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PubMed2026

Lineage-associated small inversions disrupt dosT, dnaE2, and a promoter-adjacent region in some Mycobacterium tuberculosis isolates.

UNLABELLED: Large molecular inversions in the genome of Mycobacterium tuberculosis (Mtb) due to factors like the presence of insertion sequences and transposases are widely known. However, smaller inversions within coding sequences and non-coding control elements are rarely reported. The present study aims to identify inversions and their potential impact on Mtb biology in a lineage-specific manner. Structural variants (SVs) could only be detected by long reads. For this, we simulated long reads by de novo assembling the short-read sequencing data sets and subsequently aligned representative strains from each lineage using the Progressive Mauve algorithm. Independently, long-read sequencing from the Pacific Biosciences platform was acquired and analyzed using the structural variant identification method. Variants were merged, and Fisher's exact test was carried out to identify the inversion association with lineages. To visualize deoxyribonucleic acid (DNA) features, the DNA-features-viewer tool was used. Simulated reads from short-read sequencing gave indications of lineage (L)-specific inversions. The long-read sequencing approach led to the identification of seven unique inversions: two positively associated with L1, one positively associated with L3, two negatively associated with L4, and two positively associated with L3 but negatively associated with L4 (P < 0.05). The inversions encompassed primarily non-essential genes like sdaA, dosT, Rv2026c, dnaE2, Rv1341, Rv1342, and lprD. An interesting inversion was observed in the upstream control element of purB and Rv0776c. The study sheds light on small inversions that may be causing alterations in expression, formation of fusion genes, and nonsense mutations that may have a role in lineage-specific phenotypic changes. IMPORTANCE: The role of mutations like SNPs and INDELs and their association with drug resistance is well known in Mycobacterium tuberculosis (Mtb). However, structural variations, especially inversions, are largely overlooked and unreported. In this paper, publicly available whole-genome sequencing datasets from Illumina and Pacific Biosciences-Oxford Nanopore Technologies platform have been used to detect inversions and report seven unreported Mtb lineage-specific small inversions.

Mycobacterium tuberculosis↗

PubMed2006

Most spontaneous tumors in a mouse model of Li-Fraumeni syndrome do not have a mutator phenotype.

Mutations are the substrate of cancer. Yet, little is known about the degree and nature of mutations in tumors because measurement of mutation load in tumors and normal tissues was generally not possible until the advent of transgenic mouse mutation detection systems. Herein, we present the first analysis of mutation frequency and pattern in thymic tumors from a mouse model of Li-Fraumeni syndrome (p53+/- murine model) using the Big Blue assay with sequencing of all mutants. We also make the first characterization of mutation frequency and pattern in p53-deficient extra-thymic cancers. The data more than triple the literature on all non-mismatch repair deficient tumors for which mutations are identified by sequence analysis, allowing mutation frequency and pattern to be determined. Most tumors had a normal mutation frequency and a normal mutation pattern. Five tumors showed modest increases in mutation frequency (2.3-fold or less). Alterations in mutation patterns were uncommon, tumor-specific and not necessarily associated with increases in mutation frequency. Given the data from two spontaneous tumors (normal mutation frequency with an abnormal pattern in a p53-/- mouse and low mutation frequency in a p53+/+ control mouse), we hypothesize that tumors sometimes can carry a low mutation load. The study was not without certain caveats: mutation load could not be compared between tumor and normal tissue from the same animal; sample sizes for extra-thymic tumor types were small, and only point mutations and deletions, insertions and indels up to 2 kb were detected. However, the data clearly show key differences in tumors from p53+/- mice compared with mismatch repair deficient tumors; a lack of dramatic increase in mutation frequency and absence of a signature of mutation.

Animals↗

PubMed2004

Occurrence and consequences of coding sequence insertions and deletions in Mammalian genomes.

Nucleotide insertion and deletion (indel) events, together with substitutions, represent the major mutational processes of gene evolution. Through the alignment of 8148 orthologous genes from human, mouse, and rat, we have identified 1743 indel events within rodent protein-coding sequences. Using human as an out-group, we reconstructed the mutational event underlying each of these indels. Overall, we found an excess of deletions over insertions, particularly for the rat lineage (70% excess). Sequence slippage accounts for at least 52% of insertions and 38% of deletions. We have also evaluated the selective tolerance of identifiable protein structures to indels. Transmembrane domains are the least, and low complexity regions, the most tolerant. Mapping of indels onto known protein structures demonstrated that structural cores are markedly less tolerant to indels than are loop regions. There is a specific enrichment of CpG dinucleotides in close proximity to insertion events, and both insertions and deletions are more common in higher G+C content sequences.

