ArticleGenome medicine2016
Alternate-locus aware variant calling in whole genome sequencing.
Article in Genome medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- The human genome harbours widespread exclusive yin yang haplotypes.European journal of human genetics : EJHG · 2024Article
- Short-read aligner performance in germline variant identification.Bioinformatics (Oxford, England) · 2023Review
- A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration.Cell genomics · 2023Article
- Comparison of calling pipelines for whole genome sequencing: an empirical study demonstrating the importance of mapping and alignment.Scientific reports · 2022Article
- Transposable element regulation and expression in cancer.The FEBS journal · 2022Review
- Combining callers improves the detection of copy number variants from whole-genome sequencing.European journal of human genetics : EJHG · 2022Article
- The Need for a Human Pangenome Reference Sequence.Annual review of genomics and human genetics · 2021Review
- Exome variant discrepancies due to reference-genome differences.American journal of human genetics · 2021Article
- Genetic toxicity testing using human in vitro organotypic airway cultures: Assessing DNA damage with the CometChip and mutagenesis by Duplex Sequencing.Environmental and molecular mutagenesis · 2021Article
- Germline variant inGenetics research · 2020Article
- Genomic data analysis workflows for tumors from patient-derived xenografts (PDXs): challenges and guidelines.BMC medical genomics · 2019Article
- Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study.The Lancet. Respiratory medicine · 2018Article
- Settling the score: variant prioritization and Mendelian disease.Nature reviews. Genetics · 2017Review
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe last two human genome assemblies have extended the previous linear golden-path paradigm of the human genome to a graph-like model to better represent regions with a high degree of structural variability. The new model offers opportunities to improve the technical validity of variant calling in whole-genome sequencing (WGS).
methodsWe developed an algorithm that analyzes the patterns of variant calls in the 178 structurally variable regions of the GRCh38 genome assembly, and infers whether a given sample is most likely to contain sequences from the primary assembly, an alternate locus, or their heterozygous combination at each of these 178 regions. We investigate 121 in-house WGS datasets that have been aligned to the GRCh37 and GRCh38 assemblies.
resultsWe show that stretches of sequences that are largely but not entirely identical between the primary assembly and an alternate locus can result in multiple variant calls against regions of the primary assembly. In WGS analysis, this results in characteristic and recognizable patterns of variant calls at positions that we term alignable scaffold-discrepant positions (ASDPs). In 121 in-house genomes, on average 51.8±3.8 of the 178 regions were found to correspond best to an alternate locus rather than the primary assembly sequence, and filtering these genomes with our algorithm led to the identification of 7863 variant calls per genome that colocalized with ASDPs. Additionally, we found that 437 of 791 genome-wide association study hits located within one of the regions corresponded to ASDPs.
conclusionsOur algorithm uses the information contained in the 178 structurally variable regions of the GRCh38 genome assembly to avoid spurious variant calls in cases where samples contain an alternate locus rather than the corresponding segment of the primary assembly. These results suggest the great potential of fully incorporating the resources of graph-like genome assemblies into variant calling, but also underscore the importance of developing computational resources that will allow a full reconstruction of the genotype in personal genomes. Our algorithm is freely available at https://github.com/charite/asdpex .
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