ArticleGenome medicine2023
Comprehensive de novo mutation discovery with HiFi long-read sequencing.
Article in Genome medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 54 citations in OpenAlex.
- Characterization of rare genomic structural variants across 2,981 genomes reveals significant involvements in recessive conditions.Science China. Life sciences · 2026Article
- Long-read sequencing for neurological disorders: opportunities, challenges, and future directions.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Review
- How precise are mutation rate estimates? Comparison of different approaches to estimate de novo mutation rates.Heredity · 2026Article
- Integrative approach for delineating structural variants using optical genome mapping and long-read genome sequencing.Molecular biology reports · 2026Article
- Targeted long-read RNA sequencing for rare disease diagnosis and variant interpretation.Science advances · 2026Article
- Paternal age effect in autosomal dominant or X-linked de novo variants identified by genome-wide sequencing.HGG advances · 2026Article
- Variant Prioritization by Pedigree-Based Haplotyping.Genetic epidemiology · 2026Article
- Long-read sequencing of families reveals increased germline and postzygotic mutation rates in repetitive DNA.Nature communications · 2026Article
- Identification of de novo variants from parent-proband duos via long-read sequencing.American journal of human genetics · 2026Article
- Genome-wide methylation detection and episignature analysis using PacBio long-read sequencing.Genome medicine · 2026Article
- Investigation of the Characteristics of Telomere Length in Koreans and Its Association With Chronic Metabolic Disorders: A Comprehensive Study.Journal of cellular and molecular medicine · 2025Article
- HiFi based metagenomic assembly strategy provides accuracy near isolated genome resolution in MAG assembly.iMetaOmics · 2025Article
- Individuals with intellectual disability have an increased burden ofmedRxiv : the preprint server for health sciences · 2025Article
- Article
- Mapping-based genome size estimation.BMC genomics · 2025Article
- Unraveling undiagnosed rare disease cases by HiFi long-read genome sequencing.Genome research · 2025Article
- Genome-wide profiling of highly similar paralogous genes using HiFi sequencing.Nature communications · 2025Article
- Parental germline mosaicism in genome-wide phased de novo variants: Recurrence risk assessment and implications for precision genetic counselling.PLoS genetics · 2025Article
- Uncovering recessive alleles in rare Mendelian disorders by genome sequencing of 174 individuals with monoallelic pathogenic variants.European journal of human genetics : EJHG · 2025Article
- High-Accuracy Long-Read Sequencing ofThe Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale · 2025Article
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundLong-read sequencing (LRS) techniques have been very successful in identifying structural variants (SVs). However, the high error rate of LRS made the detection of small variants (substitutions and short indels < 20 bp) more challenging. The introduction of PacBio HiFi sequencing makes LRS also suited for detecting small variation. Here we evaluate the ability of HiFi reads to detect de novo mutations (DNMs) of all types, which are technically challenging variant types and a major cause of sporadic, severe, early-onset disease.
methodsWe sequenced the genomes of eight parent-child trios using high coverage PacBio HiFi LRS (~ 30-fold coverage) and Illumina short-read sequencing (SRS) (~ 50-fold coverage). De novo substitutions, small indels, short tandem repeats (STRs) and SVs were called in both datasets and compared to each other to assess the accuracy of HiFi LRS. In addition, we determined the parent-of-origin of the small DNMs using phasing.
resultsWe identified a total of 672 and 859 de novo substitutions/indels, 28 and 126 de novo STRs, and 24 and 1 de novo SVs in LRS and SRS respectively. For the small variants, there was a 92 and 85% concordance between the platforms. For the STRs and SVs, the concordance was 3.6 and 0.8%, and 4 and 100% respectively. We successfully validated 27/54 LRS-unique small variants, of which 11 (41%) were confirmed as true de novo events. For the SRS-unique small variants, we validated 42/133 DNMs and 8 (19%) were confirmed as true de novo event. Validation of 18 LRS-unique de novo STR calls confirmed none of the repeat expansions as true DNM. Confirmation of the 23 LRS-unique SVs was possible for 19 candidate SVs of which 10 (52.6%) were true de novo events. Furthermore, we were able to assign 96% of DNMs to their parental allele with LRS data, as opposed to just 20% with SRS data.
conclusionsHiFi LRS can now produce the most comprehensive variant dataset obtainable by a single technology in a single laboratory, allowing accurate calling of substitutions, indels, STRs and SVs. The accuracy even allows sensitive calling of DNMs on all variant levels, and also allows for phasing, which helps to distinguish true positive from false positive DNMs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.