Amino Acid Sequence↗

PubMed2002

Human diallelic insertion/deletion polymorphisms.

We report the identification and characterization of 2,000 human diallelic insertion/deletion polymorphisms (indels) distributed throughout the human genome. Candidate indels were identified by comparison of overlapping genomic or cDNA sequences. Average confirmation rate for indels with a > or =2-nt allele-length difference was 58%, but the confirmation rate for indels with a 1-nt length difference was only 14%. The vast majority of the human diallelic indels were monomorphic in chimpanzees and gorillas. The ratio of deletionrcolon;insertion mutations was 4.1. Allele frequencies for the indels were measured in Europeans, Africans, Japanese, and Native Americans. New alleles were generally lower in frequency than old alleles. This tendency was most pronounced for the Africans, who are likely to be closest among the four groups to the original modern human population. Diallelic indels comprise approximately 8% of all human polymorphisms. Their abundance and ease of analysis make them useful for many applications.

Biological Evolution↗

PubMed2004

A new rare mutation (691delCC/insAAA) in exon 17 of the PYGM gene causing McArdle disease.

OBJECTIVE: To investigate the genetic effect of a new mutation found in exon 17 of the myophosphorylase (PYGM) gene as a cause of McArdle disease (also known as type 5 glycogenosis). Patients A Spanish patient with McArdle disease was screened for 3 common mutations in the PYGM gene (R49X, W797R, and G204S), as previously described. The patient was heterozygous for R49X. To find other mutations, the coding sequence of the entire PYGM gene was sequenced. The carrier status of his relatives was also studied. RESULTS: A novel rare mutation was found in codon 691 of exon 17. This is an insertion/deletion (indel) and consists simultaneously of a deletion of 2 bases and an insertion of 3 bases (691delCC/insAAA). A restriction analysis was designed to simplify the detection method. CONCLUSIONS: The 691delCC/insAAA is the third indel described in the PYGM gene. Indels represent 0.95% of the total reported mutations in the Human Gene Mutation Database. The molecular origin of this mutation is not fully understood. These findings point again to the allelic heterogeneity of McArdle disease.

Adult↗

PubMed1999

Active sites in complement components C5 and C3 identified by proximity to indels in the C3/4/5 protein family.

We recently suggested that sites of length polymorphisms in protein families (indels) might serve as useful guides for locating protein:protein interaction sites. This report describes additional site-specific mutagenesis and synthetic peptide inhibition studies aimed at testing this idea for the paralogous complement C3, C4, and C5 proteins. A series of C5 mutants was constructed by altering the C5 sequence at each of the 27 indels in this protein family. Mutants were expressed in COS cells and were assayed for hemolytic activity and protease sensitivity. Mutants at five indels showed relatively normal expression but substantially reduced sp. act., indicating that the mutations damaged sites important for C5 function. Twenty-three synthetic peptides with C5 sequences and 10 with C3 sequences were also tested for the ability to inhibit C hemolytic activity. Three of the C5 peptides and one of the C3 peptides showed 50% inhibition of both C hemolytic and bactericidal activities at a concentration of 100 microM. In several cases both the mutational and peptide methods implicated the same indel site. Overall, the results suggest that regions important for function of both C3 and C5 lie proximal to residues 150-200 and 1600-1620 in the precursor sequences. Additional sites potentially important for C5 function are near residue 500 in the beta-chain and at two or three sites between the N-terminus of the alpha'-chain and the C5d fragment. One of the latter sites, near residue 865, appears to be important for proteolytic activation of C5.

Amino Acid Sequence↗

PubMed2019

Discovering human transcription factor physical interactions with genetic variants, novel DNA motifs, and repetitive elements using enhanced yeast one-hybrid assays.

