title: Erosion of Conserved Binding Sites in Personal Genomes Points to Medical Histories.
abstract: Although many human diseases have a genetic component involving many loci, the majority of studies are statistically underpowered to isolate the many contributing variants, raising the question of the existence of alternate processes to identify disease mutations. To address this question, we collect ancestral transcription factor binding sites disrupted by an individual's variants and then look for their most significant congregation next to a group of functionally related genes. Strikingly, when the method is applied to five different full human genomes, the top enriched function for each is invariably reflective of their very different medical histories. For example, our method implicates "abnormal cardiac output" for a patient with a longstanding family history of heart disease, "decreased circulating sodium level" for an individual with hypertension, and other biologically appealing links for medical histories spanning narcolepsy to axonal neuropathy. Our results suggest that erosion of gene regulation by mutation load significantly contributes to observed heritable phenotypes that manifest in the medical history. The test we developed exposes a hitherto hidden layer of personal variants that promise to shed new light on human disease penetrance, expressivity and the sensitivity with which we can detect them.
authors: Department of Electrical Engineering, Stanford University, Stanford, California, United States of America.|Department of Pediatrics (Genetics), Stanford University, Stanford, California, United States of America.
authors: Harendra
authors: H
authors: Guturu
authors: Department of Electrical Engineering, Stanford University, Stanford, California, United States of America.|Department of Computer Science, Stanford University, Stanford, California, United States of America.
authors: Sandeep
authors: S
authors: Chinchali
authors: Department of Genetics, Stanford University, Stanford, California, United States of America.
authors: Shoa L
authors: SL
authors: Clarke
authors: Department of Pediatrics (Genetics), Stanford University, Stanford, California, United States of America.|Department of Computer Science, Stanford University, Stanford, California, United States of America.|Department of Developmental Biology, Stanford University, Stanford, California, United States of America.
authors: Gill
authors: G
authors: Bejerano
mesh_terms: D001665:Binding Sites / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D059866:HLA-DQ beta-Chains / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D015233:Models, Statistical; D009154:Mutation; D009290:Narcolepsy / Q000235:genetics; D057285:Precision Medicine
chemical_list: D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen