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)

Full text disponibile come:

[img]PDF - Solo per gli Amministratori dell'archivio fino a 09 Gennaio 2013 - Richiede un editor Pdf del tipo GSview, Xpdf o Adobe Acrobat Reader
3906Kb

Abstract

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.

Tipologia di documento:Tesi di dottorato
Parole chiave:complex diseases, natural selection, schizophrenia, autoimmunity, polygeny
Settori scientifico-disciplinari MIUR:Area 01 Scienze matematiche e informatiche > INF/01 INFORMATICA
Area 06 Scienze mediche > MED/03 GENETICA MEDICA
Area 05 Scienze biologiche > BIO/18 GENETICA
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Cocozza, Sergiococozza@unina.it
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Miele, Gennaromiele@na.infn.it
Cocozza, Sergiococozza@unina.it
Stato del full text:Inedito
Data:25 Novembre 2011
Numero di pagine:150
Istituzione:Università di Napoli Federico II
Dipartimento o Struttura:Biologia e patologia cellullare e molecolare "L. Califano"
Stato dell'Eprint:Inedito
Scuola di dottorato:Biotecnologie
Denominazione del dottorato:Biologia computazionale e bioinformatica
Ciclo di dottorato:24
Numero di sistema:8554
Depositato il:06 Dicembre 2011 15:54
Ultima modifica:24 Aprile 2012 15:40

Solo per gli Amministratori dell'archivio: edita il record