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PubMed2025

Inflammation and mutational burden differentially associated with nivolumab or ipilimumab combination efficacy in colorectal cancer.

Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Here, we report exploratory biomarker analyses from CheckMate 142 evaluating associations between various tissue biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures is associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden, and degrees of microsatellite instability are associated with improved response per investigator assessment and survival benefit with nivolumab plus ipilimumab. While interpretation is limited by the exploratory nature of these analyses, they suggest that tumor antigenicity rather than baseline tumor inflammation might be important for the combinatorial efficacy. Validation of these findings in larger, randomized studies is necessary.

Humans↗

PubMed2006

Microsatellite polymorphism across the M. tuberculosis and M. bovis genomes: implications on genome evolution and plasticity.

BACKGROUND: Microsatellites are the tandem repeats of nucleotide motifs of size 1-6 bp observed in all known genomes. These repeats show length polymorphism characterized by either insertion or deletion (indels) of the repeat units, which in and around the coding regions affect transcription and translation of genes. RESULTS: Systematic comparison of all the equivalent microsatellites in the coding regions of the three mycobacterial genomes, viz. Mycobacterium tuberculosis H37Rv, Mycobacterium tuberculosis CDC1551 and Mycobacterium bovis, revealed for the first time the presence of several polymorphic microsatellites. The coding regions affected by frame-shifts owing to microsatellite indels have undergone changes indicative of gene fission/fusion, premature termination and length variation. Interestingly, the genes affected by frame-shift mutations code for membrane proteins, transporters, PPE, PE_PGRS, cell-wall synthesis proteins and hypothetical proteins. CONCLUSION: This study has revealed the role of microsatellite indel mutations in imparting novel functions and a certain degree of plasticity to the mycobacterial genomes. There seems to be some correlation between microsatellite polymorphism and the variations in virulence, host-pathogen interactions mediated by surface antigen variations, and adaptation of the pathogens. Several of the polymorphic microsatellites reported in this study can be tested for their polymorphic nature by screening clinical isolates and various mycobacterial strains, for establishing correlations between microsatellite polymorphism and the phenotypic variations among these pathogens.

Bacterial Proteins↗

PubMed2002

Microsatellites in Zea - variability, patterns of mutations, and use for evolutionary studies.

To evaluate the performance of microsatellites or simple sequence repeats (SSRs) for evolutionary studies in Zea, 46 microsatellite loci originally derived from maize were applied to diverse arrays of populations that represent all the diploid species of Zea and 101 maize inbreds. Although null phenotypes and amplification of more than two alleles per plant were observed at modest rates, no practical obstacle was encountered for applying maize microsatellites to other Zea species. Sequencing of microsatellite alleles revealed complex patterns of mutation including frequent indels in the regions flanking microsatellite repeats. In one case, all variation at a microsatellite locus came from indels in the flanking region rather than in the repeat motif. Maize microsatellites show great variability within populations and provide a reliable means to measure intraspecific variation. Phylogeographic relationships of Zea populations were successfully reconstructed with good resolution using a genetic distance based on the infinite allele model, indicating that microsatellite loci are useful in evolutionary studies in Zea. Microsatellite loci show a principal division between tropical and temperate inbred lines, and group inbreds within these two broad germplasm groups in a manner that is largely consistent with their known pedigrees.

Journal Article↗

PubMed2001

Evolutionary dynamics in a novel L2 clade of non-LTR retrotransposons in Deuterostomia.

