All ETDs from UAB

Advisory Committee Chair

Maria De Luca

Advisory Committee Members

Shannon M Bailey

Scott W Ballinger

W Timothy Garvey

Chandrika J Piyathilake

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) School of Health Professions

Abstract

Obesity is emerging as a global public health problem and it has shown to precede and predict the development of type 2 diabetes, a complex disease that has also reached epidemic proportions in the US and worldwide. Despite that obesity-related traits are highly heritable, the genetic basis underlying their natural variation and the loci playing pleiotropic roles among organismal traits have not been fully elucidated. The overall goals of these present studies were: to shed light on the architecture of the genetic co-expression networks regulating variations in obesity-related traits, elucidate the extent to which they are regulated by pleiotropic loci, and identify pleiotropic alleles between metabolism and life-history traits to provide key insights into why different alleles are allowed to persist in natural populations, despite the fact that some of them confer susceptibility to metabolic disorders. Using a wild-derived population of Drosophila melanogaster as model system, our results highlighted the relevance of non-metabolic pathways such as immune response, neurogenesis and neuronal function, cell growth, food processing and water balance as key regulators of organismal body weight, metabolic rate and body composition traits. Differential expression of cycling/photoperiodic genes among young adult flies underlies the genetic forces shaping phenotypic variation in mitochondrial bioenergetic traits. Furthermore, the elucidation of pleiotropic transcriptional modules provided a key insight into the molecular basis of the well established trade-offs between body weight, reproduction, and survival of food deprivation. Our data further indicate that molecular regulation of mitochondrial respiration plays a critical role in mediating life history trade-offs in natural populations. In conclusion, our results confirm that the genetic basis of natural variations in obesity-related traits involves highly interactive co-regulated transcriptional networks, and identify various pleiotropic loci underlying evolutionarily conserved trade-offs among organismal survival and reproduction which account for the perpetuation of alleles that confer susceptibility to metabolic disorders among individuals from a natural population.

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