The Intolerance of Regulatory Sequence to Genetic Variation Predicts Gene Dosage Sensitivity

PLoS Genetics
Slavé PetrovskiDavid B Goldstein

Abstract

Noncoding sequence contains pathogenic mutations. Yet, compared with mutations in protein-coding sequence, pathogenic regulatory mutations are notoriously difficult to recognize. Most fundamentally, we are not yet adept at recognizing the sequence stretches in the human genome that are most important in regulating the expression of genes. For this reason, it is difficult to apply to the regulatory regions the same kinds of analytical paradigms that are being successfully applied to identify mutations among protein-coding regions that influence risk. To determine whether dosage sensitive genes have distinct patterns among their noncoding sequence, we present two primary approaches that focus solely on a gene's proximal noncoding regulatory sequence. The first approach is a regulatory sequence analogue of the recently introduced residual variation intolerance score (RVIS), termed noncoding RVIS, or ncRVIS. The ncRVIS compares observed and predicted levels of standing variation in the regulatory sequence of human genes. The second approach, termed ncGERP, reflects the phylogenetic conservation of a gene's regulatory sequence using GERP++. We assess how well these two approaches correlate with four gene lists that use different way...Continue Reading

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Datasets Mentioned

BETA
NA12878

Methods Mentioned

BETA
exome-sequencing
Exome Sequencing
genotyping

Software Mentioned

- Alignment Tool ( BWA )
ncRVIS
ncGERP
RVIS
GATK VQSLOD
MASS
ENCODE
Exome Variant Server ( EVS )
Yall
house

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