Abstract
Development of human genetics theoretical models and the integration of those models with experiment and statistical evaluation are critical for scientific progress. This perspective argues that increased effort in disease genetics theory, complementing experimental, and statistical efforts, will escalate the unraveling of molecular etiologies of complex diseases. In particular, the development of new, realistic disease genetics models will help elucidate complex disease pathogenesis, and the predicted patterns in genetic data made by these models will enable the concurrent, more comprehensive statistical testing of multiple aspects of disease genetics predictions, thereby better identifying disease loci. By theoretical human genetics, I intend to encompass all investigations devoted to modeling the heritable architecture underlying disease traits and studies of the resulting principles and dynamics of such models. Hence, the scope of theoretical disease genetics work includes construction and analysis of models describing how disease-predisposing alleles (1) arise, (2) are transmitted across families and populations, and (3) interact with other risk and protective alleles across both the genome and environmental factors to produce disease states. Theoretical work improves insight into viable genetic models of diseases consistent with empirical results from linkage, transmission, and association studies as well as population genetics. Furthermore, understanding the patterns of genetic data expected under realistic disease models will enable more powerful approaches to discover disease-predisposing alleles and additional heritable factors important in common diseases. In spite of the pivotal role of disease genetics theory, such investigation is not particularly vibrant.
Highlights
Development of human genetics theoretical models and the integration of those models with experiment and statistical evaluation are critical for scientific progress
Several simple questions need investigation: What are the probabilistic laws that govern the transmission of these epigenetic factors? That is, what is the distribution of probabilities that a given epigenetic state is transmitted to a subsequent generation? How do these probabilities attenuate across multiple generations? What are the frequencies of various epigenetic changes and the corresponding effects on disease risk? What is the fraction of an individual’s disease risk that is generated by epigenetic changes? And how is this fraction distributed across a population? Development of these theoretical models will allow for the calculation of testable predictions and aid in the construction of more powerful experimental designs
Additional work on identifying the patterns of genetic data expected under theoretical models is essential
Summary
Development of human genetics theoretical models and the integration of those models with experiment and statistical evaluation are critical for scientific progress. This perspective argues that increased effort in disease genetics theory, complementing experimental, and statistical efforts, will escalate the unraveling of molecular etiologies of complex diseases. I intend to encompass all investigations devoted to modeling the heritable architecture underlying disease traits and studies of the resulting principles and dynamics of such models. Understanding the patterns of genetic data expected under realistic disease models will enable more powerful approaches to discover disease-predisposing alleles and additional heritable factors important in common diseases. Activities in human disease genetics are primarily centered upon large-scale empirical studies and, to a lesser extent, statistical methods, with limited contribution to theory
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