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At least 19 recordsLinked to original sources
PubMed2025

Indel mutation in transcription factor PabHLH2 regulates amygdalin accumulation and kernel bitterness in apricot.

Amygdalin, the phytochemical responsible for the characteristic bitterness of apricot (Prunus armeniaca L.) kernels, also exhibits significant bioactive properties and therapeutic potential. Genetic regulation of amygdalin content is therefore a key objective in apricot breeding programs aimed at quality improvement. In this study, we conducted quantitative trait loci (QTL) mapping to uncover the genetic basis of sweet-bitter differentiation in apricot kernels. We identified a 15-bp insertion/deletion (indel) polymorphism strongly related to kernel bitterness, with marker validation achieving 100% concordance across 601 apricot germplasm accessions. Notably, this polymorphic site is located within the helix-loop-helix (HLH) domain of the basic HLH (bHLH) transcription factor PabHLH2. Protein interaction analyses revealed that the 15-bp deletion variant impaired dimerization capacity, reducing transcriptional activation of downstream targets. Using yeast one-hybrid screening and dual-luciferase reporter assays, we identified PaCYP71AN24 and PaCYP79D16 as direct transcriptional targets of PabHLH2. Functional characterization further indicated that the PabHLH2a variant (harboring the 15-bp insertion) significantly enhanced the promoter activity of these cytochrome P450 genes compared with the deletion variant. Transient overexpression and silencing experiments in apricot kernels further confirmed that the 15-bp insertion positively regulates both PaCYP71AN24/PaCYP79D16 expression and prunasin accumulation, the immediate biosynthetic precursor of amygdalin. Overall, these findings provide mechanistic insights into the allelic variation underlying kernel bitterness and delineate the molecular cascade of amygdalin biosynthesis. The identified molecular markers and functional characterization establish a basis for marker-assisted breeding of low-amygdalin apricot cultivars, supporting the dual-purpose utilization of kernels in food and pharmaceutical industries.

Amygdalin↗
PubMed2006

Mechanism of a genetic glissando: structural biology of indel mutations.

Insertions and deletions of bases in DNA (collectively termed "indels") are both common and biologically relevant, being associated with different human pathologies including cancer and diseases associated with expansions of repeats. Four decades of research have resulted in several hypotheses regarding how indels are generated during DNA synthesis and how they subsequently undergo or escape correction. Recent structural studies of DNA polymerases bound to mutagenic substrates have increased our understanding of how DNA polymerases cope with abnormal substrates. These structures provide insight into the molecular mechanisms underlying indel generation.

DNA↗
PubMed2000

Frameshift mutations in rdxA and metronidazole resistance in North American Helicobacter pylori isolates.

In Helicobacter pylori, the oxygen-insensitive nitroreductase RdxA is likely to activate metronidazole (Mtz) by reduction and formation of cytotoxic intermediates. Mutations in rdxA have been associated with Mtz resistance in H. pylori. In vitro Mtz susceptibilities of 17 randomly selected H. pylori isolates were determined by the agar dilution method. DNA sequence analysis of rdxA alleles of eight susceptible isolates (MIC range: 0.25-1.0 mg/L) and nine resistant isolates (MIC range: 16-256 mg/L) showed that six of nine Mtz-resistant H. pylori isolates contained insertion or deletion mutations ('indel' mutations). One isolate contained a substitution mutation at codon position 148 that resulted in the introduction of a premature stop codon. Creation of stop codons within the rdxA coding sequence by either frameshift or substitution mutations resulted in premature translation termination and expression of putatively truncated RdxA polypeptides.

Anti-Bacterial Agents↗
PubMed2003

Is the rate of insertion and deletion mutation male biased?: Molecular evolutionary analysis of avian and primate sex chromosome sequences.

The rate of mutation for nucleotide substitution is generally higher among males than among females, likely owing to the larger number of DNA replications in spermatogenesis than in oogenesis. For insertion and deletion (indel) mutations, data from a few human genetic disease loci indicate that the two sexes may mutate at similar rates, possibly because such mutations arise in connection with meiotic crossing over. To address origin- and sex-specific rates of indel mutation we have conducted the first large-scale molecular evolutionary analysis of indels in noncoding DNA sequences from sex chromosomes. The rates are similar on the X and Y chromosomes of primates but about twice as high on the avian Z chromosome as on the W chromosome. The fact that indels are not uncommon on the nonrecombining Y and W chromosomes excludes meiotic crossing over as the main cause of indel mutation. On the other hand, the similar rates on X and Y indicate that the number of DNA replications (higher for Y than for X) is also not the main factor. Our observations are therefore consistent with a role of both DNA replication and recombination in the generation of short insertion and deletion mutations. A significant excess of deletion compared to insertion events is observed on the avian W chromosome, consistent with gradual DNA loss on a nonrecombining chromosome.