The evolution of the novel L2 clade of non-long terminal repeat (LTR) retrotransposons and their evolutionary dynamics in Deuterostomia has been examined. The short-term evolution of long interspersed nuclear element 2s (LINE2s) has been studied in 18 reptilian species by analysis of a PCR amplified 0.7-kb fragment encoding the palm/fingers subdomain of reverse transcriptase (RT). Most of the reptilian LINE2s examined are inactive since they contain multiple stop codons, indels, or frameshift mutations that disrupt the RT. Analysis of reptilian LINE2s has shown a high degree of sequence divergence and an unexpectedly large number of deletions. The evolutionary dynamics of LINE2s in reptiles has been found to be complex. LINE2s are shown to form a novel clade of non-LTR retrotransposons that is well separated from the CR1 clade. This novel L2 clade is more widely distributed than previously thought, and new representatives have been discovered in echinoderms, insects, teleost fishes, Xenopus, Squamata, and marsupials. There is an apparent absence of LINE2s from different vertebrate classes, such as cartilaginous fishes, Archosauria (birds and crocodiles), and turtles. Whereas the LINE2s are present in echinoderms and teleost fishes in a conserved form, in most tetrapods only highly degenerated pseudogenes can be found. The predominance of inactive LINE2s in Tetrapoda indicates that, in the host genomes, only inactive copies are still present. The present data indicate that the vertical inactivation of LINE2s might have begun at the time of Tetrapoda origin, 400 MYA. The evolutionary dynamics of the L2 clade in Deuterostomia can be described as a gradual vertical inactivation in Tetrapoda, stochastic loss in Archosauria and turtles, and strict vertical transmission in echinoderms and teleost fishes.

Amino Acid Sequence↗

PubMed2000

Evolutionary lineages of RT1.Ba in the Australian Rattus.

In this study, the evolutionary history of the variable second exon of RT1.Ba and its adjoining intron b are compared across a number of species and subspecies of the Australian RATTUS: Three lineages are identified in the second intron across a range of Rattus species. Two of these lineages, separated by the insertion of a probable rodent short interspersed nucleotide element and by point mutations outside the indel region, are both found in each of the major clades of the endemic Australian RATTUS: This pattern of ancestral polymorphism is reflected in the adjoining exon 2 sequences, although phylogenetic constraints confirm that the clustering is not identical to that of the associated intron sequences. In addition, the coding sequences show evidence of the retention of ancestral polymorphism, with identical exon sequences found in two divergent species, and some indication of gene conversion detected for the exon sequences.

Amino Acid Sequence↗

PubMed2025

Rat somatic genome editing enables ER+ breast cancer modeling.

Genetically engineered mouse models have advanced cancer research but often fail to capture key features of certain human tumors. Rats, with distinct physiology and tumor biology, offer a powerful alternative, yet their use has been constrained by technical barriers to genome editing. Here, we report efficient somatic genome editing in rats, enabling both Indel and substitution mutations. We then apply this approach to model estrogen receptor (ER)-positive breast cancer, which accounts for ~70% of human cases but remains poorly represented in mice. The resulting rat tumors reproduce hallmarks of human ER+ breast cancer, including ductal histology, hormone responsiveness, and immune-microenvironmental features. By contrast, identical genetic alterations in mice failed to yield ER+ tumors, underscoring critical species differences in tumorigenesis. Together, this work establishes a versatile platform for rapid generation of clinically relevant rat tumor models, opening new avenues to dissect tumor biology, therapeutic response, and immune interactions in previously inaccessible cancer subtypes.

Journal Article↗

PubMed2026

Enhanced exonuclease-Cas9 systems promote multiple nucleotide deletions with higher efficiency and broader targeting scope in plants.

CRISPR-Cas9 is a widely used platform for plant genome editing, but its outcomes are typically dominated by small insertions and deletions (indels). Such limited mutation profiles restrict its utility in functional studies of non-coding RNAs and regulatory elements, such as microRNAs (miRNAs), untranslated regions (UTRs), and promoter sequences, where larger sequence disruptions are often required. Here, we developed enhanced exonuclease-Cas9 platforms, termed multiple nucleotide deletion Cas9 (MND-Cas9) systems, for efficient generation of large deletions in rice. By screening four exonucleases (RecJ, T5, TREX2, and SbcB), we established MND-Cas9v1 systems based on TREX2 or SbcB that produced substantially larger deletions without reducing editing efficiency. Further optimization with an inserted DNA-binding domain (DBD) between Cas9 and exonuclease yielded MND-Cas9v2, which simultaneously enhanced efficiency and deletion size. To expand PAM compatibility, we introduced PAM-relaxed Cas9-NG and SpG variants, generating MND-Cas9-NG/SpGv2 systems with broader targeting scope and superior performance compared to their parental nucleases. Finally, we demonstrated the utility of these systems in two applications: MND-Cas9v2 efficiently knocked out the miRNA gene OsMIR530, producing larger seeds, and generated extended deletions in the 3'UTR of OsGhd2, which upregulated its expression and increased grain size. These results demonstrate that MND-Cas9 systems enable high-efficiency generation of extended deletions and facilitate functional analyses of non-coding RNAs and regulatory sequences. Overall, this work establishes a versatile and expandable exonuclease-Cas9 platform that substantially broadens the mutational spectrum and application potential of CRISPR-Cas9 for plant genome engineering.

