurred at one of two mutational hotspots that predominantly produced tandem duplications of varying lengths with short repeats at their end-points. Neither of the two hotspots are present in the vegetative spectrum, suggesting that sexual-cycle-specific mutational pathways are responsible for their presence in the spectrum. One mutant was observed that appeared to have been RIPed precociously. The usual prerequisite for RIP, a duplication of the affected region, was not present in the parent stocks and was not detected in this mutant. Finally, there is a phase early in the premeiotic sexual cycle that is overrepresented in the generation of mutations. This "peak" appears to represent a phase during which the mutation rate rises significantly. This phase produces a disproportionally high fraction of frame shift mutations (3/6). In divisions subsequent to this, the mutation rate appears to be constant.
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Ellis, Nathan A. "Mutation-causing mutations". Nature 381, n. 6578 (maggio 1996): 110–11. http://dx.doi.org/10.1038/381110a0.
Testo completo
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Pawlik, Timothy M., Darrell R. Borger, Yuhree Kim, David Cosgrove, Sorin Alexandrescu, Ryan Thomas Groeschl, Vikram Deshpande et al. "Genomic profiling of intrahepatic cholangiocarcinoma: Refining prognostic determinants and identifying therapeutic targets." Journal of Clinical Oncology 32, n. 3_suppl (20 gennaio 2014): 210. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.210.
Testo completoAbstract (sommario):
210 Background: The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to define the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection. Methods: 138 patients who underwent resection at 6 centers in the United States and Europe were included in the cohort. Mutational profiling was performed using nucleic acids that were extracted from resected ICC tumor specimens; mutations were identified using a multiplexed mutational profiling platform. The frequency of mutations was ascertained and the impact on outcome determined. Results: Most patients had a solitary tumor (82%) and median tumor size was 6.0cm. Most patients had R0 resection (89%); 19% patients had N1 disease, while 15% had microscopic vascular invasion. A minority received adjuvant therapy (30%). The majority (55%) of patients had no genetic mutation identified. Among the 62 (45%) patients with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5%: IDH1 (17.4%), KRAS (8.7%), BRAF (5.8%), PIK3CA (5.1%). In contrast, other genetic mutations were identified in very low frequency: IDH2 (3.6%), NRAS (3.6%), TP53 (2.2%), MAP2K1 (1.5%), CTNNB1 (0.7%), and PTEN (0.7%). Approximately 7% of IDH1-mutant tumors were associated with a concurrent PIK3CA gene mutation, and to a much lower extent, a mutation in MAP2K1 (2%). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (OR 3.46), while KRAS-mutant tumors were more likely to be associated with perineural invasion (OR 5.72)(both P<0.05). While clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis. Conclusions: Most patients with resected ICC had no somatic mutation identified on multiplexed mutational profiling. IDH1 and KRAS were the most common mutations noted. While certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly impact long-term prognosis.
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Kang, S., S. S. Seo, H. J. Chang, C. W. Yoo, S. Y. Park e S. M. Dong. "Mutual exclusiveness between PIK3CA and KRAS mutations in endometrial carcinoma". International Journal of Gynecologic Cancer 18, n. 6 (2008): 1339–43. http://dx.doi.org/10.1111/j.1525-1438.2007.01172.x.
Testo completoAbstract (sommario):
In endometrial carcinomas (ECs), previous report suggested that PIK3CA mutations do not coexist with KRAS mutations, but the significant mutual exclusiveness has not been demonstrated. In this study, we examined the mutation frequency of PIK3CA in EC and its mutual exclusiveness with KRAS mutation. We performed mutational analysis of PIK3CA through a polymerase chain reaction single-strand conformation polymorphism assay in 44 cases of endometrial cancer and analyzed the correlation with loss of PTEN, KRAS mutation, and RASSF1A hypermethylation. Somatic mutations of PIK3CA were detected in 14 of 44 (31.8%) of endometrial cancers. In exon 9, seven PIK3CA mutations were located, while seven mutations were located in exon 20. The most common mutation was E545A (35.7%), followed by H1047R (28.6%). Concomitant loss of PTEN expression and PIK3CA mutation was found in four cases of endometrial cancer. KRAS mutations were mutually exclusive with PIK3CA mutations, and those mutations were inversely correlated with statistical significance (P= 0.039). Also, we found that mutations in ERBB2 were mutually exclusive with PIK3CA mutations. RASSF1A and hMLH1 methylation were not correlated with the presence of PIK3CA mutations. PIK3CA was frequently mutated in endometrial cancers. KRAS and PIK3CA mutations are inversely correlated, suggesting that genetic alterations of KRAS and PIK3CA may play equivalent roles in endometrial carcinogenesis.
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Chao, Mwe, Kathrin Thomay, Gudrun Goehring, Marcin Wlodarski, Victor Pastor, Brigitte Schlegelberger, Detlev Schindler, Christian Kratz e Charlotte Niemeyer. "Mutational Spectrum of Fanconi Anemia Associated Myeloid Neoplasms". Klinische Pädiatrie 229, n. 06 (novembre 2017): 329–34. http://dx.doi.org/10.1055/s-0043-117046.
Testo completoAbstract (sommario):
AbstractIndividuals with Fanconi anemia (FA) have a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), yet the secondary somatic mutations lending to these malignancies remain to be further elucidated. We employed a next-generation sequencing myeloid neoplasia gene panel to determine the mutational spectrum of FA-related MDS/AML. Ten of 16 patients showed missense, nonsense, insertion or duplication mutations in 13 genes. In contrast to findings in MDS in the general population, mutations in genes involved in RNA splicing were rarely affected. Mutations in RUNX1 and genes of the RAS pathway appeared more instrumental in the pathogenesis of FA myeloid malignancies. RUNX1 mutations were associated with more advanced disease. Interestingly, one patient with refractory anemia with ring sideroblasts harbored the SF3B1 p.K700E mutation highlighting the mutation’s causative role in MDS with ring sideroblasts even in the context of FA. On the whole, our findings implicate a different genetic architecture of FA MDS/AML from adult sporadic MDS. Notably, the genetic events resemble those described in pediatric MDS.
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Hughes, Timothy, Giuseppe Saglio, Giovanni Martinelli, Dong-Wook Kim, S. Soverini, Martin Mueller, A. Haque et al. "Responses and Disease Progression in CML-CP Patients Treated with Nilotinib after Imatinib Failure Appear To Be Affected by the BCR-ABL Mutation Status and Types." Blood 110, n. 11 (16 novembre 2007): 320. http://dx.doi.org/10.1182/blood.v110.11.320.320.