Animals↗
PubMed1998

Active sites in complement component C3 mapped by mutations at indels.

Engineered mutants of human complement component C3 were used to test the idea that sites of length polymorphisms in protein families (indels) can guide a search for protein:protein interaction sites. Sequence changes were introduced at each of the 27 indels in the C3/4/5 protein family, and mutants at 26 indels were expressed by transiently transfected COS cells. Expressed proteins were assayed 1) for concentration, by ELISA and by autoradiography of radiolabeled protein; 2) for classical pathway hemolytic activity; 3) for susceptibility to proteolytic activation by the alternative pathway and cobra venom factor C3 convertases; and 4) for susceptibility to complement factor I in the presence of factor H. Most of the mutations did not appreciably alter expression or activity relative to wild-type C3, consistent with the idea that most indels occur at the protein surface. Mutations at four indels severely damaged C3 functional activity, but did not affect the stability or structure of the protein, as assessed by their effects on expression by COS cells and on susceptibility to cleavage by C3 convertases and factor I. These indels are therefore near functionally important amino acid residues; they represent good candidates for sites of protein:protein interactions. Mutation of the sequence at a fifth indel altered the equilibrium between the latent and reacted C3 conformations, and mutations at 4 other indels substantially decreased both protein activity and expression. The mutants provided an overview of the structural and functional roles played by different parts of C3.

Amino Acid Sequence↗
PubMed2005

Identification of 32 novel mutations in the factor VIII gene in Indian patients with hemophilia A.

Seventy-five unrelated hemophilia A patients from India were analyzed for factor VIII gene defects. Intron 22 inversion was identified in 22 patients and intron 1 inversion in 2 patients. In the remaining 51 patients without inversions screening the FVIII gene by denaturing high performance liquid chromatography (DHPLC) revealed 42 different mutations in 44 unrelated subjects. These included 14 missense, 7 nonsense, 9 splice site, 8 deletional, 3 insertional mutations and one indel mutation. Of these, 32 were novel gene alterations. The hotspots included intron 22 inversion, CpG and adenine runs.

Binding Sites↗
PubMed2006

Pattern and rate of indel evolution inferred from whole chloroplast intergenic regions in sugarcane, maize and rice.

Microstructural changes such as insertions and deletions (=indels) are a major driving force in the evolution of non-coding DNA sequences. To better understand the mechanisms by which indel mutations arise, as well as the molecular evolution of non-coding regions, the number and pattern of indels and nucleotide substitutions were compared in the whole chloroplast genomes. Comparisons were made for a total of over 38 kb non-coding DNA sequences from 126 intergenic regions in two data sets representing species with different divergence times: sugarcane and maize and Oryza sativa var. indica and japonica. The main findings of this study are: (i) Approximately half of all indels are single nucleotide indels. This observation agrees with previous studies in various organisms. (ii) The distribution and number of indels was different between two data sets, and different patterns were observed for tandem repeat and non-repeat indels. (iii) Distribution pattern of tandem repeat indels showed statistically significant bias towards A/T-rich. (iv) The rate of indel mutation was estimated to be approximately 0.8 +/- 0.04 x 10(-9) per site per year, which was similar to previous estimates in other organisms. (v) The frequencies of nucleotide substitutions and indels were significantly lower in inverted repeat (IR).

Conserved Sequence↗
PubMed2026

Whole-Exome and Whole-Genome Sequencing of Candidate Pharmacogenomic and Schizophrenia-Related Genes in Sudanese Families with Schizophrenia.

BACKGROUND: Schizophrenia is considered a neuro-developmental disorder leading to disastrous lifelong disability of the patients and their families. There is a lack of data regarding pharmacogenomics of schizophrenia in Sudan. This study aimed to identify different genes affecting the treatment outcomes in Sudanese patients with schizophrenia. METHODS: A case-control study was conducted on seven families having more than one member diagnosed with schizophrenia. This was a small exploratory family-based sequencing study involving 18 affected individuals and 8 controls from seven families. Ethical clearance and informed consent were obtained. Demographic data were collected using a standardized data collection sheet. DNA was extracted from blood samples collected from patients and control groups. Then, whole-exome and genome sequencing were performed. Sixty-six genes associated with schizophrenia, treatment, and treatment resistance were selected from the variant calling file. Variants showing single-nucleotide polymorphisms (SNPs) were identified. These variants were then classified based on their impact on the protein-coding sequence into high- and moderate-impact. Moreover, indel mutations were also identified. RESULTS: Twelve variants of seven genes (COMT, FMO1, LPL, CYP2E1, ABCC1, GRM3, CYP2C9) were identified as genes with impact and potential association with schizophrenia (p-value=0.006632). Forty-three genes had a moderate impact, and they showed a potential association with schizophrenia (p-value=0.0004436). Two variants were indel mutations (CYP2D6, DTNBP1) and showed association with schizophrenia (p-value=0.004741). The p-values were generated from different databases. CONCLUSION: This exploratory family-based sequencing study identified several potentially relevant pharmacogenomic and schizophrenia-associated variants in Sudanese families, warranting validation in larger and ethnically diverse cohorts.

