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Quantifying deleterious effects of regulatory variants.

ABSTRACT: The majority of genome-wide association study (GWAS) risk variants reside in non-coding DNA sequences. Understanding how these sequence modifications lead to transcriptional alterations and cell-to-cell variability can help unraveling genotype-phenotype relationships. Here, we describe a computational method, dubbed CAPE, which calculates the likelihood of a genetic variant deactivating enhancers by disrupting the binding of transcription factors (TFs) in a given cellular context. CAPE learns sequence signatures associated with putative enhancers originating from large-scale sequencing experiments (such as ChIP-seq or DNase-seq) and models the change in enhancer signature upon a single nucleotide substitution. CAPE accurately identifies causative cis-regulatory variation including expression quantitative trait loci (eQTLs) and DNase I sensitivity quantitative trait loci (dsQTLs) in a tissue-specific manner with precision superior to several currently available methods. The presented method can be trained on any tissue-specific dataset of enhancers and known functional variants and applied to prioritize disease-associated variants in the corresponding tissue.

SUBMITTER: Li S

PROVIDER: S-EPMC5389506 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Quantifying deleterious effects of regulatory variants.

Li Shan S Alvarez Roberto Vera RV Sharan Roded R Landsman David D Ovcharenko Ivan I

Nucleic acids research 20170301 5

The majority of genome-wide association study (GWAS) risk variants reside in non-coding DNA sequences. Understanding how these sequence modifications lead to transcriptional alterations and cell-to-cell variability can help unraveling genotype-phenotype relationships. Here, we describe a computational method, dubbed CAPE, which calculates the likelihood of a genetic variant deactivating enhancers by disrupting the binding of transcription factors (TFs) in a given cellular context. CAPE learns se ...[more]

PMID: 27980060

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Project description:BACKGROUND:Ritodrine is a commonly used tocolytic to prevent preterm labour. However, it can cause unexpected serious adverse reactions, such as pulmonary oedema, pulmonary congestion, and tachycardia. It is unknown whether such adverse reactions are associated with pharmacogenomic variants in patients. METHODS:Whole-exome sequencing of 13 subjects with serious ritodrine-induced cardiac and pulmonary side-effects was performed to identify causal genes and variants. The deleterious impact of nonsynonymous substitutions for all genes was computed and compared between cases (n?=?13) and controls (n?=?30). The significant genes were annotated with Gene Ontology (GO), and the associated disease terms were categorised into four functional classes for functional enrichment tests. To assess the impact of distributed rare variants in cases with side effects, we carried out rare variant association tests with a minor allele frequency???1% using the burden test, the sequence Kernel association test (SKAT), and optimised SKAT. RESULTS:We identified 28 genes that showed significantly lower gene-wise deleteriousness scores in cases than in controls. Three of the identified genes-CYP1A1, CYP8B1, and SERPINA7-are pharmacokinetic genes. The significantly identified genes were categorized into four functional classes: ion binding, ATP binding, Ca2+-related, and ciliopathies-related. These four classes were significantly enriched with ciliary genes according to SYSCILIA Gold Standard genes (P?<?0.01), thus representing ciliary genes. Furthermore, SKAT showed a marginal trend toward significance after Bonferroni correction with Joubert Syndrome ciliopathy genes (P?=?0.05). With respect to the pharmacokinetic genes, rs1048943 (CYP1A1) and rs1804495 (SERPINA7) showed a significantly higher frequency in cases than controls, as determined by Fisher's exact test (P?<?0.05 and P?<?0.01, respectively). CONCLUSIONS:Ritodrine-induced cardiac and pulmonary side effects may be associated with deleterious genetic variants in ciliary and pharmacokinetic genes.

Project description:BackgroundMyoclonus-Dystonia (M-D) is a pleiotropic neuropsychiatric disorder of variable penetrance. Pathogenic variants in SGCE, a maternally imprinted gene, are the most frequent known genetic cause of M-D. The population prevalence of SGCE-linked M-D is unknown, the pathogenicity of SGCE variants identified in patients with M-D may be indeterminant, and SGCE variants predicted to be deleterious by in silico analysis may appear in patients undergoing whole-exome or whole-genome sequencing for seemingly unrelated disorders. The Genome Aggregation Database (gnomAD) v2 provides variant data on 125,748 exomes and 15,708 genomes from unrelated individuals sequenced as part of various disease-specific and population genetic studies.MethodsSGCE variants included in the gnomAD v2 dataset were analyzed with Combined Annotation Dependent Depletion (CADD), and database for nonsynonymous single nucleotide polymorphisms' functional predictions (dbNSFP). We determined the frequency of annotated SGCE variants, ranked by scores of deleteriousness, within the gnomAD v2 dataset. Deleteriousness scores were compared to a subset of published disease associated SGCE pathogenic variants.ResultsWithin gnomAD v2, there were 56, 408, and 1250 alleles harboring SGCE variants with CADD scores greater than 30, 25, and 20, respectively. We estimate that approximately 1/348 individuals in the United States population harbors an SGCE variant with a CADD score ≥ 25.DiscussionSGCE M-D may be underdiagnosed due to pleiotropy, mild phenotypes, variable penetrance, and impaired access to genetic testing. Due to the high population prevalence of deleterious SGCE variants, caution should be used when asserting pathogenicity without co-segregation analyses and expert neurological examination of phenotypes within pedigrees.HighlightsIn silico analyses of a large population database of genetic variants revealed that over 0.2% of individuals in the United States harbor a highly deleterious SGCE variant. This finding suggests that M-D and minor phenotypic variants such as mild isolated myoclonus may be underdiagnosed.

Project description:BACKGROUND:Speculation regarding the importance of changes in gene regulation in determining major phylogenetic patterns continues to accrue, despite a lack of broad-scale comparative studies examining how patterns of gene expression vary during development. Comparative transcriptional profiling of adult interspecific hybrids and their parental species has uncovered widespread divergence of the mechanisms controlling gene regulation, revealing incompatibilities that are masked in comparisons between the pure species. However, this has prompted the suggestion that misexpression in adult hybrids results from the downstream cascading effects of a subset of genes improperly regulated in early development. RESULTS:We sought to determine how gene expression diverges over development, as well as test the cascade hypothesis, by profiling expression in males of Drosophila melanogaster, D. sechellia, and D. simulans, as well as the D. simulans (female) x D. sechellia (male) male F1 hybrids, at four different developmental time points (3rd instar larval, early pupal, late pupal, and newly-emerged adult). Contrary to the cascade model of misexpression, we find that there is considerable stage-specific autonomy of regulatory breakdown in hybrids, with the larval and adult stages showing significantly more hybrid misexpression as compared to the pupal stage. However, comparisons between pure species indicate that genes expressed during earlier stages of development tend to be more conserved in terms of their level of expression than those expressed during later stages, suggesting that while Von Baer's famous law applies at both the level of nucleotide sequence and expression, it may not apply necessarily to the underlying overall regulatory network, which appears to diverge over the course of ontogeny and which can only be ascertained by combining divergent genomes in species hybrids. CONCLUSION:Our results suggest that complex integration of regulatory circuits during morphogenesis may lead to it being more refractory to divergence of underlying gene regulatory mechanisms--more than that suggested by the conservation of gene expression levels between species during earlier stages. This provides support for a 'developmental hourglass' model of divergence of gene expression in Drosophila resulting in a highly conserved pupal stage.

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Quantifying deleterious effects of regulatory variants.

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Quantifying deleterious effects of regulatory variants.

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