POPULATION GENETIC APPROACHES FOR THE STUDY OF COMPLEX TRAITS: FOCUS ON INFECTIOUS AND AUTOIMMUNE DISEASES
Creators: name: SIRONI, MANUELA
Publisher: name: Universit� degli Studi di Milano
Year: 2010

description: It is commonly believed that infectious diseases have represented one of the major threats to human populations and have therefore acted as a powerful selective force. Therefore, several human genes have evolved in response to infectious agents. Indeed, it has been suggested that human populations may have adapted to pathogens to such a degree that the lower exposure to infectious agents in modern developed societies results in immune imbalances, with autoimmune and allergic conditions being the outcome (hygiene hypothesis). Quite obviously, the presence of a functional variant is a prerequisite for selection to act, and the identification of non-neutrally evolving genes has been regarded as a strategy complementary to classical clinical and epidemiological studies to provide insight into the mechanisms of host defense. Similarly, analysis of the evolutionary history of genes involved in immune defense might provide novel insights into the delicate balance between efficient response to pathogens and autoimmune/allergic manifestations. In this work population genetics approaches are applied to study the evolutionary patterns of specific groups of genes such as those encoding blood group antigens and interleukins/interleukin receptors. Several of these latter genes have evolved in response to parasitic worms, but a subset of disease alleles for inflammatory bowel disease and celiac disease have increased in frequency in response to non-helminthic pathogens (i.e. viruses and bacteria). At the genome-wide level, the identification of selective signatures was exploited to identify novel susceptibility variants for virus-, protozan-, and helminth-borne infections. These analyses allowed the identification of several variants that may modulate infection susceptibility and we noticed a partial overlap between genes involved in the response to helminths and those carrying susceptibility alleles for asthma/atopy; similarly, a number of genes subjected to virus-driven selective pressure have been involved in the pathogenesis of multiple sclerosis and type 1 diabetes. One of these, namely IFIH1, was studied in detail: we revealed a complex selective pattern in human populations distributed in different geographic locations. Nonetheless, the analysis of IFIH1 variants involved in the susceptibility to type 1 diabetes indicated that they have evolved neutrally. Finally, we show that the identification of gene regions subjected to natural selection can provide information on the location of functional variants and these, in turn, may be regarded as strong candidates to prioritize on in case/control association studies. In the case of ERAP2 we carried out one such study and verified that a nonsynonymous variant subjected to natural selection affects the natural resistance to HIV-1 infection. In summary we show that selective events leave a signature on human genes that can be detected using population genetics approaches and exploited for the identification of variants that influence complex phenotypic traits such as susceptibility to infections. These studies can also shed light on the relationship between past selective events and predisposition to common diseases in modern populations.