Testo completoAbstract (sommario):
Abstract Nilotinib is a rationally designed 2nd-generation bcr-abl inhibitor. It is ∼30-fold more potent than imatinib against wild-type bcr-abl and active against 32/33 imatinib-resistant bcr-abl mutants in preclinical models. In an open-label phase II study of nilotinib in imatinib-resistant or -intolerant CML-CP patients (pts), we assessed the occurrence of mutations and the efficacy stratified by BCR-ABL mutational status. Prior to therapy, 35 mutations affecting 28 amino acids in the BCR-ABL kinase domain were identified by direct sequencing in 39% (106/270) of the pts analyzed. The incidence of baseline mutation was higher in imatinib-resistant (100/183, 55%) versus imatinib-intolerant pts (6/86, 7%). After 12 months of therapy, complete hematologic response (CHR) was achieved in 85%, major cytogenetic response (MCR) in 60%, and complete cytogenetic response (CCR) in 45% of pts without baseline mutations versus 67, 49 and 29% of pts with mutations. Among patients with baseline mutations, responses were observed broadly in all genotypes identified, but rates of responses differed by the in vitro sensitivity of the mutant clone against nilotinib. Pts with sensitive mutations of ≤100 nM cellular IC50 had the best response rate and were comparable to pts without baseline mutations. Pts with less sensitive mutations (IC50 201–800nM:Y253H, E255K, E255V, F359C) had responses but the response rate were lower then those of the two other groups (IC50 101–200nM and 201–800nM). The nilotinib-resistant T315I mutation (IC50>800nM) was identified at baseline in 5 cases (one pt had a limited response followed by progression). The less sensitive mutations (IC50 201–800nM) and the T315I mutation occurred in 8% and 2% of all pts assessed for baseline mutations, respectively. With a median follow up of 12 months, progression occurred in 15% (25/164) versus 40% (42/106) of pts without and with baseline mutations. Nine of 18 with less sensitive baseline mutations and 3 of 5 with T315I progressed, but the baseline mutation most frequently associated with progression was F359V (7/9). In 67 cases of progression, mutational data at or within 3 months of progression were available in 28 cases. Among the 28 pts, 7 (25%) had no mutation; 9 (32%) had the same baseline mutation (including F359V in 3; Y253F/H in 3; E255K in 1; and T315I in 1). A further 12 (43%) pts showed new emerging mutations at progression, 4 with T315I, 4 E255K, 3 Y253H, and 1 F359C. The other 7 pts with emerging mutations had not progressed. In total 21 pts were found with emerging mutations, 19 (90%) had a different mutation at baseline. In summary, nilotinib responses were observed across a variety of BCR-ABL mutations. Preliminary data suggest that mutational status at baseline and/or the emergence of new mutations may influence disease progression. Less sensitive or resistant mutations represented 10% of the pt population and may be associated with less favorable responses. Longer follow up is required.
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Pálinkás, Hajnalka Laura, Lőrinc Pongor, Máté Balajti, Ádám Nagy, Kinga Nagy, Angéla Békési, Giampaolo Bianchini, Beáta G. Vértessy e Balázs Győrffy. "Primary Founder Mutations in the PRKDC Gene Increase Tumor Mutation Load in Colorectal Cancer". International Journal of Molecular Sciences 23, n. 2 (6 gennaio 2022): 633. http://dx.doi.org/10.3390/ijms23020633.
Testo completoAbstract (sommario):
The clonal composition of a malignant tumor strongly depends on cellular dynamics influenced by the asynchronized loss of DNA repair mechanisms. Here, our aim was to identify founder mutations leading to subsequent boosts in mutation load. The overall mutation burden in 591 colorectal cancer tumors was analyzed, including the mutation status of DNA-repair genes. The number of mutations was first determined across all patients and the proportion of genes having mutation in each percentile was ranked. Early mutations in DNA repair genes preceding a mutational expansion were designated as founder mutations. Survival analysis for gene expression was performed using microarray data with available relapse-free survival. Of the 180 genes involved in DNA repair, the top five founder mutations were in PRKDC (n = 31), ATM (n = 26), POLE (n = 18), SRCAP (n = 18), and BRCA2 (n = 15). PRKDC expression was 6.4-fold higher in tumors compared to normal samples, and higher expression led to longer relapse-free survival in 1211 patients (HR = 0.72, p = 4.4 × 10−3). In an experimental setting, the mutational load resulting from UV radiation combined with inhibition of PRKDC was analyzed. Upon treatments, the mutational load exposed a significant two-fold increase. Our results suggest PRKDC as a new key gene driving tumor heterogeneity.
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Ahn, TaeJin, e Taesung Park. "Pathway-Driven Discovery of Rare Mutational Impact on Cancer". BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/171892.
Testo completoAbstract (sommario):
Identifying driver mutation is important in understanding disease mechanism and future application of custom tailored therapeutic decision. Functional analysis of mutational impact usually focuses on the gene expression level of the mutated gene itself. However, complex regulatory network may cause differential gene expression among functional neighbors of the mutated gene. We suggest a new approach for discovering rare mutations that have real impact in the context of pathway; the philosophy of our method is iteratively combining rare mutations until no more mutations can be added under the condition that the combined mutational event can statistically discriminate pathway level mRNA expression between groups with and without mutational events. Breast cancer patients with somatic mutation and mRNA expression were analyzed by our approach. Our approach is shown to sensitively capture mutations that change pathway level mRNA expression, concurrently discovering important mutations previously reported in breast cancer such as TP53, PIK3CA, and RB1. In addition, out of 15,819 genes considered in breast cancer, our approach identified mutational events of 32 genes showing pathway level mRNA expression differences.
Tesi sul tema "Les Mutations"
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Komp, Lindgren Patricia. "Mutations and Mutation Rate in the Development of Fluoroquinolone Resistance". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8275.
Testo completo
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Ibrahim, Daniel Murad. "ChIP-seq reveals mutation-specific pathomechanisms of HOXD13 missense mutations". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2015. http://dx.doi.org/10.18452/17102.
Testo completoAbstract (sommario):
Mutationen von Transkriptionsfaktoren (TF) betreffen nicht nur die Funktion des TFs, sondern auch die Expression seiner Zielgene und liegen häufig angeborenen Entwicklungsdefekten zugrunde. Über 20 Mutationen in HOXD13, einem TF der die Entwicklung der Extremitäten kontrolliert, sind bisher als Ursache verschiedenartiger Extremitätenfehlbildungen entdeckt worden. Eine molekularbiologische Grundlage für die Vielgestaltigkeit der HOXD13-Mutationen ist jedoch unbekannt. Die bisherigen Methoden zur funktionellen Charakterisierung von TF-Mutationen ermöglichten eine lediglich eingeschränkte Interpretation der molekularen Pathomechanismen. Die kürzlich entwickelte ChIP-seq Methode ermöglicht eine umfassende, funktionelle Charakterisierung eines TFs. In dieser Arbeit wurde eine Methode etabliert, um eine Vielzahl von Transkriptionsfaktoren und TF-Mutationen systematisch zu untersuchen. Zur Validierung wurden zwei neue Punktmutationen in HOXD13, p.Q317K und p.R298Q, charakterisiert. Beide Mutationen betreffen die DNA-bindende Domäne von HOXD13, rufen aber stark unterschiedliche Fehlbildungen hervor. Die Ergebnisse zeigen, dass die HOXD13Q317K Mutante eine veränderte Sequenzspezifität aufweist, welche nun jener eines anderen TFs, PITX1, ähnelt. Auch genomweit zeigt HOXD13Q317K ein Bindungsprofil, welches eher PITX1 als HOXD13wt entspricht. Durch weitere, unabhängige Analysen und Experimente wurde bestätigt, dass die p.Q317K Mutation HOXD13 in einen TF mit PITX1-ähnlichen Eigenschaften verändert. Die HOXD13R298Q-Mutante zeigt eine weitgehend unveränderte Bindungssequenz gegenüber HOXD13wt, jedoch eine veränderte Zusammensetzung der genomischen Bindestellen. Dies weist, in Kombination mit dem humanen Phänotyp auf einen dominant-negativen Pathomechanismus dieser Mutanten hin. Zusammengenommen zeigt diese Arbeit durch die Erhebung von experimentellen Daten, dass klar unterscheidbare molekularbiologische Mechanismen den HOXD13Q317K- und HOXD13R298Q-Mutationen zugrunde liegen.Mutations in transcription factors (TF) do not only affect the function of the TF, but also the expression of its target genes and are frequently underlying congenital malformations. More than 20 distinct pathogenic mutations in HOXD13, a TF controlling limb development, have been associated with a broad range of limb malformations. However, a molecular basis underlying the variability of HOXD13-associated phenotypes remains elusive. To date, the experimental methods used to functionally characters TF mutations have allowed only limited insights into the underlying molecular pathomechanisms. The recently developed ChIP-seq technology has proven to be a powerful method to profile the binding characteristics of TFs; however a number of technical hurdles hinder its application for functional characterization of mutant TFs. This work describes the establishment of a ChIP-seq approach to investigate a wide spectrum of TFs and TF mutations. The approach was applied to characterize two previously unknown missense mutations in HOXD13, p.Q317K and p.R298Q, which both alter the DNA-binding domain of HOXD13 but cause very different disease phenotypes. The results show that the HOXD13Q317K mutant has an altered sequence specificity that resembles the recognition sequence of another TF, PITX1. Further, the genome-wide binding pattern of HOXD13Q317K shifts towards a more PITX1-like binding pattern. Even further analysis and viral overexpression in chicken limb buds confirm that the mutation partially converts HOXD13Q317K into a TF with PITX1-like properties. The HOXD13R298Q has a largely unchanged sequence specificity, but an altered composition of genomic binding sites. This, in combination with the human phenotype, indicates that the mutant might act in a dominant-negative manner. Collectively, this work shows through generation of direct experimental evidence, that clearly distinct molecular mechanisms underlie the pathogenicity of HOXD13Q317K and HOXD13R298Q mutations.
