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Diagnostics ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 207
Author(s):  
Luke Mansard ◽  
Christel Vaché ◽  
Julie Bianchi ◽  
Corinne Baudoin ◽  
Isabelle Perthus ◽  
...  

GSDME, also known as DFNA5, is a gene implicated in autosomal dominant nonsyndromic hearing loss (ADNSHL), affecting, at first, the high frequencies with a subsequent progression over all frequencies. To date, all the GSDME pathogenic variants associated with deafness lead to skipping of exon 8. In two families with apparent ADNSHL, massively parallel sequencing (MPS) integrating a coverage-based method for detection of copy number variations (CNVs) was applied, and it identified the first two causal GSDME structural variants affecting exon 8. The deleterious impact of the c.991-60_1095del variant, which includes the acceptor splice site sequence of exon 8, was confirmed by the study of the proband’s transcripts. The second mutational event is a complex rearrangement that deletes almost all of the exon 8 sequence. This study increases the mutational spectrum of the GSDME gene and highlights the crucial importance of MPS data for the detection of GSDME exon 8 deletions, even though the identification of a causal single-exon CNV by MPS analysis is still challenging.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2220-2220
Author(s):  
Robert L. Bowman ◽  
Tanmay Mishra ◽  
Shira E. Eisman ◽  
Louise Cai ◽  
Wenbin Xiao ◽  
...  

Abstract Genomic studies in acute myeloid leukemia (AML) have generated a near complete catalogue of genes mutated at varying frequencies both across patients and in individual leukemias. The high variability of mutation burden within a given leukemia is suggestive of a stepwise evolutionary process composed of early, clonal, mutations and subsequent subclonal events. The receptor tyrosine kinase, FLT3, is the most commonly mutated gene in AML, with mutations frequently manifesting as internal tandem duplications (ITDs) in the juxtamembrane domain leading to constitutive kinase activation. Although FLT3 is commonly a subclonal mutational event, FLT3 ITD mutations portend a poor prognosis particularly when combined with DNMT3A and NPM1, earlier mutations that drive clonal expansion. Notwithstanding its role as a subclonal driver, previous preclinical FLT3 models have utilized retroviral overexpression or germline mutant expression at the endogenous locus precluding accurate temporal modeling of disease. These efforts have prohibited evaluation of FLT3 mutational acquisition in the context observed in AML patients. Here, we report the development of an endogenously targeted, Flp inducible, Flt3 ITD mouse allele which can be somatically activated subsequent to cooperating disease alleles. When activated with a tamoxifen inducible FlpoER, Flt3 mutant mice developed rapid leukocytosis peaking at 4-6 weeks post activation and resolving by 8-10 weeks, a finding not previously observed in constitutive models. This leukocytosis was disproportionately monocytic and accompanied by pronounced anemia and thrombocytopenia. Long term, these mice develop a myeloproliferative disease , reminiscent of previously reported constitutive alleles. In competitive transplantation studies, Flt3 mutant cells initiated disease and outcompeted wild-type cells. Despite this competitive advantage, disease was incapable of transplanting into secondary recipients. We further observed a non-cell autonomous depletion of SLAM+ LSKs suggesting the Flt3 mutant cells cannot propagate disease in self-renewing stem cells. To evaluate how this allele influenced leukemic evolution we crossed this Flt3 ITD allele to a Flp inducible Npm1 c mouse where a pulse of tamoxifen simultaneously activated both alleles. The combination of mutant Npm1 and Flt3 resulted in progressive leukocytosis which did not resolve. Within 6 weeks of mutational activation, these mice developed a lethal AML with robust anemia, thrombocytopenia, leukocytosis and expanded cKIT+ blasts in the blood. RNA-sequencing and immunophenotyping by CyTOF revealed distinct patterns of differentiation, gene-expression and downstream signaling.In an effort to model sequential mutational acquisition, we crossed the Flp Flt3 ITD allele to a Cre-inducible Dnmt3a R878H. Cre mRNA was electroporated into lineage negative bone marrow cells to activate the Dnmt3a R878H allele and transplanted into lethally irradiated recipients. Four weeks post engraftment, Flt3 ITD was activated with a pulse of tamoxifen. In contrast to the Flt3-Npm1 model, we observed an increase and subsequent decrease in WBC similar to the kinetics observed in Flt3 ITD only mice. However, by 20 weeks we observed a robust and consistent increase in WBC accompanied by an emergence of cKIT+ cells in the blood. Histopathology indicated that >50% of mice expressing both alleles in sequence developed AML marked by increased blasts in the marrow, with moderate anemia and thrombocytopenia compared to the Flt3-Npm1 models. Critically, in contrast to Flt3 ITD only mice, acquisition of the Flt3 ITD in Npm1 or Dnmt3a mutant HPSCs induced fully transplantable AML with immunophenotypic characteristics seen in human AML with these same genotypes. Collectively these results demonstrate that different co-occurring mutations are capable of transforming Flt3 ITD mutant cells, albeit with distinct latencies and mechanisms of cooperativity. In summary, our studies utilizing novel multi-recombinase models of leukemogenesis reveal new insights into the early phase of oncogene activation, and how cooperating alleles influence this response. This inducible Flt3 ITD allele represents a significant advance in modeling clonal evolution in myeloid malignancies and provides a critical isogenic platform for preclinical development of novel leukemia therapeutic regimens. Figure 1 Figure 1. Disclosures Bowman: Mission Bio: Honoraria, Speakers Bureau. Xiao: Stemline Therapeutics: Research Funding. Miles: Mission Bio: Honoraria, Speakers Bureau. Trowbridge: Fate Therapeutics: Patents & Royalties; H3 Biomedicine: Research Funding. Levine: Amgen: Honoraria; Lilly: Honoraria; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Imago: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Ajax: Membership on an entity's Board of Directors or advisory committees; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Zentalis: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Janssen: Consultancy; Astellas: Consultancy; Morphosys: Consultancy; Incyte: Consultancy; Auron: Membership on an entity's Board of Directors or advisory committees; Prelude: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees.


