The causes and consequences of pleiotropy across the human phenome

The last decade of human genetics research has uncovered parts of the genome associated with various traits including diseases, physical characteristics, personality, and behavior. A major finding from these studies is that most of human diseases and traits are mostly due to the additive contribution of many genetic variants, each of which has a small effect on the predisposition to a particular phenotype. This phenomenon is called polygenicity. Another observation is that regions of the genome associated with one trait also are associated with other seemingly unrelated traits. This observation is called pleiotropy. As an example of pleiotropy, one may be surprised to learn that the regions of the DNA associated with weight at birth also are positively associated with the amount of schooling one completes and disorders of the immune system. When investigating these relationships closer, scientists have uncovered evidence that evolution has played a major role in shaping the human genome and the associated phenome (i.e., all traits associated with the human condition). These observations and relationships between traits have sparked two questions: (1) if regions of the genome are arguably positive for the human condition, why hasn’t evolution given everyone in the population this “good” DNA? and (2) if certain regions of the genome are arguably negative for the human condition, why haven’t they been removed from the population by evolution? One possible answer is that regions of the genome are not solely “good” or “bad” for the human condition and that parts of the DNA are maintained in the population because of their greater positive effects on human health than their negative effects on human disease. There is a gap in knowledge about how this balance of positive and negative effects influences what we understand about the relationships between human health and disease phenotypes. This proposal aims to investigate the mechanisms that contributed to shape the effect of genetic variation on human health and disease. These findings expected will offer putative explanations regarding the shared biology among human phenotypes. This novel information may also help to develop to novel treatments for certain diseases.