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Krasovec, Marc. "Estimation des taux de mutation : implications pour la diversification et l'évolution du phytoplancton eucaryote". Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066371/document.
Testo completoAbstract (sommario):
Les mutations sont la principale source de diversité sur laquelle agit la sélection pour permettre aux espèces de s'adapter. Les études de l'effet des mutations sur la survie et du taux de mutation sont donc essentielles pour mieux comprendre l'évolution. Par une approche d'expérience d'accumulation de mutations, nous étudions ces deux questions chez cinq modèles d'algues vertes (Ostreococcus tauri, O. mediterraneus, Bathycoccus prasinos, Micromonas pusilla, et Picochlorum RCC4223). Il est mis en évidence une diminution de la fitness au cours du temps en raison des mutations délétères, et une importante interaction génotype-environnement sur l'effet des mutations. Le taux de mutation varie aux échelles intra-génomique et inter-spécifique, avec deux principaux résultats: une augmentation du taux de mutation dans les régions non codantes et une augmentation du taux de mutation avec la taille du génome chez les eucaryotes et en fonction de l'écart à l'équilibre en GC du génome. Aussi, l'assemblage et l'annotation d'une picoalgue du genre Picochlorum permettent d'étudier le rôle des transferts horizontaux de gènes chez les ChlorophytesMutations are the main source of diversity on which selection acts to allow species to adapt. Studies of the effect of mutations on survival and estimation of spontaneous mutation rates are essential to better understand evolution. Using mutation accumulation experimental approach, we investigated the issues of mutation effects and mutation rate in five models of green algae (Ostreococcus tauri, O. mediterraneus, Bathycoccus Prasinos, Micromonas pusilla, and Picochlorum RCC4223). It highlighted a decline in fitness over time because of deleterious mutations, and a significant genotype-environment interaction on the fitness effect of mutations. The mutation rate varies at inter-specific and intra-genomic scales, with two main results: a raise of the mutation rate in non-coding regions in accordance with trancriptional-coupled repair, and an increase of the mutation rate with an increase of the genome size in eukaryotes and the GC content deviation from the equilibrium. Also, a new Picochlorum genome is provided to investigate the role of horizontal gene transfer in the Chlorophyta group
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Krasovec, Marc. "Estimation des taux de mutation : implications pour la diversification et l'évolution du phytoplancton eucaryote". Electronic Thesis or Diss., Paris 6, 2016. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2016PA066371.pdf.
Testo completoAbstract (sommario):
Les mutations sont la principale source de diversité sur laquelle agit la sélection pour permettre aux espèces de s'adapter. Les études de l'effet des mutations sur la survie et du taux de mutation sont donc essentielles pour mieux comprendre l'évolution. Par une approche d'expérience d'accumulation de mutations, nous étudions ces deux questions chez cinq modèles d'algues vertes (Ostreococcus tauri, O. mediterraneus, Bathycoccus prasinos, Micromonas pusilla, et Picochlorum RCC4223). Il est mis en évidence une diminution de la fitness au cours du temps en raison des mutations délétères, et une importante interaction génotype-environnement sur l'effet des mutations. Le taux de mutation varie aux échelles intra-génomique et inter-spécifique, avec deux principaux résultats: une augmentation du taux de mutation dans les régions non codantes et une augmentation du taux de mutation avec la taille du génome chez les eucaryotes et en fonction de l'écart à l'équilibre en GC du génome. Aussi, l'assemblage et l'annotation d'une picoalgue du genre Picochlorum permettent d'étudier le rôle des transferts horizontaux de gènes chez les ChlorophytesMutations are the main source of diversity on which selection acts to allow species to adapt. Studies of the effect of mutations on survival and estimation of spontaneous mutation rates are essential to better understand evolution. Using mutation accumulation experimental approach, we investigated the issues of mutation effects and mutation rate in five models of green algae (Ostreococcus tauri, O. mediterraneus, Bathycoccus Prasinos, Micromonas pusilla, and Picochlorum RCC4223). It highlighted a decline in fitness over time because of deleterious mutations, and a significant genotype-environment interaction on the fitness effect of mutations. The mutation rate varies at inter-specific and intra-genomic scales, with two main results: a raise of the mutation rate in non-coding regions in accordance with trancriptional-coupled repair, and an increase of the mutation rate with an increase of the genome size in eukaryotes and the GC content deviation from the equilibrium. Also, a new Picochlorum genome is provided to investigate the role of horizontal gene transfer in the Chlorophyta group
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Maxwell, Megan Amanda, e n/a. "PEX1 Mutations in Australasian Patients with Disorders of Peroxisome Biogenesis". Griffith University. School of Biomolecular and Biomedical Science, 2004. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20040219.100649.
Testo completoAbstract (sommario):
The peroxisome is a subcellular organelle that carries out a diverse range of metabolic functions, including the b-oxidation of very long chain fatty acids, the breakdown of peroxide and the a-oxidation of fatty acids. Disruption of peroxisome metabolic functions leads to severe disease in humans. These diseases can be broadly grouped into two categories: those in which a single enzyme is defective, and those known as the peroxisome biogenesis disorders (PBDs), which result from a generalised failure to import peroxisomal matrix proteins (and consequently result in disruption of multiple metabolic pathways). The PBDs result from mutations in PEX genes, which encode protein products called peroxins, required for the normal biogenesis of the peroxisome. PEX1 encodes an AAA ATPase that is essential for peroxisome biogenesis, and mutations in PEX1 are the most common cause of PBDs worldwide. This study focused on the identification of mutations in PEX1 in an Australasian cohort of PBD patients, and the impact of these mutations on PEX1 function. As a result of the studies presented in this thesis, twelve mutations in PEX1 were identified in the Australasian cohort of patients. The identified mutations can be broadly grouped into three categories: missense mutations, mutations directly introducing a premature termination codon (PTC) and mutations that interrupt the reading frame of PEX1. The missense mutations that were identified were R798G, G843D, I989T and R998Q; all of these mutations affect amino acid residues located in the AAA domains of the PEX1 protein. Two mutations that directly introduce PTCs into the PEX1 transcript (R790X and R998X), and four frameshift mutations (A302fs, I370fs, I700fs and S797fs) were identified. There was also one mutation found in an intronic region (IVS22-19A>G) that is presumed to affect splicing of the PEX1 mRNA. Three of these mutations, G843D, I700fs and G973fs, were found at high frequency in this patient cohort. At the commencement of these studies, it was hypothesised that missense mutations would result in attenuation of PEX1 function, but mutations that introduced PTCs, either directly or indirectly, would have a deleterious effect on PEX1 function. Mutations introducing PTCs are thought to cause mRNA to be degraded by the nonsense-mediated decay of mRNA (NMD) pathway, and thus result in a decrease in PEX1 protein levels. The studies on the cellular impact of the identified PEX1 mutations were consistent with these hypotheses. Missense mutations were found to reduce peroxisomal protein import and PEX1 protein levels, but a residual level of function remained. PTC-generating mutations were found to have a major impact on PEX1 function, with PEX1 mRNA and protein levels being drastically reduced, and peroxisomal protein import capability abolished. Patients with two missense mutations showed the least impact on PEX1 function, patients with two PTC-generating mutations had a severe defect in PEX1 function, and patients carrying a combination of a missense mutation and a PTC-generating mutation showed levels of PEX1 function that were intermediate between these extremes. Thus, a correlation between PEX1 genotype and phenotype was defined for the Australasian cohort of patients investigated in these studies. For a number of patients, mutations in the coding sequence of one PEX1 allele could not be identified. Analysis of the 5' UTR of this gene was therefore pursued for potential novel mutations. The initial analyses demonstrated that the 5' end of PEX1 extended further than previously reported. Two co-segregating polymorphisms were also identified, termed 137 T>C and 53C>G. The -137T>C polymorphism resided in an upstream, in-frame ATG (termed ATG1), and the possibility that the additional sequence represented PEX1 coding sequence was examined. While both ATGs were found to be functional by virtue of in vitro and in vivo expression investigations, Western blot analysis of the PEX1 protein in patient and control cell extracts indicated that physiological translation of PEX1 was from the second ATG only. Using a luciferase reporter approach, the additional sequence was found to exhibit promoter activity. When examined alone the -137T>C polymorphism exerted a detrimental effect on PEX1 promoter activity, reducing activity to half that of wild-type levels, and the -53C>G polymorphism increased PEX1 promoter activity by 25%. When co-expressed (mimicking the physiological condition) these polymorphisms compensated for each other to bring PEX1 promoter activity to near wild-type levels. The PEX1 mutations identified in this study have been utilised by collaborators at the National Referral Laboratory for Lysosomal, Peroxisomal and Related Genetic Disorders (based at the Women's and Children's Hospital, Adelaide), in prenatal diagnosis of the PBDs. In addition, the identification of three common mutations in Australasian PBD patients has led to the implementation of screening for these mutations in newly referred patients, often enabling a precise diagnosis of a PBD to be made. Finally, the strong correlation between genotype and phenotype for the patient cohort investigated as part of these studies has generated a basis for the assessment of newly identified mutations in PEX1.