2020 ◽  
Author(s):  
Anny Gravdal ◽  
Xunjun Xiao ◽  
Miriam Cnop ◽  
Khadija El Jellas ◽  
Pål R. Njølstad ◽  
...  

ABSTRACTVariable number of tandem repeat (VNTR) sequences present in the genome can have functional consequences that contribute to human disease. This is the case for the CEL gene, which encodes the digestive enzyme carboxyl ester lipase. CEL has a VNTR located in exon 11, and rare single-base deletions (DELs) within this region cause MODY8, an inherited disorder characterized by exocrine pancreatic dysfunction and diabetes. Here, we have studied how the position of single-base deletions within the CEL VNTR affects the protein’s pathogenic properties. We investigated four naturally occurring CEL variants with single-base deletions in different VNTR segments (DEL1, DEL4, DEL9, DEL13), of which only DEL1 and DEL4 have been observed in MODY8 patients. When expressed in a cellular model system, only DEL1 and DEL4 exhibited significantly reduced secretion and increased intracellular aggregation compared to normal CEL. We found that all DEL variants had slightly decreased enzymatic activity and that their level of O-glycosylation was affected. Moreover, only DEL1 and DEL4 significantly increased endoplasmic reticulum (ER) stress. In conclusion, CEL single-base deletion variants have the highest pathogenic potential when the mutational event has taken place in the proximal VNTR part, resulting in the longest aberrant protein tails. Thus, DEL1 and DEL4 are pathogenic CEL variants, whereas we consider DEL13 as benign and DEL9 as likely benign. These findings have implications for our understanding of how CEL mutations cause pancreatic disease through protein misfolding and proteotoxicity, leading to ER stress and activation of the unfolded protein response.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 46-47
Author(s):  
Naranie Shanmuganathan ◽  
Carol Wadham ◽  
Nur Hezrin Shahrin ◽  
Daniel Thomson ◽  
Jinghua Feng ◽  
...  