antipsychotics↗
PubMed2006

Evolution of the P-type II ATPase gene family in the fungi and presence of structural genomic changes among isolates of Glomus intraradices.

BACKGROUND: The P-type II ATPase gene family encodes proteins with an important role in adaptation of the cell to variation in external K+, Ca2+ and Na2+ concentrations. The presence of P-type II gene subfamilies that are specific for certain kingdoms has been reported but was sometimes contradicted by discovery of previously unknown homologous sequences in newly sequenced genomes. Members of this gene family have been sampled in all of the fungal phyla except the arbuscular mycorrhizal fungi (AMF; phylum Glomeromycota), which are known to play a key-role in terrestrial ecosystems and to be genetically highly variable within populations. Here we used highly degenerate primers on AMF genomic DNA to increase the sampling of fungal P-Type II ATPases and to test previous predictions about their evolution. In parallel, homologous sequences of the P-type II ATPases have been used to determine the nature and amount of polymorphism that is present at these loci among isolates of Glomus intraradices harvested from the same field. RESULTS: In this study, four P-type II ATPase sub-families have been isolated from three AMF species. We show that, contrary to previous predictions, P-type IIC ATPases are present in all basal fungal taxa. Additionally, P-Type IIE ATPases should no longer be considered as exclusive to the Ascomycota and the Basidiomycota, since we also demonstrate their presence in the Zygomycota. Finally, a comparison of homologous sequences encoding P-type IID ATPases showed unexpectedly that indel mutations among coding regions, as well as specific gene duplications occur among AMF individuals within the same field. CONCLUSION: On the basis of these results we suggest that the diversification of P-Type IIC and E ATPases followed the diversification of the extant fungal phyla with independent events of gene gains and losses. Consistent with recent findings on the human genome, but at a much smaller geographic scale, we provided evidence that structural genomic changes, such as exonic indel mutations and gene duplications are less rare than previously thought and that these also occur within fungal populations.

Base Sequence↗
PubMed2002

Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with Marfan syndrome or Marfanoid features leads to the identification of 11 novel and three previously reported mutations.

Mutations in the gene encoding fibrillin-1 (FBN1) cause Marfan syndrome (MFS) and other related connective tissue disorders. In this study we performed SSCP to analyze all 65 exons of the FBN1 gene in 76 patients presenting with classical MFS or related phenotypes. We report 7 missense mutations, 3 splice site alterations, one indel mutation, one nonsense mutation and two mutations causing frameshifts: a 16bp deletion and a single nucleotide insertion. 5 of the missense mutations (Y1101C, C1806Y, T1908I, G1919D, C2251R) occur in calcium-binding Epidermal Growth Factor-like (EGFcb) domains of exons 26, 43, 46 and 55, respectively. One missense mutation (V449I) substitutes a valine residue in the non-calcium-binding epidermal growth factor like domain (EGFncb) of exon 11. One missense mutation (G880S) affects the "hybrid" motif in exon 21 by replacing glycine to serine. The 3 splice site mutations detected are: IVS1-1G>A in intron 1, IVS38-1G>A in intron 38 and IVS46+5G>A in intron 46. C628delinsK was identified in exon 15 leading to the substitution of a conserved cysteine residue. Furthermore two frameshift mutations were found in exon 15 (1904-1919del ) and exon 63 (8025insC) leading to premature termination codons (PTCs) in exon 17 and 64 respectively. Finally we identified a nonsense mutation (R429X) located in the proline rich domain in exon 10 of the FBN1 gene. Y1101C, IVS46+5G>A and R429X have been reported before.

Adolescent↗
PubMed2026

Efficient and precise programmable DNA knock-in without double-strand breaks.