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Maxwell, Megan Amanda. "PEX1 Mutations in Australasian Patients with Disorders of Peroxisome Biogenesis". Thesis, Griffith University, 2004. http://hdl.handle.net/10072/366184.
Testo completoAbstract (sommario):
The peroxisome is a subcellular organelle that carries out a diverse range of metabolic functions, including the b-oxidation of very long chain fatty acids, the breakdown of peroxide and the a-oxidation of fatty acids. Disruption of peroxisome metabolic functions leads to severe disease in humans. These diseases can be broadly grouped into two categories: those in which a single enzyme is defective, and those known as the peroxisome biogenesis disorders (PBDs), which result from a generalised failure to import peroxisomal matrix proteins (and consequently result in disruption of multiple metabolic pathways). The PBDs result from mutations in PEX genes, which encode protein products called peroxins, required for the normal biogenesis of the peroxisome. PEX1 encodes an AAA ATPase that is essential for peroxisome biogenesis, and mutations in PEX1 are the most common cause of PBDs worldwide. This study focused on the identification of mutations in PEX1 in an Australasian cohort of PBD patients, and the impact of these mutations on PEX1 function. As a result of the studies presented in this thesis, twelve mutations in PEX1 were identified in the Australasian cohort of patients. The identified mutations can be broadly grouped into three categories: missense mutations, mutations directly introducing a premature termination codon (PTC) and mutations that interrupt the reading frame of PEX1. The missense mutations that were identified were R798G, G843D, I989T and R998Q; all of these mutations affect amino acid residues located in the AAA domains of the PEX1 protein. Two mutations that directly introduce PTCs into the PEX1 transcript (R790X and R998X), and four frameshift mutations (A302fs, I370fs, I700fs and S797fs) were identified. There was also one mutation found in an intronic region (IVS22-19A>G) that is presumed to affect splicing of the PEX1 mRNA. Three of these mutations, G843D, I700fs and G973fs, were found at high frequency in this patient cohort. At the commencement of these studies, it was hypothesised that missense mutations would result in attenuation of PEX1 function, but mutations that introduced PTCs, either directly or indirectly, would have a deleterious effect on PEX1 function. Mutations introducing PTCs are thought to cause mRNA to be degraded by the nonsense-mediated decay of mRNA (NMD) pathway, and thus result in a decrease in PEX1 protein levels. The studies on the cellular impact of the identified PEX1 mutations were consistent with these hypotheses. Missense mutations were found to reduce peroxisomal protein import and PEX1 protein levels, but a residual level of function remained. PTC-generating mutations were found to have a major impact on PEX1 function, with PEX1 mRNA and protein levels being drastically reduced, and peroxisomal protein import capability abolished. Patients with two missense mutations showed the least impact on PEX1 function, patients with two PTC-generating mutations had a severe defect in PEX1 function, and patients carrying a combination of a missense mutation and a PTC-generating mutation showed levels of PEX1 function that were intermediate between these extremes. Thus, a correlation between PEX1 genotype and phenotype was defined for the Australasian cohort of patients investigated in these studies. For a number of patients, mutations in the coding sequence of one PEX1 allele could not be identified. Analysis of the 5' UTR of this gene was therefore pursued for potential novel mutations. The initial analyses demonstrated that the 5' end of PEX1 extended further than previously reported. Two co-segregating polymorphisms were also identified, termed –137 T>C and –53C>G. The -137T>C polymorphism resided in an upstream, in-frame ATG (termed ATG1), and the possibility that the additional sequence represented PEX1 coding sequence was examined. While both ATGs were found to be functional by virtue of in vitro and in vivo expression investigations, Western blot analysis of the PEX1 protein in patient and control cell extracts indicated that physiological translation of PEX1 was from the second ATG only. Using a luciferase reporter approach, the additional sequence was found to exhibit promoter activity. When examined alone the -137T>C polymorphism exerted a detrimental effect on PEX1 promoter activity, reducing activity to half that of wild-type levels, and the -53C>G polymorphism increased PEX1 promoter activity by 25%. When co-expressed (mimicking the physiological condition) these polymorphisms compensated for each other to bring PEX1 promoter activity to near wild-type levels. The PEX1 mutations identified in this study have been utilised by collaborators at the National Referral Laboratory for Lysosomal, Peroxisomal and Related Genetic Disorders (based at the Women's and Children's Hospital, Adelaide), in prenatal diagnosis of the PBDs. In addition, the identification of three common mutations in Australasian PBD patients has led to the implementation of screening for these mutations in newly referred patients, often enabling a precise diagnosis of a PBD to be made. Finally, the strong correlation between genotype and phenotype for the patient cohort investigated as part of these studies has generated a basis for the assessment of newly identified mutations in PEX1.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Biomedical Sciences
Full Text
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COCCIADIFERRO, DARIO. "Mutational analysis of Kabuki Syndrome patients and functional dissection of KMT2D mutations". Doctoral thesis, Università di Foggia, 2018. http://hdl.handle.net/11369/369451.
