Method and System for Assessment of Regulatory Variants in a Genome

Abstract

The present invention provides methods embodied in a system that can be applied to genetic information comprising an individual genome to assess the regulatory impact of specific genetic variants and their possible impact on biological function or disease pathology.

1 . A method of treating an individual based on genetic variants in transcription factor binding sites, comprising:
 obtaining genetic data from an individual by sequencing genetic material of the individual;   identifying at least one disease in the individual using a computer system comprising a processor and a memory, wherein the at least one disease is associated with gene regulation, wherein the at least one disease is identified by:
 receiving information regarding genome-wide quantitative and genetic profiles, information regarding genetic variants associated with disease conditions, information regarding DNA motifs associated with transcription factor binding, and molecular profiles of disease pathologies and storing this information using a computer system comprising a processor and a memory, wherein the quantitative and genetic profiles describe transcription factor binding and gene expression measured across a multitude of individual human genomes; 
 identifying a set of candidate variants using a computer system with a processor and a memory, wherein the set of candidate variants are identified by:
 mapping the genetic variants associated with disease conditions to the DNA motifs associated with transcription factor binding; and 
 determining whether the genetic variants associated with disease conditions affect gene expression by identifying the effect on gene expression of the mapped genetic variants from the quantitative and genetic profiles; 
 
 generating regulatory impact data for the set of candidate variants using a computer system comprising a processor and a memory, wherein the regulatory impact data indicates the clinical significance of the set of candidate variants, where the clinical significance identifies a disease associated with the effect of the set of candidate variants on gene expression based on the received molecular profiles of disease pathology; and 
 identifying the presence of at least one candidate variant from the set of candidate variants in the obtained genetic sequence data of the individual using a computer system comprising a processor and a memory; and 
   treating the individual for the at least one identified disease based on the clinical significance described by the regulatory impact data associated with the identified at least one candidate variant.   
     
     
         2 . The method of  claim 1 , wherein the quantitative and genetic profiles describe NFkB binding measured across a multitude of individual human genomes, and the DNA motifs associated with transcription factor binding are NFkB motifs. 
     
     
         3 . The method of  claim 1 , further comprising performing genome-wide expression profiling of the individual to confirm the clinical significance of the at least one candidate variant. 
     
     
         4 . The method of claim  9 , wherein the genome-wide expression profiling includes an RNA sequencing analysis. 
     
     
         5 . The method of  claim 1 , further comprising:
 determining the impact of the at least one candidate disease variant on disease pathology by comparing the at least one candidate variant to the molecular profiles of disease pathologies using a computer system comprising a processor and a memory.   
     
     
         6 . The method of  claim 1 , wherein the disease is at least one of an autoimmune disease and an inflammatory disease. 
     
     
         7 . The method of  claim 1 , wherein the disease is at least one of Alzheimer's disease, rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, asthma, alopecia areata, non-Hodgkin's lymphoma, malaria, drug-induced liver injury, myocardial infarction, and atherosclerosis. 
     
     
         8 . The method of  claim 1 , wherein the genetic material comprises at least one of immunoprecipitated chromatin, genomic DNA, and RNA.