Programmable gene knock-in holds substantial promise for treating genetic diseases and advancing cell therapies. However, achieving precise and efficient kilobase-scale DNA fragment integration remains challenging1,2. Here we report CRISPR kilobase-scale nickase-targeting (KNIT) editing for efficient, precise and programmable kilobase-scale DNA insertion without double-strand DNA cleavage, which is enabled through the coupling of a Cas9 nickase with a DNA donor recruiting system. KNIT editing facilitates programmable integration of DNA fragments from 0.7 kb to more than 10 kb and is effective across genomic loci and cell types. It achieves up to 89% efficiency and markedly reduces unintended insertion-deletion mutation (indels) rates, translocations and off-target editing. The system supports repeated insertion editing and multiloci gene knock-in with minimal translocations. Its enhanced version, KNIT editor 2, further improves efficiency via a single transfection. Moreover, in mutant cells with a pathological mutation, KNIT editing restores normal gene expression by inserting a therapeutic gene into a safe harbour locus or its native locus. Notably, KNIT editing enables non-viral and programmable chimeric antigen receptor T cell (CAR-T cell) engineering without double-strand breaks and with clinically relevant efficiencies. Moreover, the engineered CAR-T cells exhibit effective antitumour activity in vitro and in mouse models. Therefore, by achieving programmable and site-specific kilobase-scale DNA insertions without double-strand breaks while reducing unintended outcomes, KNIT editing provides a versatile platform for advancing personalized medicine.

Animals↗
PubMed2000

Evidence for DNA loss as a determinant of genome size.

Eukaryotic genome sizes range over five orders of magnitude. This variation cannot be explained by differences in organismic complexity (the C value paradox). To test the hypothesis that some variation in genome size can be attributed to differences in the patterns of insertion and deletion (indel) mutations among organisms, this study examines the indel spectrum in Laupala crickets, which have a genome size 11 times larger than that of Drosophila. Consistent with the hypothesis, DNA loss is more than 40 times slower in Laupala than in Drosophila.

Animals↗
PubMed2005

Positive selection for indel substitutions in the rodent sperm protein catsper1.

Catsper1 is a voltage-gated calcium channel located in the plasma membrane of the sperm tail and is necessary for sperm motility and fertility in mice. We here examine the evolutionary pattern of Catsper1 from nine species of the rodent subfamily Murinae of family Muridae. We show that the rate of insertion/deletion (indel) substitutions in exon 1 of the gene is 4-15 times that in introns or neutral genomic regions, suggesting the presence of strong positive selection that promotes fixations of indel mutations in exon 1. The number of indel polymorphisms within species appears higher than expected from interspecific comparisons, although there are too little data to provide a statistically significant conclusion. These results, together with an earlier report in primates, indicate that positive selection promoting length variation in Catsper1 may be widespread in mammals. A structural model of Catsper1 suggested the importance of the exon 1-encoded region in regulating channel inactivation, which may affect sperm mobility and sperm competition. Our findings provide a necessary foundation for future experimental investigations of Catsper1's function in sperm physiology and role in sperm competition using rodent models.

Amino Acid Sequence↗
PubMed2025

The mutation landscape of Daphnia obtusa reveals evolutionary forces shaping genome stability.

Spontaneous mutations are the primary source of genetic variation and play a central role in shaping evolutionary processes. To investigate mutational dynamics in Daphnia obtusa, we generated a chromosome-level genome assembly spanning 129.4 Mb across 12 chromosomes, encompassing 15,321 predicted protein-coding genes. Leveraging whole-genome sequencing of eight mutation accumulation (MA) lines propagated for an average of 482 generations (spanning over 20 years), we estimated a spontaneous single nucleotide mutation (SNM) rate of 2.23 × 10-9 and an indel mutation rate of 2.75 × 10-10 per site per generation. The SNM spectrum was strongly biased toward C:G > T:A transitions. Comparative analyses with natural population data revealed that exonic mutations observed in the MA lines were significantly less likely to be present in standing variation than intronic or intergenic mutations, suggesting that purifying selection in natural populations acts to remove deleterious alleles. We also identified 48 de novo loss-of-heterozygosity (LOH) events, comprising 8 heterozygous deletions and 40 gene conversion events. The genome-wide gene conversion rate was estimated at 2.62 × 10-5 per heterozygous site per generation. These findings provide a comprehensive view of the mutation spectrum, selective pressures, and mechanisms underlying genome stability in D. obtusa.

Daphnia obtusa↗
PubMed2005

The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe.