Background We previously reported a high incidence of mutated cancer-related genes at CML diagnosis in selected chronic phase patients with a poor outcome compared to those with a good outcome. We also found a novel class of variant associated with the formation of the Ph chromosome comprising fusions and/or rearrangement of genes on the translocated chromosomes, with evidence of fragmentation, inversion, and imperfect sequence reassembly. These were termed 'Ph-associated events' and were more frequent in patients with poor outcome. However, the risk attributable to these mutational events at diagnosis has not been defined in unselected cohorts. Aim To assess the impact of genomic events in a cohort of consecutively treated patients at diagnosis of chronic phase CML. Methods A hybridization capture sequencing method targeting genes implicated in myeloid and lymphoid malignancies was applied to diagnostic RNA of patients enrolled in the TIDEL II trial. Patients were treated with upfront imatinib with active intervention, dose escalation or nilotinib switch, primarily for lack of time-dependent molecular milestones. Single base variants, small insertions/deletions, splice variants, gene fusions, and focal gene deletions were assessed with pre-defined criteria for pathogenicity. These were further classified as pathogenic mutations in cancer-related genes or Ph-associated events. Univariate and multivariate analyses were performed to evaluate the influence of mutational events and other key clinical and demographic variables on outcome at 4 years. Failure events were as defined by the ELN 2020 recommendations. Results 160/210 TIDEL II patients have so far been sequenced. 33 relevant mutations with variant allele frequencies ≥5% were identified in 9 genes in 25 patients (16%). ASXL1 was most frequently mutated (10% of all patients) and other recurrently mutated genes at diagnosis were RUNX1, BCORL1, IKZF1 and DNMT3A. Ph-associated events occurred in 25 patients (16%). Most of these (14/25 patients) involved fusions between genes on chromosomes 9 and 22 consistent with deletions adjacent to BCR and ABL1, or fusions between BCR or ABL1 and genes/regions on chromosomes other than 9 or 22. These were consistent with variant translocation and some were cytogenetically cryptic. Among these and other Ph-associated events were complex rearrangements involving inversions and large duplications. These were detected in 14/25 patients. Five patients had both cancer-related gene mutations and Ph-associated events, totalling 45 patients (28%) with at least 1 genomic event. Cancer-related mutations at diagnosis were associated with inferior progression-free survival (PFS) 82% vs 91% P=.03, and failure-free survival (FFS) 55% vs 83% P<.001. Molecular outcomes were also inferior: MMR 71% vs 89% P=.02; and MR4 27% vs 71%; P=.01. Similarly, Ph-associated events predicted inferior outcomes: FFS 63% vs 81% P=.01; MMR 70% vs 88% P=.01; and MR4 47% vs 68% P=.01. Importantly, patients with either or both of these mutational events had an increased likelihood of progression to accelerated phase or blast crisis or development of a BCR-ABL1 kinase domain mutation (Figure). Independent predictors of all survival and molecular outcomes were assessed with univariate and multivariate modelling (Table). Candidate prognostic variables were age at diagnosis, sex, transcript, Sokal and ELTS scores and the genomic variables. The only independent predictor of PFS was mutations in cancer-related genes. Cancer-related gene mutations, Ph-associated events and the ELTS score were independent predictors of FFS, MMR and MR4. We evaluated whether genomic data could be additive to the ELTS risk score. Low risk ELTS patients with any mutational event had inferior outcomes: FFS 76% vs 86%, P=.07; MMR 75% vs 92%, P=.02; MR4 41% vs 75%, P=0.006. Similar findings were observed in Intermediate risk ELTS patients: FFS 22% vs 91%, P<.001; MMR 81% vs 84%, P=.06; MR4 9% vs 72%, P=0.047. The number of high risk ELTS patients were inadequate to perform this analysis. Conclusion Despite a proactive strategy for TKI switch and a higher imatinib starting dose, the presence of cancer-related gene mutations or Ph-associated events conferred inferior outcomes. Combining the ELTS score with any mutational event further differentiated patient outcomes, demonstrating the power of integrating genomic data with current risk stratification. Disclosures Shanmuganathan: Janssen: Other: travel expenses; Novartis: Honoraria, Other: Travel expenses; Gilead: Other: Travel expenses; Amgen: Other: travel expenses. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Branford:Bristol Myers Squibb: Honoraria; Cepheid: Honoraria, Membership on an entity's Board of Directors or advisory committees; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.


2020 ◽  
Vol 30 (21) ◽  
pp. 4142-4154.e9 ◽  
Author(s):  
Bénédicte Billard ◽  
Paul Vigne ◽  
Christian Braendle

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 524 ◽  
Author(s):  
Giuseppe Limongelli ◽  
Marcella Nunziato ◽  
Cristina Mazzaccara ◽  
Mariano Intrieri ◽  
Valeria D’Argenio ◽  
...  

The purpose of this paper is to present a clinical and laboratory study of a family, in which a 12-year-old boy was examined to assess his health status before starting competitive sports. A variety of clinical and instrumental tests were used to evaluate the status of the heart and its functions. Using Sanger sequencing (SS), we sequenced six related genes to verify suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) hypothesized at the cardiac assessment and, subsequently, by a next-generation sequencing (NGS)-based multi-gene panel for more paramount genetic risk of sudden cardiac death (SCD) assessment. SS revealed two variants in the PKP2 gene, one was inherited from the father and the other from the mother. The analysis on a large panel of genes (n = 138), putatively associated with sudden cardiac death, revealed, in the proband, a third variant in a different gene (DES) that encodes the protein desmin. Our results indicate that: i) NGS revealed a mutational event in a gene not conventionally screened as a first-line test in the presence of clinical suspicion of the arrhythmic disease; ii) a plurality of variants in different genes in the same subject (the proband) may increase the risk of heart disease; iii) in silico analysis with various methodological software and bioinformatic prediction tools indicates that the cumulative effects of the three variants in the same subject constitute an additional risk factor. This case report indicates that more pathogenic variants or likely pathogenic variants can contribute to the clinical phenotype of an individual, thereby contributing to the diagnosis and prognosis of inherited heart diseases.