CRISPR-Cas Systems↗

PubMed1999

Chloroplast DNA evidence for the evolution of Microseris (Asteraceae) in Australia and New Zealand after long-distance dispersal from western North America.

Restriction site mutations and trnL(UAA)-trnF(GAA) intergenic spacer length variants in the chloroplast genome were used to investigate the phylogenetic relationships among 53 Australian and New Zealand Microseris populations and to assess their position within their primarily North American genus. The study was performed to enhance understanding of evolutionary processes within this unique example of intercontinental dispersal and subsequent adaptive radiation. A southern blot method using four-base restriction enzymes and fragment separation on polyacryamide gels resulted in 55 mutations of which 30 were potentially phylogenetically informative. Most mutations were small indels of <162 bp, 80% of which were <20 bp. The small indels were useful for phylogenetic reconstruction of Australasian Microseris as judged by the high consistency indexes. The results confirmed the monophyly of the Australian and New Zealand Microseris. The occurrence of "hard" basal polytomies in the most parsimonious trees indicated that rapid radiation has occurred early in the history of the taxon. The monophyly of M. lanceolata, which includes the self-incompatible ecotypes of the Australian mainland, was confirmed. Within this species three clades were found that reflect more geographic distribution than morphological entities, suggesting that migration and possibly introgression between different ecotypes, or parallel evolution of similar adaptations, has occurred. One of the three clades was supported by a 162-bp deletion in the trnL-trnF spacer, while a subgroup of this exhibited also a tandemly repeated trnF exon. The data were inconclusive about the monophyly of the second Australasian species, M. scapigera, which comprises the New Zealand, Tasmanian, and autofertile ecotypes of Australia.

Journal Article↗

PubMed2005

[Polymorphisms and bioinformatics analysis of chicken prolactin gene].

Four chicken breeds (White Leghorn, Yangshan, Taihe Silkies, White Recessive Rocks) with different reproduction were applied to screen potential SNPs related to laying performance in the 5' flanking region, exon region and partial intron region of chicken prolactin (cPRL) gene. Totally almost 4500 bp were screened rapidly based on DNA pooling and sequencing, and thirteen single nucleotide polymorphisms (SNPs) and two indels (24 bp and 15 bp) were found, including nine SNPs and two indels in the 5' flanking region, one SNP in Exon 2, two SNPs in Exon 5 and one SNP in Intron 2 respectively. Furthermore, 5' flanking region of cPRL gene was analyzed by the website of http://motif.genome.ad.jp/. A possible Evi-1 binding site (score 93) was found in White Leghorn cPRL gene because of the 24 bp insertion, another possible C/EBPbeta binding site (score 94) was found in Yangshan cPRL gene because of the variation of C-2402T. Further studies need to be carried out to verify their effects on the expression of cPRL gene, the broodiness and laying performance of chickens.

5' Flanking Region↗

PubMed2005

Hereditary amyloidosis in early childhood associated with a novel insertion-deletion (indel) in the fibrinogen Aalpha chain gene.

