Item Details

abstract

Tumor necrosis factor (TNF) is a cytokine with critical roles in inflammation, and in mediating an intersection of chronic, low-grade inflammation and concurrent metabolic dysregulation associated with obesity and its comorbidities. As part of an ongoing initiative to further characterize the St. Kitts-origin vervet monkey as a nonhuman primate (NHP) of polygenic obesity, the human ortholog vervet TNF gene and flanking regions were sequenced and genotyped from 265 monkeys in a closed, pedigreed colony. This revealed a total of 11 single nucleotide polymorphisms (SNPs), and one 4 base pair insertion/deletion polymorphism. Many of these polymorphisms were in strong linkage disequilibrium, and were contained within one haplotype block, comprising five haplotypes. Using sequences from humans, chimpanzees, vervets, baboons, and rhesus macaques, phylogenetic shadowing of the TNF promoter region revealed that vervet and other NHP SNPs were clustered non-randomly and non-uniformly (p<0.0001) around conserved transcription factor binding sites. Thus, the distribution of SNPs in vervets and other NHPs is shown to be analogous to that of humans. The taxonomy of the St. Kitts vervet and the African Green monkey is identical and designated Chlorocebus aethiops sabaeus, although it has long been regarded as tentative. Phylogenetic analyses were perfomed using TNF putative promoter region nucleotide sequence, among the St. Kitts-origin vervet, and four other African-origin subspecies. Results show the St. Kitts vervet has significant sequence differences from the African Green monkey. This is the strongest evidence to date challenging the xi current taxonomic classification, and suggests the sabaeus subspecies designation for the St. Kitts vervet should be reconsidered. Association analyses were performed between polymorphisms of the vervet TNF orthologous gene and previously defined obesity-related phenotypes. Positive, significant associations were observed between a subset of SNPs (all within a single haplotype) and body mass index, waist circumference (p < 0.05), total plasma cholesterol, and HDL-cholestrerol (p < 0.01). The former three associations have been reported in humans and provide further model validation, whereas the latter has been reported as an inverse association in humans. The novel association with HDL-cholesterol warrants further study, but may provide insight into the newly emerging dual inflammatory and anti-inflammatory role of HDL-cholesterol.

subject

nonhuman primate (NHP)

obesity

animal model

polygenic

genetic association

diabetes

contributor

Gray, Stanton (author)

Langefeld, Carl (committee chair)

Wagner, Janice (committee member)

Howard, Timothy (committee member)

Kaplan, Jay (committee member)

Rudel, Lawrence (committee member)

date

2009-08-27T15:25:09Z (accessioned)

2010-06-18T18:58:08Z (accessioned)

2009-08-27T15:25:09Z (available)

2010-06-18T18:58:08Z (available)

2009-08-27T15:25:09Z (issued)

degree

Molecular & Cellular Pathobiology (discipline)

identifier

http://hdl.handle.net/10339/14736 (uri)

language

en_US (iso)

publisher

Wake Forest University

rights

Release the entire work immediately for access worldwide. (accessRights)

title

GENETIC CHARACTERIZATION OF THE ST. KITTS-ORIGIN VERVET MONKEY (CHLOROCEBUS AETHIOPS SSP.) AS A MODEL OF POLYGENIC OBESITY

type

Dissertation