Testo completoAbstract (sommario):
The discovery of histone methyltransferase KMT2D and demethylase KDM6A genetic alterations in Kabuki Syndrome (KS) expanded and highlighted the role of histone modifiers in causing congenital anomalies and intellectual disability syndromes. KS is a rare autosomal dominant condition characterized by facial features, various organ malformations, postnatal growth deficiency, and intellectual disability. Since 2011 we performed a mutational screening of our KS cohort, that includes now 505 KS patients, by Sanger sequencing and MLPA of KMT2D, followed by KDM6A analysis in those patients resulted as KMT2Dnegative. Of these 505 patients, we identified 196/505 (39%) patients with KMT2D variants and 208 different KMT2D variations; of them 37/208 (18%) never described before. The majority of KS patients carry nonsense and splicesite variants, suggesting the loss of function, and therefore haploinsufficiency, as the likely mechanism for the KS phenotype. RT-PCR and direct sequencing on cDNA from Kabuki patients carrying KMT2D splice site variants demonstrated that these cause aberrant splicing of the corresponding transcript, resulting in a truncating and not functional translated protein. Molecular assays also showed that KMT2D mRNAs bearing premature stop codon are degraded by the nonsense mediated mRNA decay, contributing to KMT2D protein haploinsufficiency. We hypothesized that KS patients may benefit from a readthrough therapy that mediates translational suppression of nonsense variants, restoring the physiologically levels of endogenous KMT2D protein. Fourteen KMT2D nonsense variants were tested for their response to readthrough treatment through an in vitro dual reporter luciferase vector system, identifying 11/14 variants that displayed high levels of readthrough in response to gentamicin treatment. Among our cohort we identified three new cases with a mosaic variants in KMT2D gene, consisting in single nucleotide change resulting in two already reported nonsense variants, the c.13450C=/>T (p.R4484X) and the c.15061C=/>T (p.R5021X) and in a new frameshift variant, the c.3596_3597=/del (p.L1199HfsX7) KMT2D, respectively. Moreover, relevant for diagnostic and counselling purposes, we implemented a number of bioinformatics tools to assess the pathogenicity of 69 KMT2D missense variants, found overall in our cohort of 505 KS patients, and for 14 of them we adopted a combination of biochemical and cellular approaches to investigate their role and characterize their functional impact in the pathogenesis of the disease. We found 9/14 missense variants showing altered H3K4 methylation activity. We additionally assessed the impact on complex formation with WRAD protein complex, and we found that the reduced methyltransferase activity could be a consequence of lack of interaction.
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Davis, Brad. "Compensatory and deleterious mutations". Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/7722.
Testo completoAbstract (sommario):
My Ph.D. research has focused on some general properties of compensatory mutations, as well as the impact of compensatory mutations on fitness recovery and deleterious mutations on populations extinction risks. I have addressed these topics using a variety of techniques.
Chapter 2 addresses mutational meltdown using computer simulation models to explicitly incorporate both environmental stochasticity and mutation accumulation. The results show that a small amount of environmental stochasticity can significantly hasten extinction times and that the mutational meltdown process hastens time to extinction even when levels of environmental stochasticity are high enough to cause rapid extinctions on their own. Even large populations with 1000 individuals can be at risk of going extinct via the mutational meltdown with sufficient environmental stochasticity.
Chapter 3 looks at the potential for low fitness lines of Caenorhabditis elegans to recover lost fitness due to gene knockouts. Using gene knockout assures that any fitness recovery is due to compensatory mutations elsewhere in the genome and not back mutation. We show that rapid fitness recovery is possible, even in relatively small populations.
Chapter 4 examines the distribution of the number of compensatory mutations that exist per deleterious mutation, using published datasets. We determined that the distribution of number of compensatory mutations is best fit by a gamma distribution, with a mean of 11 compensatory mutations per deleterious mutation.
Chapter 5 utilizes the same dataset as was gathered for Chapter 4, but addresses a different set of questions. Are all amino acid positions equally capable of producing a compensatory mutation? Do compensatory mutations significantly cluster around the site of their associated deleterious mutations? Above and beyond the clustering found in the second question, do compensatory mutations cluster amongst themselves? All of these questions were answered in the affirmative.
Chapter 6 is concerned with the evolution of cooperation through resource sharing. Here we showed that the evolution of cooperation through resource sharing is difficult to achieve and requires heterogeneity in resource state within the population and that an individual’s resource state must change frequently in order to create the conditions by which the evolution of cooperation is favoured.
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Bendall, Kate E. "Inheritance of mitochondrial mutations". Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320141.
Testo completo
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Salamat, Majid. "Coalescent, recombinaisons et mutations". Thesis, Aix-Marseille 1, 2011. http://www.theses.fr/2011AIX10059.
Testo completoAbstract (sommario):
Cette thèse se concentre sur certains sujets en génétique des populations. Dans la première partie, nous donnons des formules y compris l'espérance et la variance de la hauteur et celles de la longueur du graphe de recombinaison ancestral (ARG) et l'espérance et la variance du nombre de recombinaison et nous montrons que l'espérance de la longueur de l'ARG est une combinaison linéaire de l'espérance de la longueur de la coalescence de Kingman et l'espérance de la hauteur de l'ARG. En outre, nous avons obtenu une relation entre l'espérance la longueur de l'ARG et l'espérance du nombre de recombinaisons. À la fin de cette partie, nous montrons que l'ARG descend de l'infini de telle sorte que X_0 =∞, alors que X_t < ∞ ; pour tout t et on trouve la vitesse à laquelle l'ARG descend de l'infini. Dans la deuxième partie on généralise la formule d'échantillonnage d'Ewens (GESF) en présence de la recombinaison pour les échantillons de taille n = 2 et n = 3. Dans la troisième partie de la thèse, nous étudions l'ARG le long du génome et nous avons trouvé la distribution du nombre de mutations dans le cas avec une seule recombinaison dans la généalogie de l'échantillonThis thesis is concentrated on some sub jects on population genetics. In the first part we give formulae including the expectation and variance of the height and the length of the ancestral recombination graph (ARG) and the expectation and variance of the number of recombination events and we show that the expectation of the length of the ARG is a linear combination of the expectation of the length of Kingman's coalescent and the expectation of the height of the ARG. Also we show give a relation between the expectation of the ARG and the expectation of the number of recombination events. At the end of this part we show that the ARG comes down from infinity in the sense that we can dfine it with X_0 = ∞, while X_t <∞ ; for all t and we find the speed that the ARG comes down from infinity. In the second part wfind a generalization of the the Ewens sampling formula (GESF) in the presence of recombination for sample of sizes n = 2 and n = 3. In the third part of the thesis we study the ARG along the genome and we we find the distribution of the number of mutations when we have one recombination event in the genealogy of the sample
Libri sul tema "Les Mutations"
1
Thomas, Hugh. Mutations. Toronto: BookThug, 2004.
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2
Centre d'études et de recherche sur les civilisations et les littératures européennes (Boulogne-sur-Mer, France) e Université du Littoral Côte d'Opale. Équipe de recherche "HLLI.", a cura di. Mutations de société, mutations de cinéma. Aachen: Shaker Verlag, 2015.
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3
Aubin, Denis. Mutations/fluctuations. [Outremont, Québec]: NBJ, 1985.
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4
Wedge, Martin. Per-mutations. Belfast: Ormeau Baths Gallery, 1997.
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5
Francesco, Casetti, Odin Roger e Centre d'études transdisciplinaires, a cura di. Télévisions mutations. Paris: Éditions du Seuil [for] Centre d'Études Transdisciplinaires, 1990.
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Carlos, Pacheco, Townsend Timothy, Hosek Dan, Harris Bob e Atomic Media, a cura di. X-Men: Mutations. New York: Marvel Comics, 1996.
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Jay, Prosser, a cura di. Sublime mutations: Photographs. Tübingen: Konkursbuch Verlag, 2000.
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international, Institut CEDIMES Colloque, a cura di. Mutations contemporaines & développement. Paris: CEDIMES, 2003.
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Castella, Vincenzo, Davis Lynn 1944- e Roberto Pugliese. Recursions and mutations. Cinisello Balsamo, Milano: Silvana editoriale, 2019.
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Couturier, Stéphane. Stéphane Couturier: Mutations. [Paris]: Bibliothèque nationale de France, 2004.
Cerca il testo completoCapitoli di libri sul tema "Les Mutations"
1
Konzak, C. F. "Mutations and Mutation Breeding". In Agronomy Monographs, 428–43. Madison, WI, USA: American Society of Agronomy, Crop Science Society of America, Soil Science Society of America, 2015. http://dx.doi.org/10.2134/agronmonogr13.2ed.c24.
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2
Sebald, Madeleine. "Mutations". In Brock/Springer Series in Contemporary Bioscience, 64–97. New York, NY: Springer New York, 1993. http://dx.doi.org/10.1007/978-1-4615-7087-5_5.