BACKGROUND: Systemic amyloidosis occurring in early childhood is extremely rare, and is usually of AA type complicating chronic inflammatory diseases. We report the molecular basis of amyloidosis in a Korean girl who presented at 7 years of age with asymptomatic proteinuria and developed amyloid hepatomegaly and end-stage renal failure within 2 years. METHODS: Renal biopsy showed enlarged glomeruli virtually replaced by amyloid, but without interstitial or vascular involvement. The histologic appearance was identical to that seen in patients with hereditary fibrinogen Aalpha chain Glu526Val amyloidosis, and the amyloid deposits stained specifically with antibodies to fibrinogen. Mutations were sought in the genes of the amyloidogenic proteins, transthyretin, apolipoprotein AI, lysozyme and fibrinogen Aalpha chain genes by polymerase chain reaction (PCR) and sequencing. RESULTS: A unique frameshift insertion-deletion (indel) mutation was identified in one allele of her fibrinogen Aalpha chain gene, which encodes a partly novel peptide and a premature stop signal, similar to the two previously reported amyloidogenic point deletions at codons 522 and 524 in this molecule. The mutation was absent in samples verified to be from her parents, indicating that it had occurred de novo. CONCLUSION: This is the first description of hereditary fibrinogen Aalpha chain amyloidosis in an Asian individual, and the distinctive renal histology offered a strong clue to the diagnosis. The disease is potentially curable by combined hepatorenal transplantation.

Amino Acid Sequence↗

PubMed2005

Mutation rates in the dystrophin gene: a hotspot of mutation at a CpG dinucleotide.

An analysis of mutations was performed in 141 Duchenne muscular dystrophy (DMD) patients previously found to be negative for large deletions by standard multiplex PCR assays. Comprehensive mutation scanning of all coding exons, adjacent intronic splice regions, and promoter sequences was performed by DOVAM-S, a robotically enhanced, high throughput method that detects essentially all point mutations. Samples negative for point mutations were further analyzed for duplications by multiplex amplifiable probe hybridization (MAPH). Presumptive causative mutations were detected in 90% of the patients (70% protein truncating point mutations, 13% duplications, and 7% deletions not detected by the standard multiplex screening method). A total of 40 of the mutations are putatively novel. Most duplications involve multiple exons with an average and median size of about 160 and 153 kb, respectively. This is the first analysis of the absolute and relative rates of point mutations in the dystrophin gene. Relative to microdeletions (0.68 x 10(-9) per bp per generation), transitions at CpG dinucleotides are enhanced 150-fold while complex indels, the least common mutation type, are less frequent than microdeletions by a factor of five. The frequency of microdeletions and microinsertions at mononucleotide repeats increases exponentially with length. When compared to the well-studied human factor IX gene (F9), the results are similar, with two exceptions: a hotspot of mutation in the dystrophin gene (c.8713C>T/p.R2905X) at a CpG dinucleotide and an altered size distribution of microdeletions. The hotspot reflects a difference in the underlying pattern of mutation, while the altered size distribution of microdeletions reflects certain abundant sequence motifs within the dystrophin coding sequence (relative to factor IX).

Adolescent↗

PubMed2000

mtDNA tandem repeats in domestic dogs and wolves: mutation mechanism studied by analysis of the sequence of imperfect repeats.

The mitochondrial (mt) DNA control region (CR) of dogs and wolves contains an array of imperfect 10 bp tandem repeats. This region was studied for 14 domestic dogs representing the four major phylogenetic groups of nonrepetitive CR and for 5 wolves. Three repeat types were found among these individuals, distributed so that different sequences of the repeat types were formed in different molecules. This enabled a detailed study of the arrays and of the mutation events that they undergo. Extensive heteroplasmy was observed in all individuals; 85 different array types were found in one individual, and the total number of types was estimated at 384. Among unrelated individuals, no identical molecules were found, indicating a high rate of evolution of the region. By performing a pedigree analysis, array types which had been inherited from mother to offspring and array types which were the result of somatic mutations, respectively, could be identified, showing that about 20% of the molecules within an individual had somatic mutations. By direct pairwise comparison of the mutated and the original array types, the physiognomy of the inserted or deleted elements (indels) and the approximate positions of the mutations could be determined. All mutations could be explained by replication slippage or point mutations. The majority of the indels were 1-5 repeats long, but deletions of up to 17 repeats were found. Mutations were found in all parts of the arrays, but at a higher frequency in the 5' end. Furthermore, the inherited array types within the mother-offspring pair were aligned and compared so that germ line mutations could be studied. The pattern of the germ line mutations was approximately the same as that of the somatic mutations.

