PacBio sequencing detects genome‐wide ultra‐low‐frequency substitution mutations resulting from exposure to chemical mutagens

2021 ◽  
Vol 62 (8) ◽  
pp. 438-445
Author(s):  
Javier R. Revollo ◽  
Jaime A. Miranda ◽  
Vasily N. Dobrovolsky
Keyword(s):  
Low Frequency ◽  
Pacbio Sequencing ◽  
Chemical Mutagens ◽  
Genome Wide ◽  
Substitution Mutations

scholarly journals Genome-wide Association of Copy-Number Variation Reveals an Association between Short Stature and the Presence of Low-Frequency Genomic Deletions

2011 ◽  
Vol 89 (6) ◽  
pp. 751-759 ◽  
Author(s):  
Andrew Dauber ◽  
Yongguo Yu ◽  
Michael C. Turchin ◽  
Charleston W. Chiang ◽  
Yan A. Meng ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Short Stature ◽  
Copy Number ◽  
Low Frequency ◽  
Genome Wide Association ◽  
Genomic Deletions ◽  
Genome Wide ◽  
Number Variation

scholarly journals Detection of genome-wide low-frequency mutations with Paired-End and Complementary Consensus Sequencing (PECC-Seq) revealed end-repair derived artifacts as residual errors

2019 ◽  
Author(s):  
Xinyue You ◽  
Suresh Thiruppathi ◽  
Weiying Liu ◽  
Yiyi Cao ◽  
Mikihiko Naito ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Low Frequency ◽  
Repair Process ◽  
Sequencing Error ◽  
Base Substitution ◽  
Next Generation ◽  
Background Error ◽  
Technical Errors ◽  
Genome Wide ◽  
Generation Sequencing

ABSTRACTTo improve the accuracy and the cost-efficiency of next-generation sequencing in ultralow-frequency mutation detection, we developed the Paired-End and Complementary Consensus Sequencing (PECC-Seq), a PCR-free duplex consensus sequencing approach. PECC-Seq employed shear points as endogenous barcodes to identify consensus sequences from the overlap in the shortened, complementary DNA strands-derived paired-end reads for sequencing error correction. With the high accuracy of PECC-Seq, we identified the characteristic base substitution errors introduced by the end-repair process of mechanical fragmentation-based library preparations, which were prominent at the terminal 6 bp of the library fragments in the 5’-NpCpA-3’ or 5’-NpCpT-3’ trinucleotide context. As demonstrated at the human genome scale (TK6 cells), after removing these potential end-repair artifacts from the terminal 6 bp, PECC-Seq could reduce the sequencing error frequency to mid-10−7 with a relatively low sequencing depth. For TA base pairs, the background error rate could be suppressed to mid-10−8. In mutagen-treated TK6, slight increases in mutagen treatment-related mutant frequencies could be detected, indicating the potential of PECC-Seq in detecting genome-wide ultra-rare mutations. In addition, our finding on the patterns of end-repair artifacts may provide new insights in further reducing technical errors not only for PECC-Seq, but also for other next-generation sequencing techniques.

scholarly journals Common and Rare Variants in Genes Associated with von Willebrand Factor Level Variation: No Accumulation of Rare Variants in Swedish von Willebrand Disease Patients

TH Open ◽  
2020 ◽  
Vol 04 (04) ◽  
pp. e322-e331
Author(s):  
Eric Manderstedt ◽  
Christina Lind-Halldén ◽  
Stefan Lethagen ◽  
Christer Halldén
Keyword(s):  
Von Willebrand Factor ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Von Willebrand Disease ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
The Common ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractGenome-wide association studies (GWASs) have identified genes that affect plasma von Willebrand factor (VWF) levels. ABO showed a strong effect, whereas smaller effects were seen for VWF, STXBP5, STAB2, SCARA5, STX2, TC2N, and CLEC4M. This study screened comprehensively for both common and rare variants in these eight genes by resequencing their coding sequences in 104 Swedish von Willebrand disease (VWD) patients. The common variants previously associated with the VWF level were all accumulated in the VWD patients compared to three control populations. The strongest effect was detected for blood group O coded for by the ABO gene (71 vs. 38% of genotypes). The other seven VWF level associated alleles were enriched in the VWD population compared to control populations, but the differences were small and not significant. The sequencing detected a total of 146 variants in the eight genes. Excluding 70 variants in VWF, 76 variants remained. Of the 76 variants, 54 had allele frequencies > 0.5% and have therefore been investigated for their association with the VWF level in previous GWAS. The remaining 22 variants with frequencies < 0.5% are less likely to have been evaluated previously. PolyPhen2 classified 3 out of the 22 variants as probably or possibly damaging (two in STAB2 and one in STX2); the others were either synonymous or benign. No accumulation of low frequency (0.05–0.5%) or rare variants (<0.05%) in the VWD population compared to the gnomAD (Genome Aggregation Database) population was detected. Thus, rare variants in these genes do not contribute to the low VWF levels observed in VWD patients.

