Bystro: rapid online variant annotation and natural-language filtering at whole-genome scale

Kotlar, Alex V.; Trevino, Cristina E.; Zwick, Michael E.; Cutler, David J.; Wingo, Thomas S.

doi:10.1186/s13059-018-1387-3

Cited by 30 publications

(19 citation statements)

References 20 publications

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“…The raw sequence reads were assembled relative to the Genome Reference Consortium Human GRCh38 (hg38) using the PEMapper software tool, and PECaller was used to identify single‐nucleotide variants, insertions and deletions (INDELs) . These unique variants were functionally annotated using Bystro (https://bystro.io/) and ANNOVAR, which report the variant’s type, functional classification (nonsense, replacement, silent, 5′ or 3′ untranslated region, splice junction, or other intronic, intergenic), presence in the Single Nucleotide Polymorphism Database, and measures of evolutionary conservation …”

Section: Methodsmentioning

confidence: 99%

Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

Berauer¹,

Mezina²,

Okou³

et al. 2019

Hepatology

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Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations—a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole‐exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient–parent trios, from the National Institute of Diabetes and Digestive and Kidney Diseases–supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a prespecified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other noncholestatic diseases. Conclusion: WES identified biallelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN data set; the dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome.

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Section: Methodsmentioning

confidence: 99%

Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

Berauer¹,

Mezina²,

Okou³

et al. 2019

Hepatology

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“…Annotation of the multi-sample VCF (n=1,196) was performed using Bystro [18] and supplemented by the Broad's ChromHMM annotation of dPFC tissue [19,20]. A total of 1,133 samples passed all quality control measures and 63 samples were excluded for one or more of the following reasons.…”

Section: Genetic Datamentioning

confidence: 99%

Genetic control of the human brain proteome

Robins

Wingo

Fan

et al. 2019

Preprint

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Alteration of protein abundance and conformation are widely believed to be the hallmark of neurodegenerative diseases. Yet relatively little is known about the genetic variation that controls protein abundance in the healthy human brain. The genetic control of protein abundance is generally thought to parallel that of RNA expression, but there is little direct evidence to support this view. Here, we performed a large-scale protein quantitative trait locus (pQTL) analysis using single nucleotide variants (SNVs) from whole-genome sequencing and tandem mass spectrometry-based proteomic quantification of 12,691 unique proteins (7,901 after quality control) from the dorsolateral prefrontal cortex (dPFC) in 144 cognitively normal individuals. We identified 28,211 pQTLs that were significantly associated with the abundance of 864 proteins. These pQTLs were compared to dPFC expression quantitative trait loci (eQTL) in cognitive normal individuals (n=169; 81 had protein data) and a meta-analysis of dPFC eQTLs (n=1,433). We found that strong pQTLs are generally only weak eQTLs, and that the majority of strong eQTLs are not detectable pQTLs. These results suggest that the genetic control of mRNA and protein abundance may be substantially distinct and suggests inference concerning protein abundance made from mRNA in human brain should be treated with caution.

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“…All biallelic variants with a genotyping rate of 90% or greater, regardless of MAF, were investigated within each region of interest (defined as 1 Mb centered on each lead variant). Each interval was annotated for possible roles in craniofacial development by literature searches of all genes contained within that interval, functional annotation of variants using multiple tools including Bystro (Kotlar et al 2018), Variant Effect Predictor (McLaren et al 2016), and HaploReg (Ward and Kellis 2016). We also queried the UCSC genome browser's gene-by-gene interaction track for known OFC genes/regions.…”

Section: Fine-mapping and Rare-variant Association In 21q Regionmentioning

confidence: 99%

Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21

et al. 2019

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Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.

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Bystro: rapid online variant annotation and natural-language filtering at whole-genome scale

Cited by 30 publications

References 20 publications

Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

Genetic control of the human brain proteome

Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21

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