Animals↗

PubMed2026

Co-occurrence of bronchiolar adenoma and lung adenocarcinoma: a study of nine cases revealing distinct clonal origins via integrated histologic, immunophenotypic and molecular analysis.

PURPOSE: This study sought to elucidate the possible biological association between BA and lung adenocarcinoma through an analysis of cases in which both lesions coexist within the same specimen. METHODS: In our cohort, the BA and lung cancer components of nine concurrent-type BAs were microdissected using the Millisect system and subjected to whole-exome sequencing (WES). Their histopathological, immunohistochemical, and genomic profiles were comparatively evaluated. RESULTS: Histopathologically, the BA regions of concurrent-type BAs exhibited a classic bilayered architecture, composed of continuous luminal and basal cell layers. The adjacent monolayered concurrent components were diagnosed as adenocarcinoma in situ (AIS, N = 4), minimally invasive adenocarcinoma (MIA, N = 2), and invasive adenocarcinoma (ADC, N = 3). Immunohistochemically, both luminal and basal cells in BA regions expressed thyroid transcription factor 1 (TTF1), albeit with more heterogeneous staining intensity compared to that observed in tumor components. Molecularly, EGFR mutations were the most frequently identified in either BA or tumor components, or in both (Case 9). In BA components, mutations included exon 19 p.S752F, exon 19 deletions (p.L747_T751delinsP and p.E746_T751delinsVP), and compound G719C/S768I mutations. Tumor components harbored exon 28 S1130C, exon 19 indel (p.E746_S752delins), and exon 18 p.G719C mutations. Notably, only three cases demonstrated limited overlap of mutations and copy number variations (CNVs) between the two components. Phylogenetic analysis revealed that six cases shared truncal alterations in genes including KMT2A, PIK3CA, SETD2, MITF, PBRM1, and SRSF3, one case harbored a shared canonical EGFR mutation (p.G719C), with an additional p.S768I alteration uniquely detected in the BA component. CONCLUSION: There is insufficient evidence to support BA as a premalignant lesion for lung adenocarcinoma base on morphological and molecular variables, and they may represent distinct pathological entities.

Concurrent-type bronchiolar adenoma↗

PubMed1997

Complex evolution of a salmonid microsatellite locus and its consequences in inferring allelic divergence from size information.

Sequence analysis of 78 alleles of a microsatellite locus was resolved at various taxonomic levels among salmonid fishes to test for congruence between size and sequence information. Allelic variability of this locus involved changes in number of dinucleotide repeats as expected for microsatellite loci. However, additional mutational events involving large indels and base substitutions also occurred frequently among and within species. These caused the evolution of different imperfect microsatellite variants, from an ancestral perfect one, which was undetectable from allelic size information only. Alleles of the same length resulting from different mutational events were also observed among and within species. Altogether, these results revealed the incongruence between size and number of mutation events, implying that it may be imprecise to interpret mutational rates and relationships on the basis of size information alone in interspecific comparisons and, to a lesser extent, within species.

Alleles↗

PubMed2006

An unusual pattern of spontaneous mutations recovered in the halophilic archaeon Haloferax volcanii.

Spontaneous mutations in the orotate:phosphoribosyl transferase (pyrE2) gene of the halophilic archaeon Haloferax volcanii were selected by 5-fluoroorotic acid plus uracil at a rate of approximately 2 x 10(-8)/cell division in fluctuation and null-fraction tests but approximately 6 x 10(-8)/cell division in mutation-accumulation tests. The corresponding genomic mutation rates were substantially lower than those observed for other mesophilic microbial DNA genomes on the basis of similar target genes. The mutational spectrum was dominated by indels adding or deleting multiples of 3 bp. Properties of the organism contributing to this unusual mutational pattern may include phenotypic lag caused by a high chromosomal copy number and efficient promotion of strand misalignments by short direct repeats.

Genes, Archaeal↗

PubMed2004

Insertions and deletions are male biased too: a whole-genome analysis in rodents.