scholarly journals Screening Low-Frequency SNPS From Genome-Wide Association Study Reveals a New Risk Allele for Progression to AIDS

2011 ◽  
Vol 56 (3) ◽  
pp. 279-284 ◽  
Author(s):  
Sigrid Le Clerc ◽  
Cédric Coulonges ◽  
Olivier Delaneau ◽  
Danielle Van Manen ◽  
Joshua T Herbeck ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Low Frequency ◽  
Genome Wide Association ◽  
Genome Wide

scholarly journals The cause of on-target point mutations generated by CRISPR-Cas9 treatment in the yeast Xanthophyllomyces dendrorhous

2021 ◽  
Author(s):  
Jixuan Hong ◽  
Ziyue Meng ◽  
Zixi Zhang ◽  
Hang Su ◽  
Yuxuan Fan ◽  
...  
Keyword(s):  
Dna Repair ◽  
Dna Polymerases ◽  
Point Mutations ◽  
Low Frequency ◽  
Genomic Rearrangements ◽  
Target Point ◽  
Xanthophyllomyces Dendrorhous ◽  
Nucleotide Substitutions ◽  
Sequence Dependence ◽  
Substitution Mutations

ABSTRACTRecognizing outcomes of DNA repair induced by CRISPR-Cas9 cutting is vital for precise genome editing. Reported DNA repair outcomes after Cas9 cutting include deletions/insertions and low frequency of genomic rearrangements and nucleotide substitutions. Thus far, substitution mutations caused by CRISPR-Cas9 has not attracted much attention. Here, we identified on-target point mutations induced by CRISPR-Cas9 treatment in the yeast Xanthophyllomyces dendrorhous by Sanger and Illumina sequencing. Different from previous studies, our findings suggested that the on-target mutations are not random and they cannot render the gRNA effective. Moreover, these point mutations showed strong sequence dependence that is not consistent with the observations in Hela cells, in which CRISPR-mediated substitutions were considered lacking sequence dependence and conversion preferences. Furthermore, this study demonstrated that the NHEJ components Ku70, Ku80, Mre11, or RAD50, and the overlapping roles of non-essential DNA polymerases were necessary for the emergence of point mutations, increasing the knowledge on CRISPR-Cas9 mediated DNA repair.

scholarly journals Lancet: genome-wide somatic variant calling using localized colored DeBruijn graphs

2017 ◽  
Author(s):  
Giuseppe Narzisi ◽  
André Corvelo ◽  
Kanika Arora ◽  
Ewa A. Bergmann ◽  
Minita Shah ◽  
...  
Keyword(s):  
Low Frequency ◽  
Variant Calling ◽  
Experimental Comparison ◽  
Variant Prioritization ◽  
Somatic Variant ◽  
Indel Detection ◽  
Source Program ◽  
Genome Wide ◽  
Reliable Detection ◽  
Local Assembly

Reliable detection of somatic variations is of critical importance in cancer research. Lancet is an accurate and sensitive somatic variant caller which detects SNVs and indels by jointly analyzing reads from tumor and matched normal samples using colored DeBruijn graphs. Extensive experimental comparison on synthetic and real whole-genome sequencing datasets demonstrates that Lancet has better accuracy, especially for indel detection, than widely used somatic callers, such as MuTect, MuTect2, LoFreq, Strelka, and Strelka2. Lancet features a reliable variant scoring system which is essential for variant prioritization and detects low frequency mutations without sacrificing the sensitivity to call longer insertions and deletions empowered by the local assembly engine. In addition to genome-wide analysis, Lancet allows inspection of somatic variants in graph space, which augments the traditional read alignment visualization to help confirm a variant of interest. Lancet is available as an open-source program at https://github.com/nygenome/lancet.