2020 ◽  
Vol 10 (5) ◽  
pp. 1809-1815 ◽  
Author(s):  
Julie A. Klaric ◽  
Eli L. Perr ◽  
Susan T. Lovett

DNA can assemble into non-B form structures that stall replication and cause genomic instability. One such secondary structure results from an inverted DNA repeat that can assemble into hairpin and cruciform structures during DNA replication. Quasipalindromes (QP), imperfect inverted repeats, are sites of mutational hotspots. Quasipalindrome-associated mutations (QPMs) occur through a template-switch mechanism in which the replicative polymerase stalls at a QP site and uses the nascent strand as a template instead of the correct template strand. This mutational event causes the QP to become a perfect or more perfect inverted repeat. Since it is not fully understood how template-switch events are stimulated or repressed, we designed a high-throughput screen to discover drugs that affect these events. QP reporters were engineered in the Escherichia coli lacZ gene to allow us to study template-switch events specifically. We tested 700 compounds from the NIH Clinical Collection through a disk diffusion assay and identified 11 positive hits. One of the hits was azidothymidine (zidovudine, AZT), a thymidine analog and DNA chain terminator. The other ten were found to be fluoroquinolone antibiotics, which induce DNA-protein crosslinks. This work shows that our screen is useful in identifying small molecules that affect quasipalindrome-associated template-switch mutations. We are currently assessing more small molecule libraries and applying this method to study other types of mutations.


2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Alice Goldenberg ◽  
Florent Marguet ◽  
Vianney Gilard ◽  
Aude-Marie Cardine ◽  
Adnan Hassani ◽  
...  

AbstractThe contribution of mosaic alterations to tumors of the nervous system and to non-malignant neurological diseases has been unmasked thanks to the development of Next Generation Sequencing (NGS) technologies. We report here the case of a young patient without any remarkable familial medical history who was first referred at 7 years of age, for an autism spectrum disorder (ASD) of Asperger type, not associated with macrocephaly. The patient subsequently presented at 10 years of age with multiple nodular lesions located within the trigeminal, facial and acoustic nerve ganglia and at the L3 level. Histological examination of this latter lesion revealed a glioneuronal hamartoma, exhibiting heterogeneous PTEN immunoreactivity, astrocyte and endothelial cell nuclei expressing PTEN, but not ganglion cells. NGS performed on the hamartoma allowed the detection of a PTEN pathogenic variant in 30% of the reads. The presence of this variant in the DNA extracted from blood and buccal swabs in 3.5 and 11% of the NGS reads, respectively, confirmed the mosaic state of the PTEN variant. The anatomical distribution of the lesions suggests that the mutational event affecting PTEN occurred in neural crest progenitors, thus explaining the absence of macrocephaly. This report shows that mosaic alteration of PTEN may result in multiple central and peripheral nervous system hamartomas and that the presence of such alteration should be considered in patients with multiple nervous system masses, even in the absence of cardinal features of PTEN hamartoma tumor syndrome, especially macrocephaly.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3900-3900
Author(s):  
Guillaume Beziat ◽  
Suzanne Tavitian ◽  
Sarah Bertoli ◽  
Francoise Huguet ◽  
Laetitia Largeaud ◽  
...  

