Dindel: Accurate indel calls from short-read data

Albers, Cornelis A.; Lunter, Gerton; MacArthur, Daniel G.; McVean, Gil; Ouwehand, Willem H.; Durbin, Richard

doi:10.1101/gr.112326.110

Cited by 399 publications

(353 citation statements)

References 30 publications

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“…11 Substitutions were called using the Genome Analysis ToolKit (GATK v.1.0.4487) Unified Genotyper, 11 while small insertions/deletions (indels) were detected using Dindel v1.01. 12 Substations and indels in the coding region of the captured regions were selected for further analysis.…”

Section: Patient Selectionmentioning

confidence: 99%

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

et al. 2013

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Distal hereditary motor neuropathies (dHMNs) are a heterogenous group of genetic disorders with length-dependent degeneration of motor axons. Obtaining a genetic diagnosis in patients with dHMN remains challenging. We performed exome sequencing in a diagnostic setting in 12 patients with a clinical diagnosis of dHMN. Potential disease-causing variants in genes associated with dHMN and other forms of inherited neuropathies/motor neuron diseases were validated using Sequenom. The coverage in the genes studied was 495% with an average coverage of 450 times. In none of the patients a mutations was found in genes previously reported to be associated with dHMN. However, in 2/12 patients a recessive mutation in histidine triad nucleotide binding protein 1 (HINT1, recently discovered as a cause of axonal neuropathy with neuromyotonia) was identified. Our results demonstrate the diagnostic value of exome sequencing for patients with inherited neuropathies. The phenotypic spectrum of recessive mutations in HINT1 includes dHMN. HINT1 should be added to the list of genes to check for in dHMN.

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Section: Patient Selectionmentioning

confidence: 99%

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

et al. 2013

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“…To find small indel mutations occurring during the MA experiment, we ran all gapped read alignments through the program Dindel (Albers et al 2011). As with single-nucleotide mutations, for both inbred lines we looked only at sites having at least five reads in each MA subline.…”

Section: Identifying Small Indelsmentioning

confidence: 99%

Rates and Genomic Consequences of Spontaneous Mutational Events inDrosophila melanogaster

et al. 2013

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Because spontaneous mutation is the source of all genetic diversity, measuring mutation rates can reveal how natural selection drives patterns of variation within and between species. We sequenced eight genomes produced by a mutation-accumulation experiment in Drosophila melanogaster. Our analysis reveals that point mutation and small indel rates vary significantly between the two different genetic backgrounds examined. We also find evidence that 2% of mutational events affect multiple closely spaced nucleotides. Unlike previous similar experiments, we were able to estimate genome-wide rates of large deletions and tandem duplications. These results suggest that, at least in inbred lines like those examined here, mutational pressures may result in net growth rather than contraction of the Drosophila genome. By comparing our mutation rate estimates to polymorphism data, we are able to estimate the fraction of new mutations that are eliminated by purifying selection. These results suggest that 99% of duplications and deletions are deleterious-making them 10 times more likely to be removed by selection than nonsynonymous mutations. Our results illuminate not only the rates of new small-and large-scale mutations, but also the selective forces that they encounter once they arise.B ECAUSE all genetic variation on which natural selection acts originates via spontaneous mutation, the rate at which various types of mutations appear in natural populations has important consequences for the manner in which organisms evolve. Once we determine the rate at which adaptive and deleterious alleles arise, we can understand how natural selection shapes the spectrum of variation within and between species (Lynch et al. 2008). Mutationaccumulation (MA) experiments are the most widely used method for directly measuring spontaneous mutation rates (Halligan and Keightley 2009). In these experiments genetically identical individuals are subdivided into initially homogeneous sublines, and these sublines are maintained over many generations. At each generation a minimum number of individuals are randomly selected to reproduce and propagate the MA subline, thereby limiting the ability of natural selection to purge new deleterious mutations or to favor new adaptive alleles. Because the MA sublines are initially identical (barring any contamination or residual heterozygosity), any genetic differences among lines must arise via mutations occurring during the course of the experiment.Mutation-accumulation experiments were initially used to assess the phenotypic impacts of mutation (e.g., Mukai et al. 1972). More recently, mutation-accumulation has been used to assess the rate of spontaneous mutation on the genome at specific loci (Mukai and Cockerham 1977), selected genomic regions (Haag-Liautard et al. 2007), or, with the advent of next-generation sequencing technology, genome-wide. Mutation accumulation is now used to estimate genome-wide estimates of per-site mutation rates in a variety of eukaryotes, including Saccharomyces cerevis...

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“…We identified short insertions and deletions, using the Dindel algorithm (Albers et al 2011) in all samples together. Briefly, Dindel identifies candidate indels within the read data and then attempts to align them to haplotypes that represent alternative sequences to the reference (detailed protocol in Materials and Methods).…”

Section: Structural Variationmentioning

confidence: 99%

Low-Pass Genome-Wide Sequencing and Variant Inference Using Identity-by-Descent in an Isolated Human Population

Gusev

Shah²,

Kenny

et al. 2012

Genetics

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Whole-genome sequencing in an isolated population with few founders directly ascertains variants from the population bottleneck that may be rare elsewhere. In such populations, shared haplotypes allow imputation of variants in unsequenced samples without resorting to complex statistical methods as in studies of outbred cohorts. We focus on an isolated population cohort from the Pacific Island of Kosrae, Micronesia, where we previously collected SNP array and rich phenotype data for the majority of the population. We report identification of long regions with haplotypes co-inherited between pairs of individuals and methodology to leverage such shared genetic content for imputation. Our estimates show that sequencing as few as 40 personal genomes allows for inference in up to 60% of the 3000-person cohort at the average locus. We ascertained a pilot data set of whole-genome sequences from seven Kosraean individuals, with average 5· coverage. This assay identified 5,735,306 unique sites of which 1,212,831 were previously unknown. Additionally, these variants are unusually enriched for alleles that are rare in other populations when compared to geographic neighbors (published Korean genome SJK). We used the presence of shared haplotypes between the seven Kosraen individuals to estimate expected imputation accuracy of known and novel homozygous variants at 99.6% and 97.3%, respectively. This study presents whole-genome analysis of a homogenous isolate population with emphasis on optimal rare variant inference.

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Dindel: Accurate indel calls from short-read data

Cited by 399 publications

References 30 publications

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

Rates and Genomic Consequences of Spontaneous Mutational Events inDrosophila melanogaster

Low-Pass Genome-Wide Sequencing and Variant Inference Using Identity-by-Descent in an Isolated Human Population

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