It is presently accepted that, in mammals, due to the greater number of cell divisions in the male germline than in the female germline, nucleotide substitutions occur more frequently in males. The data on mutation bias in insertions and deletions (indels) are contradictory, with some studies indicating no sex bias and others indicating either female or male bias. The sequenced rat and mouse genomes provide a unique opportunity to investigate a potential sex bias for different types of mutations. Indeed, mutation rates can be accurately estimated from a large number of orthologous loci in organisms similar in generation time and in the number of germline cell divisions. Here we compare the mutation rates between chromosome X and autosomes for likely neutral sites in eutherian ancestral interspersed repetitive elements present at orthologous locations in the rat and mouse genomes. We find that small indels are male biased: The male-to-female mutation rate ratio (alpha) for indels in rodents is approximately 2. Similarly, our whole-genome analysis in rodents indicates an approximately twofold excess of nucleotide substitutions originating in males over that in females. This is the same as the male-to-female ratio of the number of germline cell divisions in rat and mouse. Thus, this is consistent with nucleotide substitutions and small indels occurring primarily during DNA replication.

Animals↗

PubMed2000

Molecular evidence for repetitive parallel evolution of shell structure in Clausiliidae (Gastropoda, pulmonata).

The division of clausiliid genera, using the type of clausilial apparatus (CA) as the decisive criterion, is ambiguous. Two types of CA can be distinguished: the normal (N) type and the Graciliaria (G) type. Morphological resemblance between species with different types of CA led to the hypothesis that the CA type is homoplasious. Therefore sequence variation, phylogenetic relationships, and the evolution of the CA were studied in the genera Albinaria, Isabellaria, and Sericata. Phylogenetic relations were inferred from parsimony and neighbor-joining analyses of the nucleotide sequences of both internal transcribed spacers (ITS1 and ITS2) of the rDNA of 36 species. The variation among the sequences was great: 21.8% of the sequences were ambiguously aligned and excluded from the analysis. A high GC content in the unambiguously aligned portions and a substitutional bias toward a higher GC content are indicators of substitutional constraints in the spacers. We analyzed the data in several ways: using both spacers together and separately, weighting all mutations equally, correcting for transition/transversion bias by weighting, and using transversions only. In all resulting trees, Isabellaria is not a monophyletic group. Its division into two clades is supported by over 40 mutations and one large indel. Clade 1 consists of Isabellaria and Sericata and clade 2 consists of Isabellaria and Albinaria species. The present distribution of the CA type was plotted on the tree and its most parsimonious evolution was reconstructed. The CA type was shown to be highly homoplasious. In clade 1 and clade 2 both types of CA were found; depending on the ancestral state, either the G or the N type evolved several times in parallel. These results contribute decisively to the current debate on the morphological diagnoses of Albinaria, Sericata, and Isabellaria as monophyletic taxa.

Animals↗

PubMed2005

Genetic studies of 20 Japanese families of dystrophic epidermolysis bullosa.

Dystrophic EB (DEB) is clinically characterized by mucocutaneous blistering in response to minor trauma, followed by scarring and nail dystrophy, and is caused by mutations in the COL7A1 gene encoding type VII collagen. DEB is inherited in either an autosomal dominant (DDEB) or recessive (RDEB) fashion. DDEB basically results from a glycine substitution mutation within the collagenous domain on one COL7A1 allele, while a combination of mutations such as premature stop codon, missense, and splice-site mutations on both alleles causes RDEB. In this study, mutation analysis was performed in 20 distinct Japanese DEB families (16 RDEB and four DDEB). The result demonstrated 30 pathogenic COL7A1 mutations with 16 novel mutations, which included four missense, five nonsense, one deletion, two insertion, one indel, and three splice-site mutations. We confirmed that Japanese COL7A1 mutations were basically family specific, although three mutations, 5818delC, 6573 + 1G > C, and E2857X, were recurrent based on previous reports. Furthermore, the Q2827X mutation found in two unrelated families would be regarded as a candidate recurrent Japanese COL7A1 mutation. The study furthers our understanding of both the clinical and allelic heterogeneity displayed in Japanese DEB patients.

Adult↗