Identifying transcription factor (TF) binding to noncoding variants, uncharacterized DNA motifs, and repetitive genomic elements has been technically and computationally challenging. Current experimental methods, such as chromatin immunoprecipitation, generally test one TF at a time, and computational motif algorithms often lead to false-positive and -negative predictions. To address these limitations, we developed an experimental approach based on enhanced yeast one-hybrid assays. The first variation of this approach interrogates the binding of >1000 human TFs to repetitive DNA elements, while the second evaluates TF binding to single nucleotide variants, short insertions and deletions (indels), and novel DNA motifs. Using this approach, we detected the binding of 75 TFs, including several nuclear hormone receptors and ETS factors, to the highly repetitive Alu elements. Further, we identified cancer-associated changes in TF binding, including gain of interactions involving ETS TFs and loss of interactions involving KLF TFs to different mutations in the TERT promoter, and gain of a MYB interaction with an 18-bp indel in the TAL1 superenhancer. Additionally, we identified TFs that bind to three uncharacterized DNA motifs identified in DNase footprinting assays. We anticipate that these enhanced yeast one-hybrid approaches will expand our capabilities to study genetic variation and undercharacterized genomic regions.

Algorithms↗

PubMed2005

Mutational decay and age of chloroplast and mitochondrial genomes transferred recently to angiosperm nuclear chromosomes.

Transfers of organelle DNA to the nucleus established several thousand functional genes in eukaryotic chromosomes over evolutionary time. Recent transfers have also contributed nonfunctional plastid (pt)- and mitochondrion (mt)-derived DNA (termed nupts and numts, respectively) to plant nuclear genomes. The two largest transferred organelle genome copies are 131-kb nuptDNA in rice (Oryza sativa) and 262-kb numtDNA in Arabidopsis (Arabidopsis thaliana). These transferred copies were compared in detail with their bona fide organelle counterparts, to which they are 99.77% and 99.91% identical, respectively. No evidence for purifying selection was found in either nuclear integrant, indicating that they are nonfunctional. Mutations attributable to 5-methylcytosine hypermutation have occurred at a 6- to 10-fold higher rate than other point mutations in Arabidopsis numtDNA and rice nuptDNA, respectively, revealing this as a major mechanism of mutational decay for these transferred organelle sequences. Short indels occurred preferentially within homopolymeric stretches but were less frequent than point mutations. The 131-kb nuptDNA is absent in the O. sativa subsp. indica or Oryza rufipogon nuclear genome, suggesting that it was transferred within the O. sativa subsp. japonica lineage and, as revealed by sequence comparisons, after its divergence from the indica chloroplast lineage. The time of the transfer for the rice nupt was estimated as 148,000 (74,000--296,000) years ago and that for the Arabidopsis numtDNA as 88,000 (44,000--176,000) years ago. The results reveal transfer and integration of entire organelle genomes into the nucleus as an ongoing evolutionary process and uncover mutational mechanisms affecting organelle genomes recently transferred into a new mutational environment.

Arabidopsis↗

PubMed2005

InSNP: a tool for automated detection and visualization of SNPs and InDels.

Availability of high quality SNP data is a rate-limiting factor in understanding the impact of genetic variability on gene function and phenotype. Although global projects like HAPMAP generate large numbers of SNPs in an even spacing throughout the human genome, many variation studies have a more focused approach: in the follow-up of positional association findings, candidate gene studies, and functional genomics experiments, knowledge of all variations in a limited amount of sequence (e.g., a gene) is needed. This leads to a large number of resequencing experiments, for which there is a surprising lack of analysis software. We have thus developed specialized software (InSNP) for targeted mutation detection and compared its performance to Polyphred and Mutation Surveyor using 28 amplicons. Out of a total of 579 (InSNP), 644 (Polyphred), and 526 (Mutation Surveyor) SNP predictions, 39 SNPs were confirmed by human expert inspection, with five SNPs missed by Polyphred and one missed by InSNP using the default settings. For InDel detection, out of 70 (InSNP), 28 (Polyphred), and 693 (Mutation Surveyor) InDel predictions, two InDels were confirmed by human expert inspection, with one InDel missed by Polyphred. InSNP provides a user-friendly interface with better functionality for mutation detection than general-purpose sequence handling software. It provides similar SNP detection sensitivity and specificity as the public domain and commercial alternatives in the investigated dataset. We hope that InSNP lowers the barriers to the use of automated mutation detection software and aids in the improvement of the efficiency of such experiments. The Windows installer (setup) program and sample datasets are available at www.mucosa.de/insnp/.