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Sharma, Dhirendra Kumar. "Mutations". In Encyclopedia of Animal Cognition and Behavior, 4519–24. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-319-55065-7_567.
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Sharma, Dhirendra Kumar. "Mutations". In Encyclopedia of Animal Cognition and Behavior, 1–6. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-319-47829-6_567-1.
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5
Biswas, Nabendu. "Mutations". In Practical GraphQL, 49–75. Berkeley, CA: Apress, 2023. http://dx.doi.org/10.1007/978-1-4842-9621-9_3.
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van Eyk, Clare L., e Robert I. Richards. "Dynamic Mutations". In Advances in Experimental Medicine and Biology, 55–77. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4614-5434-2_5.
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Michaelides, K., R. Schwaab, M. R. A. Lalloz, W. Schmidt, e E. G. D. Tuddenham. "Mutational analysis: new mutations". In PCR2, 255–88. Oxford University PressOxford, 1995. http://dx.doi.org/10.1093/oso/9780199634255.003.0013.
Testo completoAbstract (sommario):
Abstract In the last few years the search for mutations and sequence polymorphisms has been dramatically accelerated by the use of PCR and subsequently by direct sequencing of PCR products (1, 2). In spite of these powerful new methods, direct sequencing is not always practicable in detecting mutations because they may be positioned anywhere in some of the very large genes which are being studied. For example, mutations have now been found in nearly every one of the 26 exons of the factor VIII gene. Thus a number of prescreening methods have been developed, such as discriminant oligonucleotide hybridization (3), enzymatic (4) and chemical cleavage methods (5), single stranded conformation polymorphism (SSCP) (6) and denaturing gradient gel electrophoresis (DGGE) (7). These methods are described and by way of example, some results of their application to screening the coding sequences and splice sites of the factor VIII gene for mutations amongst haemophilia A patients (8-10) are shown.
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Newton, Clive R. "Mutational analysis: known mutations". In PCR2, 219–54. Oxford University PressOxford, 1995. http://dx.doi.org/10.1093/oso/9780199634255.003.0012.
Testo completoAbstract (sommario):
Abstract This chapter attempts to illustrate the various PCR options that are available to detect specific mutations and/or polymorphisms in genomic DNA. In so doing, the relative merits and drawbacks of each technique are addressed in the respective sections. For some methods of PCR-assisted mutation detection covered in this chapter, a protocol has not been included. In these instances the respective method is rarely used and is therefore discussed and the seminal reference cited. Protocols have, as far as possible, been described so that they can be applied in a generic fashion. However, detection of some mutations or polymorphisms may require deviations from the respective protocols as a result of adjacent genomic DNA sequence. This is more likely where detection of the specific DNA variation is dependent on oligonucleotide hybridization as opposed to primer/template annealing.
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Levine, Michael A., e Steven A. Lietman. "Molecular and Clinical Characteristics of the McCune–Albright Syndrome". In Oxford Textbook of Endocrinology and Diabetes 3e, a cura di John A. H. Wass, Wiebke Arlt e Robert K. Semple, 1075–88. Oxford University Press, 2021. http://dx.doi.org/10.1093/med/9780198870197.003.0121.
Testo completoAbstract (sommario):
The McCune–Albright syndrome (MAS) is characterized by the clinical triad of polyostotic fibrous dysplasia, café-au-lait pigmented skin lesions, and endocrinopathy. MAS is due to postzygotic mutation of the GNAS gene that leads to activation of Gαs, the alpha chain of the heterotrimeric G protein, Gs. Cells that carry the activating GNAS mutation, termed gsp, are distributed in a mosaic pattern, and the extent of the distribution of mutation-bearing cells is based on the timing of the mutational event. Thus, gsp mutations that occur late in development can cause mono-ostotic fibrous dysplasia or an isolated endocrine lesion, whereas earlier mutational events lead to widespread distribution of lesional cells and MAS. Molecular studies now enable the detection of somatic GNAS mutations in circulating cells from most patients with MAS as well as many patients who have only one affected tissue, and therefore diagnosis of MAS continues to rely upon clinical assessment.
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Jennings, Barbara, Nandu Thalange e Gavin Willis. "Mutations and Genetic Variation". In Genetics in Medicine. Oxford University Press, 2020. http://dx.doi.org/10.1093/hesc/9780198841555.003.0002.
Testo completoAbstract (sommario):
This chapter introduces mutations and genetic variation. It looks at how mutations could alter DNA sequences. A mutation is a rare heritable change in the nucleotide sequence. The chapter then notes the functional impact of mutations on phenotypes like genetic nomenclature, before comparing the impact of germline and somatic mutations on health and diseases. In addition, it presents key terms of genetic variants such as private mutation, rare variant, and polymorphism. It then examines the application of human genetic variation in medical practice. The chapter also considers genetic counselling and presents it as the communication of information and advice about inherited and other genetic conditions, which include taking a family history and constructing a pedigree diagram.
Atti di convegni sul tema "Les Mutations"
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SEPE, MARICHELA. "MEASURING UNCERTAINTY: FACING PLACE MUTATIONS SUSTAINABLY". In SDP 2024, 155–64. Southampton UK: WIT Press, 2024. http://dx.doi.org/10.2495/sdp240131.
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Souza, Beatriz, e Rohit Gheyi. "A Lightweight Technique to Identify Equivalent Mutants". In XI Congresso Brasileiro de Software: Teoria e Prática. Sociedade Brasileira de Computação - SBC, 2020. http://dx.doi.org/10.5753/cbsoft_estendido.2020.14630.
Testo completoAbstract (sommario):
Mutation analysis is a popular but costly approach to assess the quality of test suites. Equivalent mutants are useless and contribute to increase costs. We propose a lightweight technique to identify equivalent mutants by proving equivalences with Z3 in the context of weak mutation testing. To evaluate our approach, we apply our technique for 40 mutation targets (mutations of an expression or statement) and automatically identify 13 equivalent mutations for seven mutation targets. We manually confirm that the equivalent mutants detected by our technique are indeed equivalent. Moreover, we evaluate our approach in the context of strong mutation testing against mutants generated by MuJava for 5 projects. Our technique detects all equivalent mutants detected by TCE. The results of our technique can be useful to improve mutation testing tools by avoiding the application of 13 mutations for 7 mutation targets.
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Cambraia, Amanda, Mario Campos Junior, Fernanda Gubert, Juliana Ferreira Vasques, Marli Pernes da Silva Loureiro, Claudio Heitor Gress, José Mauro Bráz de Lima, Rosalia Mendez Otero e Verônica Marques Zembrzuski. "A novel mutation in the RRM2 domain of TDP-43 in a Brazilian sporadic ALS patient." In XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.486.
Testo completoAbstract (sommario):
Introduction: Amyotrophic Lateral Sclerosis (ALS) is an adult-onset progressive and fatal neurodegenerative disease that selectively affects upper and lower motor neurons. Death occurs within 3 to 5 years of onset, usually from respiratory complications. Most cases of ALS are sporadic (SALS), but familial forms of the disease (FALS) represent approximately 10% of the cases. More than 30 genes have been associated with ALS and mutations in these genes account for more than a half of all familial cases and about 10% of sporadic cases. One of the most prevalent genes is TARDBP, responsible for approximately 4-6% of FALS and nearly 1-2% of SALS cases. The aim of this study was to perform the screening of known ALS genes, to increase the knowledge of the mutations that circulate in the population from Rio de Janeiro. Methods: The screening of mutations was performed through the Illumina Next Generation Sequencing (NGS) platform with the use of a sequencing panel that contained the TARDBP, SOD1, FUS, VAPB, SMN1 and SMN2 genes. Results: A novel missense mutation (p.Phe194Leu) in exon 5 of the TARDBP gene was found in a sporadic male patient who died at the age of 58 (2018). The mutation, a TTT/CTT substitution, was not detected in any mutation databases and in the literature. In silico analysis of this variant with different algorithms were performed and the results pointed to a probably damaging impact and that the mutation is disease causing. Conclusion: Through the study of the ALS genes by the NGS, we were able to identify a novel TARDBP mutation in a non-familial ALS patient. In addition, this study also increases the number of known TARDBP mutations in ALS patients and our knowledge of the mutations that affect the patients from of population from Rio de Janeiro.
