Accuracy and efficiency of germline variant calling pipelines for human genome data

Zhao, Sen; Agafonov, Oleg; Azab, Abdulrahman; Stokowy, Tomasz; Hovig, Eivind

doi:10.1101/2020.03.27.011767

Cited by 17 publications

(18 citation statements)

References 35 publications

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“…Variants were called across all samples in a single batch with GATK 3.8 using the -newQual flag to minimize false negative singleton calls. The recall rate for GATK against truth sets is between 93 and 99% for single nucleotide variants and 85 and 98% for small (less than 50 bp) indel events [19]. Genome annotation was performed using SnpEff 4.3 [20] after splitting multi-allelic sites with Vt [21].…”

Section: Genome Sequencingmentioning

confidence: 99%

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

et al. 2022

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Background The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

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Section: Genome Sequencingmentioning

confidence: 99%

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

et al. 2022

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“…In recent decades, the technologies used for detecting germline and somatic mutations have been greatly improved. The F1-scores of germline variant calling have exceeded 0.99 17 . Clonal somatic mutation calling (e.g., cancer) has gained credence on a clinical level, by lowering the limit of detection down to around 1% 24 .…”

Section: Discussionmentioning

confidence: 99%

“…This ambiguity is reflected in the disparate set of approaches applied in recent studies, such as targeting variants with unlikely VAFs for normal zygosity in a single sample 7,8 , searching for shared variants in a pair of samples 9 , and machine-learning algorithms 10,11 . These circumstances urgently demand a rigorous cataloging and assessment of mosaic detection algorithms, as conducted for germline and somatic variants [12][13][14][15][16][17] , but should be in a more sophisticated manner to cover the full extent of scenarios that mosaic variants can represent. Above all, the construction of robust and biologically compatible reference standards is a prerequisite.…”

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confidence: 99%

A robust benchmark for evaluating and improving mosaic variant calling strategies

Kim

Kang

et al. 2022

Preprint

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The rapid advances in sequencing and analysis technologies have enabled the accurate detection of diverse forms of genomic variants, including germline, somatic, and mosaic mutations. However, unlike for the former two mutations, the best practices for mosaic variant calling still remain chaotic due to the technical and conceptual difficulties faced in evaluation. Here, we present our benchmark of nine feasible strategies for mosaic variant detection based on a systematically designed reference standard that mimics mosaic samples, with 390,153 control positive and 35,208,888 negative single-nucleotide variants and insertion–deletion mutations. We identified the condition-dependent strengths and weaknesses of the current strategies, instead of a single winner, regarding variant allele frequencies, variant sharing, and the usage of control samples. Moreover, feature-level investigation directs the way for immediate to prolonged improvements in mosaic variant calling. Our results will guide researchers in selecting suitable calling algorithms and suggest future strategies for developers.

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“…Deduped BAM les were rstly processed by "QualCal" tool to conduct base quality score recalibration, and variants were called by "Haplotyper" tool to provide the matching result of GATK. VQSR was not performed because we don't believe this extra step will improve overall variant calling accuracy [31].…”

Section: Running Dnaseq (Gatk Re-implementation) and Dnascopementioning

confidence: 99%

Accuracy benchmark of the GeneMind GenoLab M sequencing platform for WGS and WES analysis

Fan

Guo

et al. 2022

Preprint

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Background: GenoLab M is a recently developed next-generation sequencing (NGS) platform from GeneMind Biosciences. To establish the performance of GenoLab M, we present the first report to benchmark and compare the WGS and WES sequencing data of the GenoLab M sequencer to NovaSeq 6000 and NextSeq 550 platform in various types of analysis. 30-fold sequencing from Illumina NovaSeq platform and processed by GATK pipeline is currently considered as the golden standard of WGS. Thus this dataset is generated as a benchmark reference in this study.Results: GenoLab M showed an average of 94.62% of Q20 percentage for base quality, while the NovaSeq was slightly higher at 96.97%. However, GenoLab M outperformed NovaSeq or NextSeq at a duplication rate, suggesting more usable data after deduplication. For WGS short variant calling, GenoLab M showed significant accuracy improvement over the same depth dataset from NovaSeq, and reached similar accuracy to NovaSeq 33X dataset with 22x depth. For 100X WES, the F-score and Precision in GenoLab M were higher than NovaSeq or NextSeq, especially for InDel calling.Conclusions: GenoLab M is a promising NGS platform for high-performance WGS and WES applications. For WGS, 22X depth in the GenoLab M sequencing platform offers a cost-effective alternative to the current mainstream 33X depth on Illumina.

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Accuracy and efficiency of germline variant calling pipelines for human genome data

Cited by 17 publications

References 35 publications

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

A robust benchmark for evaluating and improving mosaic variant calling strategies

Accuracy benchmark of the GeneMind GenoLab M sequencing platform for WGS and WES analysis

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