Long-read sequencing in human genetics

Kraft, Florian; Kurth, Ingo

doi:10.1007/s11825-019-0249-z

Cited by 15 publications

(10 citation statements)

References 64 publications

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“…However, with the advance of new tools such as ExpansionHunter some of these challenges can be overcome 13 . Long read sequencing technology such as those offered by PacBio and Oxford Nanopore are also able to circumvent these obstacles, but they are still costly at the human genome level and prone to errors 14 .…”

Section: Introductionmentioning

confidence: 99%

Large scale in silico characterization of repeat expansion variation in human genomes

et al. 2020

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Significant progress has been made in elucidating single nucleotide polymorphism diversity in the human population. However, the majority of the variation space in the genome is structural and remains partially elusive. One form of structural variation is tandem repeats (TRs). Expansion of TRs are responsible for over 40 diseases, but we hypothesize these represent only a fraction of the pathogenic repeat expansions that exist. Here we characterize long or expanded TR variation in 1,115 human genomes as well as a replication cohort of 2,504 genomes, identified using ExpansionHunter Denovo. We found that individual genomes typically harbor several rare, large TRs, generally in non-coding regions of the genome. We noticed that these large TRs are enriched in their proximity to Alu elements. The vast majority of these large TRs seem to be expansions of smaller TRs that are already present in the reference genome. We are providing this TR profile as a resource for comparison to undiagnosed rare disease genomes in order to detect novel disease-causing repeat expansions.

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Section: Introductionmentioning

confidence: 99%

Large scale in silico characterization of repeat expansion variation in human genomes

et al. 2020

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“…These SV include both large insertions/duplications and deletions (also known as copy number variants, CNVs) and large inversions and can have a great impact on health [97]. Longer-read sequencers hold the promise to identify large structural variations and the causative mutations in unsolved genetic diseases [36,98,99]. Incorporating the calling of such SV would increase the diagnostic yield of these NGS approaches, overcoming some of the limitations present in other methods and with the potential to eventually replace them.…”

Section: Structural Variants Callingmentioning

confidence: 99%

“…causative mutations in unsolved genetic diseases [36,98,99]. Incorporating the calling of such SV would increase the diagnostic yield of these NGS approaches, overcoming some of the limitations present in other methods and with the potential to eventually replace them.…”

Section: Structural Variants Callingmentioning

confidence: 99%

Bioinformatics and Computational Tools for Next-Generation Sequencing Analysis in Clinical Genetics

Pereira

Oliveira

Sousa

2020

JCM

184

119

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Clinical genetics has an important role in the healthcare system to provide a definitive diagnosis for many rare syndromes. It also can have an influence over genetics prevention, disease prognosis and assisting the selection of the best options of care/treatment for patients. Next-generation sequencing (NGS) has transformed clinical genetics making possible to analyze hundreds of genes at an unprecedented speed and at a lower price when comparing to conventional Sanger sequencing. Despite the growing literature concerning NGS in a clinical setting, this review aims to fill the gap that exists among (bio)informaticians, molecular geneticists and clinicians, by presenting a general overview of the NGS technology and workflow. First, we will review the current NGS platforms, focusing on the two main platforms Illumina and Ion Torrent, and discussing the major strong points and weaknesses intrinsic to each platform. Next, the NGS analytical bioinformatic pipelines are dissected, giving some emphasis to the algorithms commonly used to generate process data and to analyze sequence variants. Finally, the main challenges around NGS bioinformatics are placed in perspective for future developments. Even with the huge achievements made in NGS technology and bioinformatics, further improvements in bioinformatic algorithms are still required to deal with complex and genetically heterogeneous disorders.

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“…One of the major limitations to long read sequencing, however, is the higher chances of sequencing errors. In some cases, this may be overcome by increasing the sequencing coverage, and using optimized filtering strategies (Kraft and Kurth, 2019;Mantere et al, 2019). Alternatively, subsequent short read sequencing can be used to optimize for any errors in long read sequencing data (Goodwin et al, 2015).…”

Section: Selecting An Ngs and Bioinformatics Strategymentioning

confidence: 99%

Next Generation Sequencing and Bioinformatics Analysis of Family Genetic Inheritance

et al. 2020

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Mendelian and complex genetic trait diseases continue to burden and affect society both socially and economically. The lack of effective tests has hampered diagnosis thus, the affected lack proper prognosis. Mendelian diseases are caused by genetic mutations in a singular gene while complex trait diseases are caused by the accumulation of mutations in either linked or unlinked genomic regions. Significant advances have been made in identifying novel diseases associated mutations especially with the introduction of next generation and third generation sequencing. Regardless, some diseases are still without diagnosis as most tests rely on SNP genotyping panels developed from population based genetic analyses. Analysis of family genetic inheritance using whole genomes, whole exomes or a panel of genes has been shown to be effective in identifying disease-causing mutations. In this review, we discuss next generation and third generation sequencing platforms, bioinformatic tools and genetic resources commonly used to analyze family based genomic data with a focus on identifying inherited or novel disease-causing mutations. Additionally, we also highlight the analytical, ethical and regulatory challenges associated with analyzing personal genomes which constitute the data used for family genetic inheritance.

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Long-read sequencing in human genetics

Cited by 15 publications

References 64 publications

Large scale in silico characterization of repeat expansion variation in human genomes

Large scale in silico characterization of repeat expansion variation in human genomes

Bioinformatics and Computational Tools for Next-Generation Sequencing Analysis in Clinical Genetics

Next Generation Sequencing and Bioinformatics Analysis of Family Genetic Inheritance

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