Dataset Information

Interpretation of genomic variants using a unified biological network approach.

ABSTRACT: The decreasing cost of sequencing is leading to a growing repertoire of personal genomes. However, we are lagging behind in understanding the functional consequences of the millions of variants obtained from sequencing. Global system-wide effects of variants in coding genes are particularly poorly understood. It is known that while variants in some genes can lead to diseases, complete disruption of other genes, called 'loss-of-function tolerant', is possible with no obvious effect. Here, we build a systems-based classifier to quantitatively estimate the global perturbation caused by deleterious mutations in each gene. We first survey the degree to which gene centrality in various individual networks and a unified 'Multinet' correlates with the tolerance to loss-of-function mutations and evolutionary conservation. We find that functionally significant and highly conserved genes tend to be more central in physical protein-protein and regulatory networks. However, this is not the case for metabolic pathways, where the highly central genes have more duplicated copies and are more tolerant to loss-of-function mutations. Integration of three-dimensional protein structures reveals that the correlation with centrality in the protein-protein interaction network is also seen in terms of the number of interaction interfaces used. Finally, combining all the network and evolutionary properties allows us to build a classifier distinguishing functionally essential and loss-of-function tolerant genes with higher accuracy (AUC?=?0.91) than any individual property. Application of the classifier to the whole genome shows its strong potential for interpretation of variants involved in mendelian diseases and in complex disorders probed by genome-wide association studies.

SUBMITTER: Khurana E

PROVIDER: S-EPMC3591262 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Interpretation of genomic variants using a unified biological network approach.

Khurana Ekta E Fu Yao Y Chen Jieming J Gerstein Mark M

PLoS computational biology 20130307 3

The decreasing cost of sequencing is leading to a growing repertoire of personal genomes. However, we are lagging behind in understanding the functional consequences of the millions of variants obtained from sequencing. Global system-wide effects of variants in coding genes are particularly poorly understood. It is known that while variants in some genes can lead to diseases, complete disruption of other genes, called 'loss-of-function tolerant', is possible with no obvious effect. Here, we buil ...[more]

PMID: 23505346

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Project description:Genetic variants in low-density lipoprotein receptor (LDLR) are known to cause familial hypercholesterolemia (FH), occurring in up to 1 in 200 people (Youngblom E. et al. 1993 and Nordestgaard BG et al. 34:3478-3490a, 2013) and leading to significant risk for heart disease. Clinical genomics testing using high-throughput sequencing is identifying novel genomic variants of uncertain significance (VUS) in individuals suspected of having FH, but for whom the causal link to the disease remains to be established (Nordestgaard BG et al. 34:3478-3490a, 2013). Unfortunately, experimental data about the atomic structure of the LDL binding domains of LDLR at extracellular pH does not exist. This leads to an inability to apply protein structure-based methods for assessing novel variants identified through genetic testing. Thus, the ambiguities in interpretation of LDLR variants are a barrier to achieving the expected clinical value for personalized genomics assays for management of FH. In this study, we integrated data from the literature and related cellular receptors to develop high-resolution models of full-length LDLR at extracellular conditions and use them to predict which VUS alter LDL binding. We believe that the functional effects of LDLR variants can be resolved using a combination of structural bioinformatics and functional assays, leading to a better correlation with clinical presentation. We have completed modeling of LDLR in two major physiologic conditions, generating detailed hypotheses for how each of the 1007 reported protein variants may affect function. KEY MESSAGES: • Hundreds of variants are observed in the LDLR, but most lack interpretation. • Molecular modeling is aided by biochemical knowledge. • We generated context-specific 3D protein models of LDLR. • Our models allowed mechanistic interpretation of many variants. • We interpreted both rare and common genomic variants in their physiologic context. • Effects of genomic variants are often context-specific.

Dataset Information

Interpretation of genomic variants using a unified biological network approach.

Publications

Interpretation of genomic variants using a unified biological network approach.

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