scholarly journals Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

2018 ◽  
Author(s):  
Anubha Mahajan ◽  
Daniel Taliun ◽  
Matthias Thurner ◽  
Neil R Robertson ◽  
Jason M Torres ◽  
...  
Keyword(s):  
Sample Size ◽  
Fine Mapping ◽  
Low Frequency ◽  
High Density ◽  
Regulatory Sequence ◽  
Polygenic Risk Score ◽  
Risk Alleles ◽  
Genome Wide ◽  
Credible Set ◽  
Size Heterogeneity

We aggregated genome-wide genotyping data from 32 European-descent GWAS (74,124 T2D cases, 824,006 controls) imputed to high-density reference panels of >30,000 sequenced haplotypes. Analysis of ˜27M variants (˜21M with minor allele frequency [MAF]<5%), identified 243 genome-wide significant loci (p<5×10−8; MAF 0.02%-50%; odds ratio [OR] 1.04-8.05), 135 not previously-implicated in T2D-predisposition. Conditional analyses revealed 160 additional distinct association signals (p<10−5) within the identified loci. The combined set of 403 T2D-risk signals includes 56 low-frequency (0.5%≤MAF<5%) and 24 rare (MAF<0.5%) index SNPs at 60 loci, including 14 with estimated allelic OR>2. Forty-one of the signals displayed effect-size heterogeneity between BMI-unadjusted and adjusted analyses. Increased sample size and improved imputation led to substantially more precise localisation of causal variants than previously attained: at 51 signals, the lead variant after fine-mapping accounted for >80% posterior probability of association (PPA) and at 18 of these, PPA exceeded 99%. Integration with islet regulatory annotations enriched for T2D association further reduced median credible set size (from 42 variants to 32) and extended the number of index variants with PPA>80% to 73. Although most signals mapped to regulatory sequence, we identified 18 genes as human validated therapeutic targets through coding variants that are causal for disease. Genome wide chip heritability accounted for 18% of T2D-risk, and individuals in the 2.5% extremes of a polygenic risk score generated from the GWAS data differed >9-fold in risk. Our observations highlight how increases in sample size and variant diversity deliver enhanced discovery and single-variant resolution of causal T2D-risk alleles, and the consequent impact on mechanistic insights and clinical translation.

scholarly journals Genome-wide organellar analyses from the hornwort Leiosporoceros dussii show low frequency of RNA editing

PLoS ONE ◽  
2018 ◽  
Vol 13 (8) ◽  
pp. e0200491 ◽  
Author(s):  
Juan Carlos Villarreal A. ◽  
Monique Turmel ◽  
Maurane Bourgouin-Couture ◽  
Jérôme Laroche ◽  
Noris Salazar Allen ◽  
...  
Keyword(s):  
Rna Editing ◽  
Low Frequency ◽  
Genome Wide

scholarly journals Engines of change: Transposable element mutation rates are high and variable within Daphnia magna

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009827
Author(s):  
Eddie K. H. Ho ◽  
Emily S. Bellis ◽  
Jaclyn Calkins ◽  
Jeffrey R. Adrion ◽  
Leigh C. Latta IV ◽  
...  
Keyword(s):  
Daphnia Magna ◽  
Insertion Site ◽  
Low Frequency ◽  
Interspecific Variation ◽  
Mutation Rates ◽  
Evolutionary Forces ◽  
Genome Wide ◽  
Short And Long Term ◽  
Powerful Mechanism

Transposable elements (TEs) represent a major portion of most eukaryotic genomes, yet little is known about their mutation rates or how their activity is shaped by other evolutionary forces. Here, we compare short- and long-term patterns of genome-wide mutation accumulation (MA) of TEs among 9 genotypes from three populations of Daphnia magna from across a latitudinal gradient. While the overall proportion of the genome comprised of TEs is highly similar among genotypes from Finland, Germany, and Israel, populations are distinguishable based on patterns of insertion site polymorphism. Our direct rate estimates indicate TE movement is highly variable (net rates ranging from -11.98 to 12.79 x 10−5 per copy per generation among genotypes), differing both among populations and TE families. Although gains outnumber losses when selection is minimized, both types of events appear to be highly deleterious based on their low frequency in control lines where propagation is not limited to random, single-progeny descent. With rate estimates 4 orders of magnitude higher than base substitutions, TEs clearly represent a highly mutagenic force in the genome. Quantifying patterns of intra- and interspecific variation in TE mobility with and without selection provides insight into a powerful mechanism generating genetic variation in the genome.

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