We investigated the molecular basis of hereditary fructose intolerance (HFI) in 80 patients from 72 families by means of a PCR-based mutation screening strategy, consisting of heteroduplex analysis, restriction enzyme digest, DNA single strand electrophoresis, and direct sequencing. For a subset of patients mutation screening with DHPLC was established which turned out to be as fast and as sensitive as the more conventional methods. Fifteen different mutations of the aldolase B (ALDOB) gene were identified in HFI patients. As in smaller previous studies, p.A150P (65%), p.A175D (11%) and p.N335K (8%) were the most common mutated alleles, followed by c.360_363delCAAA, p.R60X, p.Y204X, and c.865delC. Eight novel mutations were identified in eight families with HFI: a small indel mutation (c.1044_1049delTTCTGGinsACACT), two small deletions (c.345_372del28; c.841_842delAC), two splice site mutations (c.113-1G>A, c.799+2T>A), one nonsense mutation (c.612T>G (p.Y204X)), and two missense mutations (c.532T>C (p.C178R), c.851T>C (p.L284P)). By mutation screening for the three most common ALDOB mutations by DHPLC in 2,000 randomly selected newborns we detected 21 heterozygotes. Based on these data and after correction for less common and private ALDOB mutations, HFI prevalence in central Europe is estimated to be 1:26,100 (95% confidence interval 1: 12,600-79,000).

Chromatography, High Pressure Liquid↗
PubMed2004

Complete chloroplast genome sequences from Korean ginseng (Panax schinseng Nees) and comparative analysis of sequence evolution among 17 vascular plants.

The nucleotide sequence of Korean ginseng (Panax schinseng Nees) chloroplast genome has been completed (AY582139). The circular double-stranded DNA, which consists of 156,318 bp, contains a pair of inverted repeat regions (IRa and IRb) with 26,071 bp each, which are separated by small and large single copy regions of 86,106 bp and 18,070 bp, respectively. The inverted repeat region is further extended into a large single copy region which includes the 5' parts of the rpsl9 gene. Four short inversions associated with short palindromic sequences that form stem-loop structures were also observed in the chloroplast genome of P. schinseng compared to that of Nicotiana tabacum. The genome content and the relative positions of 114 genes (75 peptide-encoding genes, 30 tRNA genes, 4 rRNA genes, and 5 conserved open reading frames [ycfs]), however, are identical with the chloroplast DNA of N. tabacum. Sixteen genes contain one intron while two genes have two introns. Of these introns, only one (trnL-UAA) belongs to the self-splicing group I; all remaining introns have the characteristics of six domains belonging to group II. Eighteen simple sequence repeats have been identified from the chloroplast genome of Korean ginseng. Several of these SSR loci show infra-specific variations. A detailed comparison of 17 known completed chloroplast genomes from the vascular plants allowed the identification of evolutionary modes of coding segments and intron sequences, as well as the evaluation of the phylogenetic utilities of chloroplast genes. Furthermore, through the detailed comparisons of several chloroplast genomes, evolutionary hotspots predominated by the inversion end points, indel mutation events, and high frequencies of base substitutions were identified. Large-sized indels were often associated with direct repeats at the end of the sequences facilitating intra-molecular recombination.

Base Sequence↗
PubMed2005

Molecular and functional analyses of poi-2, a novel gene highly expressed in sexual and perithecial tissues of Neurospora crassa.

The poi-2 gene is highly and specifically expressed in starved and sexual tissues of the filamentous fungus Neurospora crassa. It encodes a 27-kDa protein, as shown by in vitro transcription and translation. The POI2 protein contains a hydrophobic signal sequence at the amino terminus followed by novel 16 tandem repeats of 13 to 14 amino acid residues; all repeats are separated by Kex2 processing sites. Repeat-induced point mutation (RIP)-mediated gene disruption was used to generate poi-2 mutants, and the mutated sequences showed either one of two distinct patterns: typical RIPs (GC-to-AT transitions) or insertion-deletion (indel) mutations. Although the poi-2 strains contained numerous mutations, all retained intact open reading frames (ORFs) of various lengths. They showed greatly reduced vegetative growth and protoperithecial formation and low viability of their sexual progeny. All poi-2 mutants had similar defects in male fertility and the mating response, but the nature of female fertility defects varied and corresponded to the length of the residual poi-2 ORF. Mutants with ORFs of approximately normal length occasionally completed sexual development and produced viable ascospores, while a mutant with a severely truncated ORF was female sterile due to its inability to form protoperithecia. Thus, poi-2 is essential for differentiation of female reproductive structures and perithecial development as well as for normal vegetative growth. The POI2 protein is involved in the mating response, probably as a component in the pathway rather than as a pheromone.

Amino Acid Sequence↗