Algorithms↗

PubMed2004

Insertion-deletion biases and the evolution of genome size.

Numerous theories have been proposed to account for the pronounced differences in the quantity of non-coding DNA among eukaryotic genomes, but the current repertoire remains incomplete because the only explicit mechanisms it provides involve DNA gain. It has been proposed more recently that biases in spontaneous insertions and deletions (indels) can lead to genome shrinkage by mutational mechanisms alone. The present article provides the first detailed critical discussion of this approach, and covers three different ideas related to it: (1) the general notion of DNA loss by deletion bias, (2) the "DNA loss hypothesis" which supposes that variation in genome size can be attributed to differences in DNA loss rate, and (3) the "mutational equilibrium model" which attempts to describe the long-term evolution of genome size. The mutational equilibrium model is found to be problematic, and it is noted that DNA loss by small indels is too slow in real time to determine variation in genome size above a relatively low threshold. Some alternative explanations for the observed patterns are provided, and the critique also identifies some potential problems with the current dataset. These include a failure to cite a more detailed (and somewhat contradictory) mammalian dataset, a questionable use of arithmetic means with highly skewed data, and important discrepancies among the particular DNA sequences so far analyzed. Overall, evolutionary reductions in genome size are considered important, but the specific mechanism relating to small deletion bias is far too weak to be accepted as a primary determinant of genome size variation in general.

Animals↗

PubMed2026

Mutation accumulation in a hybrid parthenogenetic vertebrate.

Asexual lineages are thought to experience elevated extinction rates compared with sexual species, yet direct evidence for the underlying genetic causes remains scarce. Muller's ratchet predicts that the absence of recombination in asexual organisms facilitates the accumulation of deleterious mutations, thereby reducing long-term fitness. Here, we test this hypothesis in the hybrid-origin, parthenogenetic whiptail lizard Aspidoscelis tesselatus by integrating short-read RNAseq and long-read IsoSeq data from both the asexual lineage and its parental sexual species. We reconstructed phased transcripts for A. tesselatus to quantify mutation accumulation relative to the parental sexual species. Comparative analyses revealed elevated ω ratios in both parental genomic complements (subgenomes) of the parthenogenetic lineage, consistent with accelerated accumulation of nonsynonymous mutations. Structural variant analyses identified multiple indels in expressed transcripts predicted to disrupt protein domains. Functional annotation indicated that genes affected by both single-nucleotide variants and indels were enriched for roles in chromatin organization, apoptosis regulation, and transcriptional control. While both parental subgenomes showed similar evolutionary patterns, the maternal complement exhibited more structural and missense mutations than the paternal complement. Together, these results provide evidence that mutations accumulate in asexual A. tesselatus in genes involved in core cellular functions, supporting theoretical predictions that Muller's ratchet contributes to mutation accumulation in asexual lineages.

Animals↗

PubMed2002

Genomic structure and homoeologous relationship of the two alpha-subunit genes of a heterotrimeric GTP-binding protein in tobacco.

A heterotrimeric GTP-binding protein (G protein) plays a number of important roles in the signal-transduction pathways of eukaryotic cells. The allotetraploid tobacco genome has two alpha-subunit genes, NtGA1 and NtGA2, of the heterotrimeric G protein. In this study, we determined the nucleotide sequences and the exon-intron structures of the NtGA loci in tobacco and its ancestral diploid species. The genomic sequences of the NtGA loci were interrupted by 13 introns. The sizes of most exons (12 of 14) were completely conserved among the NtGA genes and the Arabidopsis alpha-subunit gene (GPA1), but most introns (11 of 13) in the NtGA genes were longer than those in GPA1. In comparison with the genomic sequences of the NtGA orthologues of ancestral Nicotiana sylvestris and Nicotiana tomentosiformis, the tobacco NtGA1 and NtGA2 were concluded to be homoeologous and assigned to the S and T genomes, respectively. More than 300 mutations including insertions-deletions (indels) and nucleotide substitutions were found in the intron regions between the NtGA1 and NtGA2 loci, whereas the exon sequences were highly conserved among these and GPA1. The structural comparison revealed larger divergence at the NtGA2 locus than at NtGA1.

