Julia C Basso, Medha K Satyal, Kevin L McKee, Sarah Lynn, Daphne Gyamfi, Warren K Bickel
Dissociation and other trauma symptomatology are linked to imbalance in the competing neurobehavioral decision systems
Frontiers in psychology
genetic variants severely alter protein products eg nonsense frameshift often associated disease genes predicted lossoffunction variants plofs observed throughout gene whilst others occur specific locations hypothesised genes linked monogenic diseases display incomplete penetrance plof variants present apparently unaffected individuals may limited regions plofs tolerated test investigated whether plof location could explain instances incomplete penetrance variants expected pathogenic mendelian conditions used exome sequence data 454773 individuals uk biobank ukb investigate locations plofs population cohort counted numbers unique plof missense synonymous variants ukb quintile coding sequence cds proteincoding genes clustered variants using gaussian mixture models limited analyses genes 5 variants type 16473 genes compared locations plofs ukb theoretically possible plofs transcript pathogenic plofs clinvar performed simulations estimate falsepositive rate nonuniformly distributed variants genes variant classes fell clusters representing broadly uniform variant distributions genes haploinsufficiency causes developmental disorders less likely uniform plof distribution genes p 22 106 identified number genes including arid1b gata6 plof variants first quarter cds rescued presence alternative translation start site reported pathogenic genes odc1 plofs located approximately uniformly across gene pathogenic plofs clustered end consistent gainoffunction disease mechanism results suggest potential benefits localised constraint metrics location plof variants considered interpreting variants