A Genetic Model of Common, Complex Disease Hints at Genomic Architecture: Brindle Coat Color in Canines
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Date
2018-05
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The Ohio State University
Abstract
Background: One of the greatest challenges facing scientists today is an understanding of genetic factors associated with the development of common, complex diseases such as diabetes, depression, and cancer. In addition to symptom burden (effecting quality of life), premature death, and disability caused by such diseases, the economic burden to society is vastly overwhelming. Last year, Major Depression alone cost nearly $211 Billion [USD] to US taxpayers. Yet, these diseases have been incredibly arduous to study due to the hundreds of genes that contribute very small effects that lead to disease development. We suggest that an alternative model of complex diseases is needed to elucidate the causative genetic mechanisms. We exploit a naturally occurring clear phenotype (brindle color) present on a simplified genetic background (pet dogs) and analyze large-scale genomic variation (CNVs) effecting gene expression (epigenetics – DNA methylation). Significance: Common, complex disease is a tremendous burden for patients, families, and clinicians alike. Elucidation of the genetic mechanisms leading to disease development would result in personalized therapies and improved patient outcomes. Purpose: To identify large-scale genomic variations present in Brindle color dogs and determine if epigenetic regulation is leading to phenotype development. Conceptual Framework: We used the genetic single gene-two hit model (Hussian, 2015) to guide this work. This framework combines rare and common variant theories with the addition of mutator/anti-mutator modulation to lead to disease development. Methods: Using a custom-designed aCGH to interrogate genomic structural variation, we analyzed 12 dogs of 3 different coat colors (Black, yellow, and brindle). Then, we performed genome-wide DNA methylation analysis on a subset of 8 dogs to determine the effect genomic variation has on epigenetic silencing of gene expression. Results: We identified a 67 Kb complex genetic variation (10 probes, p=0.001) that disrupts gene expression and is epigenetically silenced in certain skin cells producing pigment differences (p=0.04). Conclusion: Brindle coat color in canines is a complex genetic mechanism involving structural changes leading to epigenetic effects. Identifying this mechanism provides the first tractability for understanding complex diseases and is particularly exciting as a model for identifying such features in human diseases.
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Keywords
genomics, complex disease, canine, cancer, genetics, coat color