NPM1 mutations are frequent in acute myeloid leukemia (AML) and define a distinct entity according to the 2016 WHO classification. NPM1 mutations are generally associated with chemosensitivity and a favorable prognosis. However, outcome may vary according to co-mutational events, and still approximately 40% of patients relapse after achieving complete response. Wild-type NPM1 is mainly located in the nucleolus where it plays a key role in the regulation of ribosome biogenesis, protein synthesis and tumor suppression through TP53 activation. Mutated NPM1 loses its predominant nucleolar location and accumulates in cytoplasm contributing to leukemogenesis (Falini B, Blood 2011). Moreover, this mutational event leads to haploinsufficiency and cytoplasmic retention of wild type NPM1 creating a vulnerability to nucleolar stress. Indeed, complete responses have been observed in NPM1-mutated AML patients with dactinomycin, a nucleolar stress-inducing drug (Falini B, NEJM 2015). Here, we report our experience of off-label dactinomycin in untreated or relapsed/ refractory NPM1-mutated AML. Inclusion criteria for this retrospective study were: age ≥ 18 years-old, AML with NPM1 mutation, relapsed or refractory disease as well as treatment-naive patients unfit for intensive chemotherapy. Patients should also have completed one cycle of dactinomycin 12.5 µg/kg/day for 5 days every 28 days. From September 2015 to February 2019, 26 patients received dactinomycin. Median age was 62.5y, WBC count was > 50 giga/L in 8 patients (31%), 13 patients (50%) had FLT3-ITD mutation whereas 10 (38%) and 11 (42%) patients were classified as favorable or intermediate-I according to the ELN-2010 classification. There were 7 (27%) relapses post-allogeneic transplantation. Median number of dactinomycin cycle was 1 (1-8) and 7 patients (27%) received more than 3 cycles. Sorafenib was added in 6 patients with associated FLT3-ITD mutations whereas 2 others patients received ATRA in combination with dactinomycin. Dactinomycin was administered in different situations: front-line treatment in 4 unfit patients (16%); morphologic (n=16, 62%) or molecular relapses (n=4, 16%) following intensive chemotherapy, refractory disease (n=1, 13%) or post remission therapy in second complete response (CR) following salvage chemotherapy (n=1, 13%). Three out of 17 patients (18%) in morphologic relapse or refractory to chemotherapy reached complete remission after the first cycle of dactinomycin. The duration of response was 4 and 6 months in 2 patients whereas the third patient is still in CR 3 years after dactinomycin. One out of 4 patients in molecular relapses achieved a complete molecular remission with dactinomycin. None of the 4 patients unfit for intensive chemotherapy responded to dactinomycin as front-line therapy. The only patient treated in post-CR2 with dactinomycin achieved a complete molecular remission before allogeneic transplantation. Overall, 5 patients (19%) appeared to benefit from dactinomycin treatment. Grade 3-4 adverse events were thrombocytopenia (n=11, 42%), neutropenia (n=11, 42%), GI toxicity (n=6, 23%), mucositis (n=5, 19%), lung infection (n=5, 19%) and skin rash (n=2, 7.6%). Dactinomycin is an inexpensive and easily available drug that may induce significant responses in AML patients with NPM1 mutations with an acceptable safety profile. Prospective and controlled clinical trials are mandatory to clearly define the role of this agent in AML with NPM1 mutations. Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Bertoli:Sanofi: Honoraria. Huguet:Incyte Biosciences: Honoraria; Servier: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria. Bories:Abbvie: Consultancy. Recher:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: NPM1 mutations are frequent in acute myeloid leukemia (AML) and define a distinct entity according to the 2016 WHO classification. Wild-type NPM1 is mainly located in the nucleolus where it plays a key role in the regulation of ribosome biogenesis, protein synthesis and tumor suppression through TP53 activation. Mutated NPM1 loses its predominant nucleolar location and accumulates in cytoplasm contributing to leukemogenesis (Falini B, Blood 2011). Moreover, this mutational event leads to haploinsufficiency and cytoplasmic retention of wild type NPM1 creating a vulnerability to nucleolar stress. Indeed, complete responses have been observed in NPM1-mutated AML patients with dactinomycin, a nucleolar stress-inducing drug (Falini B, NEJM 2015).


2019 ◽  
Author(s):  
Julien Y. Dutheil ◽  
Karin Münch ◽  
Klaas Schotanus ◽  
Eva H. Stukenbrock ◽  
Regine Kahmann

AbstractHoming endonucleases (HE) are enzymes capable of cutting DNA at highly specific target sequences, the repair of the generated double-strand break resulting in the insertion of the HE-encoding gene (“homing” mechanism). HEs are present in all three domains of life and viruses; in eukaryotes, they are mostly found in the genomes of mitochondria and chloroplasts, as well as nuclear ribosomal RNAs. We here report the case of a HE that accidentally integrated into a telomeric region of the nuclear genome of the fungal maize pathogen Ustilago maydis. We show that the gene has a mitochondrial origin, but its original copy is absent from the U. maydis mitochondrial genome, suggesting a subsequent loss or a horizontal transfer from a different species. The telomeric HE underwent mutations in its active site and lost its original start codon. A potential other start codon was retained downstream, but we did not detect any significant transcription of the newly created open reading frame, suggesting that the inserted gene is not functional. Besides, the insertion site is located in a putative RecQ helicase gene, truncating the C-terminal domain of the protein. The truncated helicase is expressed during infection of the host, together with other homologous telomeric helicases. This unusual mutational event altered two genes: the integrated HE gene subsequently lost its homing activity, while its insertion created a truncated version of an existing gene, possibly altering its function. As the insertion is absent in other field isolates, suggesting that it is recent, the U. maydis 521 reference strain offers a snapshot of this singular mutational event.


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