Analytical “bake-off” of whole genome sequencing quality for the Genome Russia project using a small cohort for autoimmune hepatitis

Zhernakova, Daria V.; Kliver, Sergei; Cherkasov, Nikolay; Tamazian, Gaik; Rotkevich, Mikhail; Krasheninnikova, Ksenia; Evsyukov, Igor; Sidorov, Sviatoslav; Dobrynin, Pavel; Yurchenko, Andrey A.; Shimansky, Valentin; Shcherbakova, Irina V.; Glotov, Andrey S.; Valle, David; Tang, Minzhong; Shin, Emilia; Schwarz, Kathleen B.; O’Brien, Stephen J.

doi:10.1371/journal.pone.0200423

Cited by 7 publications

(7 citation statements)

References 51 publications

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“…Concordantly with the aforementioned findings, we observed the lowest average difference for the NFE populations (Figure e). These results are in good concordance with the primary data of the Genomes Russia project (Zhernakova et al, ).…”

Section: Resultssupporting

confidence: 90%

Whole‐exome sequencing provides insights into monogenic disease prevalence in Northwest Russia

Barbitoff

Skitchenko

Poleshchuk

et al. 2019

Molec Gen & Gen Med

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BackgroundAllele frequency data from large exome and genome aggregation projects such as the Genome Aggregation Database (gnomAD) are of ultimate importance to the interpretation of medical resequencing data. However, allele frequencies might significantly differ in poorly studied populations that are underrepresented in large‐scale projects, such as the Russian population.MethodsIn this work, we leveraged our access to a large dataset of 694 exome samples to analyze genetic variation in the Northwest Russia. We compared the spectrum of genetic variants to the dbSNP build 151, and made estimates of ClinVar‐based autosomal recessive (AR) disease allele prevalence as compared to gnomAD r. 2.1.ResultsAn estimated 9.3% of discovered variants were not present in dbSNP. We report statistically significant overrepresentation of pathogenic variants for several Mendelian disorders, including phenylketonuria (PAH, rs5030858), Wilson's disease (ATP7B, rs76151636), factor VII deficiency (F7, rs36209567), kyphoscoliosis type of Ehlers‐Danlos syndrome (FKBP14, rs542489955), and several other recessive pathologies. We also make primary estimates of monogenic disease incidence in the population, with retinal dystrophy, cystic fibrosis, and phenylketonuria being the most frequent AR pathologies.ConclusionOur observations demonstrate the utility of population‐specific allele frequency data to the diagnosis of monogenic disorders using high‐throughput technologies.

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Section: Resultssupporting

confidence: 90%

Whole‐exome sequencing provides insights into monogenic disease prevalence in Northwest Russia

Barbitoff

Skitchenko

Poleshchuk

et al. 2019

Molec Gen & Gen Med

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“…Whole-genome sequencing. For comparison of exome capture technologies with conventional WGS approach, we used several recent samples sequenced at Biobank genome facility 27 . WGS libraries were prepared using TruSeq DNA PCR-Free LT Library Prep Kit (Illumina, USA) according to the manufacturer's protocol.…”

Section: Discussionmentioning

confidence: 99%

Systematic dissection of biases in whole-exome and whole-genome sequencing reveals major determinants of coding sequence coverage

Barbitoff

Polev²,

Glotov

et al. 2020

Sci Rep

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Advantages and diagnostic effectiveness of the two most widely used resequencing approaches, whole exome (WES) and whole genome (WGS) sequencing, are often debated. WES dominated largescale resequencing projects because of lower cost and easier data storage and processing. Rapid development of 3 rd generation sequencing methods and novel exome sequencing kits predicate the need for a robust statistical framework allowing informative and easy performance comparison of the emerging methods. In our study we developed a set of statistical tools to systematically assess coverage of coding regions provided by several modern WES platforms, as well as PCR-free WGS. We identified a substantial problem in most previously published comparisons which did not account for mappability limitations of short reads. Using regression analysis and simple machine learning, as well as several novel metrics of coverage evenness, we analyzed the contribution from the major determinants of CDS coverage. Contrary to a common view, most of the observed bias in modern WES stems from mappability limitations of short reads and exome probe design rather than sequence composition. We also identified the ~ 500 kb region of human exome that could not be effectively characterized using short read technology and should receive special attention during variant analysis. Using our novel metrics of sequencing coverage, we identified main determinants of WES and WGS performance. Overall, our study points out avenues for improvement of enrichment-based methods and development of novel approaches that would maximize variant discovery at optimal cost. Next-generation sequencing (NGS) is rapidly becoming an invaluable tool in human genetics research and clinical diagnostics 1-3. Practical use of NGS methods has dramatically increased with the development of targeted sequencing approaches, such as whole-exome sequencing (WES) or targeted sequencing of gene panels. WES emerged as an efficient alternative to whole-genome sequencing (WGS) due to both lower sequencing cost and simplification of variant analysis and data storage 4. More than 80% of all variants reported in ClinVar, and more than 89% of variants reported to be pathogenic, come from the protein-coding part of the genome; this number increases to 99% when immediate CDS vicinity is included. Even allowing for the sampling bias, there is an overall agreement that most heritable diseases appear to be caused by alterations in the protein-coding regions of the

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“…A pilot study of the project used the WGS approach for analysis of genetic variability in a cohort of 264 samples obtained from 52 isolated populations across the Russian federation. The variant calling showed 8 million SNPs and 2 million indels per population and 4% of these SNPs were classified as novel when compared to dbSNP [ 69 ].…”

Section: Resultsmentioning

confidence: 99%

National Genome Initiatives in Europe and the United Kingdom in the Era of Whole-Genome Sequencing: A Comprehensive Review

Smetana

Brož

2022

Genes

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Identification of genomic variability in population plays an important role in the clinical diagnostics of human genetic diseases. Thanks to rapid technological development in the field of massive parallel sequencing technologies, also known as next-generation sequencing (NGS), complex genomic analyses are now easier and cheaper than ever before, which consequently leads to more effective utilization of these techniques in clinical practice. However, interpretation of data from NGS is still challenging due to several issues caused by natural variability of DNA sequences in human populations. Therefore, development and realization of projects focused on description of genetic variability of local population (often called “national or digital genome”) with a NGS technique is one of the best approaches to address this problem. The next step of the process is to share such data via publicly available databases. Such databases are important for the interpretation of variants with unknown significance or (likely) pathogenic variants in rare diseases or cancer or generally for identification of pathological variants in a patient’s genome. In this paper, we have compiled an overview of published results of local genome sequencing projects from United Kingdom and Europe together with future plans and perspectives for newly announced ones.

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Analytical “bake-off” of whole genome sequencing quality for the Genome Russia project using a small cohort for autoimmune hepatitis

Cited by 7 publications

References 51 publications

Whole‐exome sequencing provides insights into monogenic disease prevalence in Northwest Russia

Whole‐exome sequencing provides insights into monogenic disease prevalence in Northwest Russia

Systematic dissection of biases in whole-exome and whole-genome sequencing reveals major determinants of coding sequence coverage

National Genome Initiatives in Europe and the United Kingdom in the Era of Whole-Genome Sequencing: A Comprehensive Review

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