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Iliushchenko, D. V., B. E. Efimenko, K. V. Gunbin e K. Y. Popadin. "DEEP MUTATIONAL SPECTRUM OF MITOCHONDRIAL GENOME IN VERTEBRATES AS A NEW TYPE OF SPECIES — SPECIFIC MOLECULAR PHENOTYPE". In OpenBio-2023. ИПЦ НГУ, 2023. http://dx.doi.org/10.25205/978-5-4437-1526-1-4.
Testo completoAbstract (sommario):
The deep mutational spectrum (MS), an informative representation of de novo mutations with contextual data, offers valuable biological insights into the primary sources ofmutations across diverse genes, cancers, and species. However, reconstructing a comprehensive mutational spectrum demands substantial data, which is often lacking for non-model species. To address this challenge, we present a novel approach integrating sparse species-specific mitochondrial DNA (mtDNA) mutational spectra based on 122,031 polymorphic reconstructed synonymous mutations within the CytB gene of 974 vertebrate species. Leveraging this dataset, we reconstructed a 192-component mutational spectrum encompassing all vertebrates.
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Mukhopadhyay, Asima, Nicola Curtin e Richard Edmondson. "Evaluation of different methods to assess homologous recombination status and sensitivity to PARP inhibitors in ovarian cancer". In 16th Annual International Conference RGCON. Thieme Medical and Scientific Publishers Private Ltd., 2016. http://dx.doi.org/10.1055/s-0039-1685289.
Testo completoAbstract (sommario):
Methods: Matched samples of ascites and tumor tissue were taken from patients undergoing surgery for epithelial ovarian cancer. Tumor samples were formalin fixed and paraffin embedded (FFPE); ascites samples were used to generate primary cultures (PC). HR status was determined in PCs as previously described.[1] IC50 for the PARP inhibitor Rucaparib was estimated using SRB assays. DNA was extracted from the FFPE tissue. The following techniques were evaluated in PCs or paired FFPE samples: DR-GFP reporter assay, PARP activity assay, BRCA1 expression on immunohistochemistry, BRCA1 methylation status and BRCA1/2 mutation analysis. A next generation sequencing based assay was used to detect mutations and other genomic alterations in a large panel of cancer-associated genes, including BRCA1/2. Results: Paired samples were collected from 64 patients and characterized for HR function. 47/64 (76%) were high grade serous. 44% (28/64)) were HR defective (HRD) by Rad51 assay and correlated with Rucaparib sensitivity (PPV-92%, NPV-100%). Molecular analysis revealed that all mutations and other genomic alterations detected in ascites derived PCs were also found in matched FFPE tumor tissues. All tumors with serous histology contained p53 mutations, whilst the remaining tumors without p53 mutations were non-serous in histology. DR-GFP assay was unreliable in PC due to poor transfection. In a subset of 50 cancers there was reduced BRCA1 expression in the HRD vs. HRC tumours (34.8% vs. 22.7%, ns) whilst in a further subset of 30 cases there was no difference in endogenous or stimulated PARP activity between HRD and HRC tumours. Deleterious BRCA2 mutations were identified in 7 tumors, 6 of which were HRD. Only 1 deleterious BRCA1 mutation was detected but methylation of BRCA1 was identified in 13 of 64 (20%) tumors, 7 of which were HRD. Mutation of BRCA2 was mutually exclusive to methylation of BRCA1. HRD vs. HRC tumours showed BRCA1 methylation (25% vs. 17%) and BRCA1/2 mutation (21% vs. 0.3%). 14/28 (50%) HR defective tumors do not have BRCA1/2 mutations or BRCA1 methylation, suggesting other mechanisms can also result in a HR defective phenotype. 28/64 (43%) of samples demonstrated the HR defective phenotype. In all cases HR status correlated with sensitivity to Rucaparib. Conclusion: As expected, deleterious BRCA2 mutations conferred a HRD phenotype in cells but methylation of BRCA1 was not universally associated with HRD. This may be as a result of only partial silencing of the gene by methylation and further work is required to identify thresholds of methylation which may predict HR status. The use of BRCA1/2 mutation testing alone is unlikely to identify the majority of HR defective ovarian tumors. Assessment of functional status of HRD is the preferred option and further technologies should be developed to simplify the Rad51 assay.
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Bittencourt, Yuri Cardoso Rodrigues Beckedorff, Lucas Soares Almada, Tatiana Strava Corrêa, Daniele Xavier Assad, Marina Sahade Gonçalves, Andrea Kazumi Shimada, Artur Katz e Romualdo Barroso-Sousa. "SOMATIC MUTATIONAL LANDSCAPE CHARACTERIZATION OF METASTATIC BREAST CANCER IN BRAZIL". In Brazilian Breast Cancer Symposium 2022. Mastology, 2022. http://dx.doi.org/10.29289/259453942022v32s2025.
Testo completoAbstract (sommario):
Objective: Breast cancer (BC) is the most common malignancy among Brazilian women after non-melanoma skin cancer. The mutational landscape of BC in Brazil is unknown. This study describes the mutational profile of a cohort of patients with metastatic breast cancer (MBC) who had undergone next-generation sequencing (NGS) using a comprehensive somatic tumor panel. Methods: We retrospectively reviewed medical records from MBC patients. The mutational profile, clinical, and demographic characteristics were abstracted. Furthermore, the patterns of ordering the panel and its usefulness for a clinical decision were evaluated. Results: We found 54 female patients who fulfilled the above criteria. The median age was 58 years (32–86). Most tumors tested were hormone receptor-positive (74%), followed by triple-negative (20.3%), hormone receptor-positive/HER2-positive (3.7%), and HER-2 positive (1.85%). The median time between the diagnosis of metastatic disease and the NGS execution was 40 months (0–112), and only three patients (5.5%) had not received systemic treatment prior to the test recommendation. Somatic mutations were identified in 94.4% (n=51) of the patients, mainly in PIK3CA (48.1%), TP53 (42.5%), and ESR1 (18.5%) genes. Tumor burden mutation (TMB) was informed in 61.1% (n=33) somatic panels, and 15.1% (n=5) had tumors with TMB ≥10 mutations/megabase. Approved genome-driven cancer therapy was found in 54.9% (n=28), and eight patients (28.5%) received it. Conclusion: This study showed a high proportion of actionable somatic genomic alterations, and it reinforces the growing usefulness of a comprehensive NGS tumor somatic panel in managing patients with MBC.
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Birch, David G., Gabriel H. Travis, Kirsten G. Locke e Donald C. Hood. "Rod Ergs in Mice and Humans with Putative Null Mutations in the RDS Gene". In Vision Science and its Applications. Washington, D.C.: Optica Publishing Group, 1997. http://dx.doi.org/10.1364/vsia.1997.ma.4.
Testo completoAbstract (sommario):
Mutations causing autosomal dominant retinitis pigmentosa (RP) have been identified in RDS, the human homologue of the gene that was first identified and isolated as the cause of mouse "retinal degeneration slow" or rds (1, 2). The rds gene encodes rds/peripherin, an integral membrane glycoprotein located in outer segment disks (1, 3, 4). More than 15 distinct disease-causing mutations in the RDS gene have been reported (5). The clinical phenotypes include adRP, dominant retinitis punctata albescens, dominant butterfly shaped pigment dystrophy of the fovea and autosomal dominant macular degeneration (6). That RDS mutation can cause either RP and/or macular degeneration is consistent with the observation that the protein is expressed in both rods and cones, though its exact functional role in each photoreceptor must be different. Finally, there is an additional form of retinitis pigmentosa, digenic RP (7) that results from a combination of one mutation in RDS and one in R0M1. Neither mutation alone in a heterozygote causes degeneration.
