Networks and Disease

One of the most important advances in understanding the molecular basis of diseases and the promise of novel therapeutic discoveries has been the use of network data as well as network paradigms. As we show in this chapter, these approaches are leading to the identification of important genes that are implicated in various diseases, the understanding of common origins of disparate diseases, disease comorbidity, prediction of patient response to disease states, and the design of novel treatment methods. Before we embark on an exploration of the connections between net-

work biology and disease, we must first understand the concept of a disease gene. A disease gene is a gene in which specific mutations, or whose abnormal expression, cause the disease in question. A disease may have one or more disease genes associated with it. The abnormal protein sometimes coded by the disease gene is often termed a disease-causing protein. There is growing realization that susceptibility to nearly all human diseases, including infectious diseases, may have at least some genetic component. A comprehensive atlas of genetic diseases and the genes associated with them is provided by the Online Mendelian Inheritance in Man (OMIM) database (https://www.omim.org). As of August 2012, the OMIM database contained over 21,000 entries. In some instances, different sets of mutations in the same gene may give rise to different disorders, just as most disorders are polygenic (i.e., caused by mutations in more than one gene). This “multi-gene-multidisease” association immediately suggests a network-like paradigm for understanding the relationships among human diseases. Before we delve deeper into this paradigm, however, it is instructive to further understand how a disease can be caused by single gene mutations. Such diseases are termed Mendelian diseases. Examples are the so-called in-born errors of metabolism, such as phenylketonuria (PKU). In this disease, the affected patients cannot metabolize a particular amino acid effectively, leading to toxic accumulation of a degradation product and

consequent disorders. Other examples are sickle-cell anemia, which is caused by a mutation that produces an aberrant hemoglobin molecule (that is unable to carry sufficient oxygen) in the red blood cells, and hemophilia, which causes a blood clotting disorder. Genetic diseases can be due to a dominant or a recessive mutation,

depending on whether one or both copies, respectively, of the disease gene (one inherited from the mother and one inherited from the father) are required for the individual to be afflicted with the disease. Mendelian diseases are further classified as autosomal diseases if their disease gene resides on one of the twenty-two non-sex chromosomes, Xlinked if their disease gene resides on the X-chromosome, and Y-linked if their disease gene resides on the Y -chromosome. Thus, autosomal recessive diseases are those in which both copies of the disease gene (that resides on the two homologous non-sex chromosomes) must be mutated for the individual to be affected. In such diseases, it is possible that two parents, each possessing one copy of the disease gene (and therefore, not afflicted by the disease) can have a child who has two copies of the disease gene and is therefore afflicted. Examples of autosomal recessive diseases include cystic fibrosis and sickle-cell anemia. In autosomal dominant diseases, on the other hand, one copy of the mutated gene is sufficient for the disease to be expressed. It is therefore not possible for an individual to be afflicted with an autosomal dominant disease unless at least one of his/her parents is afflicted with it1. Huntington’s disease is an autosomal dominant disease. X-linked recessive diseases are only expressed in females if they carry

two copies of the disease gene, one on each chromosome. Only one copy of the disease gene is sufficient for the disease to be expressed in males, because males carry only one X chromosome. Thus, X-linked recessive diseases occur more frequently in males than in females. Hemophilia and color blindness are examples of X-linked recessive diseases. Y - linked diseases occur exclusively in males and are passed from father to son. Because there is only one Y chromosome (which exists only in males), the notions of recessive and dominant forms do not usu-

ally apply to Y -linked diseases. The most well known Y -linked diseases are those associated with mutations of the SRY (Sex-determining Region Y) gene. This gene codes for a protein that initiates male sex determination. Thus, mutations in this gene in men lead to an externally female-like appearance with under-developed gonads, a condition known as Swyer syndrome.