Complex diseases: a genome-wide assessment of the role of selective pressure on the human genome
Amato, Roberto (2011) Complex diseases: a genome-wide assessment of the role of selective pressure on the human genome. [Tesi di dottorato] (Inedito)
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Genetic based diseases are commonly thought as an "error", i.e. as the result of one or few rare mutations in the DNA. While this explanation can work fine for Mendelian, high penetrance, diseases, it is less plausible for complex diseases (CD). Indeed, this important class of diseases is characterized by the fact of being caused by hundreds of variants, each of them "common" in the population and with a small effect. As a possible explanation for such an apparent paradox, it has been proposed that variants associated with CD are the result of direct or indirect evolutionary pressures in ancient times. According to this hypothesis, those variants (or variants close to them) were selected in our ancestors for being advantageous and that they became dangerous only recently because of the totally different environment we live in. Then, the very recent changes in the environment, together with the late onset characterizing these diseases, provided no time for natural selection to act against them. As a first step toward addressing this hypothesis, I analyzed the genomic distribution of a specific marker of selective pressure, namely F(ST). I examined, in particular, its relationship with genes associated to human CD finding indeed suggestions of positive selection occurred on them. To better understand the role of natural selection on genes associated with CD I then focused on two different cases of study corresponding to two different scenarios. In the first one, I found hints for schizophrenia to be, at least partially, a maladaptive by-product of natural selection which acted on vitamin D related genes when first humans moved to higher latitudes. In the second example, I focused on the case in which variants increasing the risk for autoimmune diseases are most likely to be the actual and direct target of selection. I found that a plausible hypothesis is that the diseases themselves are the results of an environmental mismatch with respect to that our ancestors, when these variants were selected.
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