8
Antonarakis, E. "The Molecular Genetics of Hemophilia A Stylianos". In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643980.
Testo completoAbstract (sommario):
Hemophilia A is a common X linked hereditary disorder of blood coagulation due to deficiency of factor 8. The gene for factor 8 has been cloned and characterized (Nature 312:326-342, 1984). It is divided into 26 exons and 25 introns and spans 186 kb of DNA. The CGNA is 9 kb and codes for 2351 amino acids. The first 19 amino acids comprise the secretory leader peptide and the mature excreted polypeptide consists of 2332 amino acids. The nucleotide sequence of the exons and the exon-intron junctions is known and the complete amino acid sequence has been deducedSeveral laboratories have used cloned factor 8 DNA sequences as probes to characterized mutations that are responsible for hemophilia A in certain pedigrees. These mutations have been characterized by restriction analysis, oligonucleotide hybridization, cloning and sequencing of DNA from appropriate patientsIn about 500 patients with hemophilia A examined, the molecular defect has been recognized in 39. Both gross alterations (mainly deletions) and point mutations of the factor 8 gene have been found.A total of 19 different deletions have been observed. No two unrelated pedigrees share the same exact deletion.The size of the deleted DNA varies from 1.5 kb to more than 210 kb. All but one of these deletions are associated with severe hemophilia A. A deletion of 6 kb that contains exon 22 only is associated with moderate hemophilia. Some deletions are present in patients with inhibitors to factor 8. No correlation of the size or the position of the deletions can be found with the presence of inhibitors to factor 8.A total of 20 point mutations have been characterized. All are recognized by restriction analysis and involve Taq I sites. All are mutations of CpG dinucleotides and generate nonsense or missence codons. Unrelated pedigrees have the same single nucleotide change because of independent origin of the same mutation. In many instances de novo occurrence of a point mutation has been observed. CpG dinucleotides are hot spots for mutation to TG or CA presumably because of spontaneous deamination of methylcytosine. Some point mutations are present in patients with inhibitors but no correlation of the site of mutation and inhibitor formation has been found. The nonsense mutations are present in patients with severe hemophilia A. A missense mutation (Arg Gin) in exon 26 was found in a patient with mild hemophilia while another Arg Gin mutation in exon 24 has been observed in a patient with severe disease. The creation of a donor splice site in IVS 4 of factor 8 gene has been observed in a patient with mild hemophilia.Few DNA polymorphisms within the factor 8 gene and two other closely linked polymorphisms have been used for carrier detection and prenatal diagnosis of hemophilia A. These DNA markers are useful in more than 90% of families at risk for hemophilia A.The author thanks Drs. Gitschier, Din, Olek, Pirastou, Lawn for communication of their data prior to publication.The hemophilia project at Johns Hopkins was supported by an Institutional grant and NIH grant to S.S.A. and Haig H. Kazazian, Jr.
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Higuchi, M., L. Kochhan, R. Schwaab, H. H. Brackmann, H. Egli e K. Olek. "DETECTION OF MUTATIONS IN HEMOPHILIA A". In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644012.
Testo completoAbstract (sommario):
Hemophilia A (HA) is a x-linked bleeding disordercaused by lack or abnormality of factor VIII:C. Because of the heterogeneity of the clinical picture thedisease might result from many different molecular lesions.We examined 202 patients of HA from 160 families by restriction analysis with Taq I, Msp I and EcoR I using three subcloned cDNA fragments of factor VIII:C.We detected 13 mutations within the factor VI11:C gene. All of these patients suffer from the severe form of HA.Table I shows six deletions which we characterized. We also identified seven point mutations on four different exons using restriction enzyme Taq I. The results are shown in Table II.That means in approximately 3.8% of the patients we found deletions and in 4.4% we found point mutations.This confirms the results of Youssofian et al (1986):These authors consider the CpG-dimer as a mutation hotspot in the factor VI11:C gene.
10
Youssoufiän, H., A. Patel, D. Phillips, H. H. Kazazian e S. E. Antonarakis. "RECURRENT MUTATIONS AND AN UNUSUAL DELETION IN HEMOPHILIA A". In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644014.
Testo completoAbstract (sommario):
We have identified 15 mutations of the factor VIII (F8) gene from a panel of 107 patients with hemophilia A and have characterized these gene defects byrestriction analysis, oligonucleotide hybridization, cloning and DNA sequencing. Recurrent point mutations that involve CG to TG transitions were identified in exon 18, exon 22, and exon 24; a single CG to TG transition was identified in exon 23; and a CG to CA transition was identified in exon 24. In addition, a Taq I site alteration in intron 4 was identified in a patient with mild hemophilia, which arose dg. S23&in a grandpaternal germ cell. Cloning and sequencing of this region suggests the generation of a newsplice donor site. These data suggest that CG to TG transition is a prominent mechanism of mutation in hemophilia A. Six different deletions were also characterized. In one family, the deletion involved exon 26. However, the deletion endpoints in the male proband were different from those in his carrier mother, suggesting either gonadal mosaicism or a second deletion event in maternal meiosis.Of the 15 mutations, 6 occurred de novo within 2 generations: 4 in males and 2 in females. In these djg.novo mutations paternal age at conception was 35 (range = 32-38) and maternal age was 24 and 27. The ability to discover a sizable number of mutations in the F8 gene producing hemophilia A enables us to determine the frequency and nature of de novo mutations in man.
Rapporti di organizzazioni sul tema "Les Mutations"
1
Yang, Mengge, e Lin Liao. Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, dicembre 2022. http://dx.doi.org/10.37766/inplasy2022.12.0031.
Testo completo
2
Henry, Stephen Michael, Mark A. Smith e John P. Eddy. Holistic Portfolio Optimization using Directed Mutations. Office of Scientific and Technical Information (OSTI), febbraio 2016. http://dx.doi.org/10.2172/1618206.
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3
Yeung, Anthony T. Detection of Mutations Using a Novel Endonuclease. Fort Belvoir, VA: Defense Technical Information Center, giugno 1998. http://dx.doi.org/10.21236/adb238444.
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4
Dr. Elizabeth Iorns, Dr Elizabeth Iorns. Can we prevent the transmission of BRCA mutations? Experiment, febbraio 2013. http://dx.doi.org/10.18258/0090.
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5
Lapedes, A. S., B. G. Giraud, L. C. Liu e G. D. Stormo. Correlated mutations in protein sequences: Phylogenetic and structural effects. Office of Scientific and Technical Information (OSTI), dicembre 1998. http://dx.doi.org/10.2172/296863.
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6
Beernink, P., D. Barsky e B. Pesavento. Mutations that Cause Human Disease: A Computational/Experimental Approach. Office of Scientific and Technical Information (OSTI), gennaio 2006. http://dx.doi.org/10.2172/898012.
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7
Grapes, Laura, Stephen Rudd, Rohan L. Fernando, Karine Megy, Dominique Rocha e Max F. Rothschild. Searching for mutations in pigs using the human genome. Ames (Iowa): Iowa State University, gennaio 2005. http://dx.doi.org/10.31274/ans_air-180814-1070.
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8
Barkan, A. Transposon-induced nuclear mutations that alter chloroplast gene expression. Office of Scientific and Technical Information (OSTI), gennaio 1992. http://dx.doi.org/10.2172/6686800.
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9
Nelson, Peter S. Global Characterization of Protein-Altering Mutations in Prostate Cancer. Fort Belvoir, VA: Defense Technical Information Center, agosto 2012. http://dx.doi.org/10.21236/ada568599.
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10
Sieburth, Derek. Genetic and Molecular Analysis of Suppressors of Ras Mutations. Fort Belvoir, VA: Defense Technical Information Center, ottobre 1997. http://dx.doi.org/10.21236/ada340946.
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