Blotting, Southern↗

PubMedDate not supplied

Comparing tandem repeats with duplications and excisions of variable degree.

Traditional sequence comparison by alignment employs a mutation model comprised of two events, substitutions and indels (insertions or deletions) of single positions. However, modern genetic analysis knows a variety of more complex mutation events (e.g., duplications, excisions, and rearrangements), especially regarding DNA. With ever more DNA sequence data becoming available, the need to accurately compare sequences which have clearly undergone more complicated types of mutational processes is becoming critical. Herein we introduce a new method for pairwise alignment and comparison of sequences with respect to the special evolution of tandem repeats: substitutions and indels of single positions and, additionally, duplications and excisions of variable degree (i.e., of one or more repeat copies simultaneously) are taken into account. To evaluate our method, we apply it to the spa VNTR (variable number of tandem repeats) cluster of Staphylococcus aureus, a bacterium of high medical importance.

Algorithms↗

PubMed2004

A probabilistic model for the evolution of RNA structure.

BACKGROUND: For the purposes of finding and aligning noncoding RNA gene- and cis-regulatory elements in multiple-genome datasets, it is useful to be able to derive multi-sequence stochastic grammars (and hence multiple alignment algorithms) systematically, starting from hypotheses about the various kinds of random mutation event and their rates. RESULTS: Here, we consider a highly simplified evolutionary model for RNA, called "The TKF91 Structure Tree" (following Thorne, Kishino and Felsenstein's 1991 model of sequence evolution with indels), which we have implemented for pairwise alignment as proof of principle for such an approach. The model, its strengths and its weaknesses are discussed with reference to four examples of functional ncRNA sequences: a riboswitch (guanine), a zipcode (nanos), a splicing factor (U4) and a ribozyme (RNase P). As shown by our visualisations of posterior probability matrices, the selected examples illustrate three different signatures of natural selection that are highly characteristic of ncRNA: (i) co-ordinated basepair substitutions, (ii) co-ordinated basepair indels and (iii) whole-stem indels. CONCLUSIONS: Although all three types of mutation "event" are built into our model, events of type (i) and (ii) are found to be better modeled than events of type (iii). Nevertheless, we hypothesise from the model's performance on pairwise alignments that it would form an adequate basis for a prototype multiple alignment and genefinding tool.

Evolution, Molecular↗

PubMed2026

Targeted multiplex gene knockouts in Lemna minor using CRISPR/Cas9.

Lemna minor (commonly known as duckweed) is a fast-growing aquatic plant recognized as a promising green bioreactor for recombinant protein production. Its rapid proliferation, high protein yield, environmental adaptability, and edibility make it highly attractive for biotechnological applications. It is essential to develop and expand genetic tools tailored to this species to maximize these advantages and further unlock its biotechnological potential. A key strategy for achieving this goal is the implementation of advanced genome editing technologies, such as the CRISPR/Cas9 system. Although multiplex CRISPR/Cas9 gene editing has previously been successfully applied in Lemna aequinoctialis, the capability of the endogenous plant tRNA processing system for multiplex editing in L. minor using the polycistronic tRNA-sgRNA (PTG)/Cas9 system has not yet been explored. In this study, a PTG construct was engineered to include four sgRNAs designed to simultaneously target two plant-specific glycosyltransferase genes: α-1,3-fucosyltransferase (FucT) and β-1,2-xylosyltransferase (XylT). As anticipated, the PTG-Cas9 system successfully induced frameshift mutations, characterized by insertions and deletions (indels), in regenerated L. minor plants derived from transformed calli. Validation via PCR and RT-PCR analysis, followed by sequencing of the target loci, confirmed the presence of indels at the target sites. Furthermore, western blot analyses utilizing antibodies specific to XylT and FucT in two homozygous lines (lines 44 and 217) revealed truncated XylT proteins in both lines. Moreover, an in-frame FucT protein was detected in line 217, whereas FucT expression was absent in line 44. This study marked the first successful demonstration of PTG-Cas9 system for multiplex genome editing in L. minor, paving the way for advanced genetic engineering in this species.

