Epigenetics characterized by the inheritance of regulatory information stored on chromosomes by meansother than DNA sequence is at the forefront of complex disease research. Epigenetics is a rich term thatdescribes many phenomena however the studies with the broadest disease relevance are those ofenvironmentally-induced changes to gene expression states that are inherited through mitosis and/or meiosis.This transgenerational epigenetic inheritance is thought to account for accumulated disease risk in individualsand for transmission of disease risk to offspring. Understanding how a disease state is epigenetically inheritedis critically important to the NIH's mission to enhance health lengthen life and reduce illness and disability. However many data concerning the basic mechanisms of epigenetic inheritance in model organisms areinconsistent with how the epigenetic models are applied to human disease and highlight major roadblocks inresearch. These data do not just challenge the models for epigenetic inheritance they suggest that the way wethink about epigenetic inheritance is the impediment. The serious and persistent roadblocks can beimmediately removed by considering that transgenerational epigenetic defects are in fact caused by particulartypes of mutations: induced by the environment high-frequency and preferentially affecting specic regions ofgenomes that have pleiotropic regulatory and physiological effects. Considering this alternative explanationcreates a paradigmatic conict because it doesn't challenge data it questions the expectations of epigeneticand challenges how we approach the problem and identify the gaps that need to be lled by research. This Transformative Research Award proposal: (i) highlights the problems with the existing model fortransgenerational epigenetic inheritance (ii) explains the data-supported alternative model that carries with ita new paradigm (iii) explains why it is the paradigmatic conict that impedes research (iv) demonstrates theutility of the alternative in solving current research problems and (v) explains how acceptance of the paradigmwill sidestep roadblocks and redirect research to better utilize precious resources. Two sets of experimental directions are planned. The rst set whether epigenetic information is encodedat a gene and whether epigenetic information can distinguish two identical genes focuses on irreconcilabledifferences between the paradigms to determine which is valid. The second set the genetic basis ofepigenetic inheritance and the differences between two cells that differ only in their epigenetic status willadvance our understanding of epigenetic defects in disease. If my alternative paradigm is correct theseexperiments will open new areas of research into (i) how intrinsically unstable repeat DNAs in the genomerespond to environmental stress disease and mutation (ii) how repeat DNAs inuence expression of genenetworks throughout the genome and (iii) how defects in repeat DNA stability lead to permanent damage tothe genome. These areas are expected to establish new approaches to prevent and treat complex diseases.