CRISPR-Cas Systems↗

PubMed2005

A phylogeny of cycads (Cycadales) inferred from chloroplast matK gene, trnK intron, and nuclear rDNA ITS region.

Phylogenetic relationships among the three families and 12 living genera of cycads were reconstructed by distance and parsimony criteria using three markers: the chloroplast matK gene, the chloroplast trnK intron and the nuclear ITS/5.8S rDNA sequence. All datasets indicate that Cycadaceae (including only the genus Cycas) is remotely related to other cycads, in which Dioon was resolved as the basal-most clade, followed by Bowenia and a clade containing the remaining nine genera. Encephalartos and Lepidozamia are closer to each other than to Macrozamia. The African genus Stangeria is embedded within the New World subfamily Zamiodeae. Therefore, Bowenia is an unlikely sister to Stangeria, contrary to the view that they form the Stangeriaceae. The generic status of Dyerocycas and Chigua is unsupportable as they are paraphyletic with Cycas and the Zamia, respectively. Nonsense mutations in the matK gene and indels in the other two datasets lend evidence to reinforce the above conclusions. According to the phylogenies, the past geography of the genera of cycads and the evolution of character states are hypothesized and discussed. Within the suborder Zamiieae, Stangeria, and the tribe Zamieae evolved significantly faster than other genera. The matK gene and ITS/5.8S region contain more useful information than the trnK intron in addressing phylogeny. Redelimitations of Zamiaceae, Stangeriaceae, subfamily Encephalartoideae and subtribe Macrozamiineae are necessary.

Chloroplasts↗

PubMed2006

Heterotachy in mammalian promoter evolution.

We have surveyed the evolutionary trends of mammalian promoters and upstream sequences, utilising large sets of experimentally supported transcription start sites (TSSs). With 30,969 well-defined TSSs from mouse and 26,341 from human, there are sufficient numbers to draw statistically meaningful conclusions and to consider differences between promoter types. Unlike previous smaller studies, we have considered the effects of insertions, deletions, and transposable elements as well as nucleotide substitutions. The rate of promoter evolution relative to that of control sequences has not been consistent between lineages nor within lineages over time. The most pronounced manifestation of this heterotachy is the increased rate of evolution in primate promoters. This increase is seen across different classes of mutation, including substitutions and micro-indel events. We investigated the relationship between promoter and coding sequence selective constraint and suggest that they are generally uncorrelated. This analysis also identified a small number of mouse promoters associated with the immune response that are under positive selection in rodents. We demonstrate significant differences in divergence between functional promoter categories and identify a category of promoters, not associated with conventional protein-coding genes, that has the highest rates of divergence across mammals. We find that evolutionary rates vary both on a fine scale within mammalian promoters and also between different functional classes of promoters. The discovery of heterotachy in promoter evolution, in particular the accelerated evolution of primate promoters, has important implications for our understanding of human evolution and for strategies to detect primate-specific regulatory elements.

Animals↗

PubMed2005

Fine-mapping milk production quantitative trait loci on BTA6: analysis of the bovine osteopontin gene.

Bovine chromosome six (BTA6) harbors up to six quantitative trait loci (QTL) influencing the milk production of dairy cattle. In stark contrast to human, there is long-range linkage disequilibrium in dairy cattle, which has previously made it difficult to identify the mutations underlying these QTL. Using 38 microsatellite markers in a pedigree of 3,147 Holstein bulls, we fine mapped regions of BTA6 that had previously been shown to harbor QTL. Next, we sequenced a 12.3-kb region harboring Osteopontin, a positional candidate for the statistically most significant of the identified QTL. Nine mutations were identified, and only genotypes for the OPN3907 indel were concordant with the QTL genotypes of eight bulls that were established by segregation analysis. Four of these mutations were genotyped, and a joint linkage/linkage disequilibrium mapping analysis was used to demonstrate the existence of only two functionally distinct clusters of haplotypes within the QTL region, which were uniquely defined by OPN3907 alleles. We estimate a probability of 0.40 that no other mutation within this region is concordant with the QTL genotypes of these eight bulls. Finally, we demonstrate that the motif harboring OPN3907, which is upstream of the promoter and within a region known to harbor tissue-specific osteopontin regulatory elements, is moderately conserved among mammals. The motif was not retrieved from database queries and may be a novel regulatory element.

Alleles↗