Abstract
Genetic pathways underlying the initiation and progression of age-related macular degeneration (AMD) have not been yet sufficiently revealed, and the correlations of AMD's genotypes, phenotypes, and disease spectrum are still awaiting resolution. We are tackling both problems with systems biology phylogenetic parsimony analysis. Gene expression data (GSE29801: NCBI, Geo) of macular and extramacular specimens of the retinas and retinal pigment epithelium (RPE) choroid complexes representing dry AMD without geographic atrophy (GA), choroidal neovascularization (CNV), GA, as well as pre-AMD and subclinical pre-AMD were polarized against their respective normal specimens and then processed through the parsimony program MIX to produce phylogenetic cladograms. Gene lists from cladograms' nodes were processed in Genomatix GePS to reveal the affected signaling pathway networks. Cladograms exposed a highly heterogeneous transcriptomic profiles within all the conventional phenotypes. Moreover, clades and nodal synapomorphies did not support the classical AMD phenotypes as valid transcriptomal genotypes. Gene lists defined by cladogram nodes showed that the AMD-related deregulations occurring in the neural retina were different from those in RPE-choroidal tissue. Our analysis suggests a more complex transcriptional profile of the phenotypes than expected. Evaluation of the disease in much earlier stages is needed to elucidate the initial events of AMD.
Highlights
Age-related macular degeneration (AMD) is the main cause of permanent central blindness in the developed countries [1]
A more recent clinical classification of AMD has been published recently [5], we are using that of Newman et al [1] since the study specimens were categorized in the public data according to their phenotypes, these encompass (1) dry AMD, (2) choroidal neovascularization (CNV) or Wet AMD, (3) geographic atrophy (GA) in macular region of retinal pigmented epithelium (RPE), (4) GA/CNV, (5) pre-AMD, and (6) subclinical pre-AMD
Our analytical strategy can be summarized in the following steps: classify the patient specimens into clades onto cladogram through parsimony analysis of their gene-expression data; identify shared genes with abnormal expression for each clade; and identify genetic pathways affected by abnormal gene expression for all AMD specimens and/or for each clade
Summary
Age-related macular degeneration (AMD) is the main cause of permanent central blindness in the developed countries [1]. A more recent clinical classification of AMD has been published recently [5], we are using that of Newman et al [1] since the study specimens were categorized in the public data according to their phenotypes (see Table 1 for details), these encompass (1) dry AMD, (2) choroidal neovascularization (CNV) or Wet AMD, (3) geographic atrophy (GA) in macular region of RPE, (4) GA/CNV, (5) pre-AMD, and (6) subclinical pre-AMD These phenotypes are typically the progressing manifestations of the disease, and their gene expressions may not harbor the early events responsible for the initiation and progression of the disease. We used systems biology analytical paradigm called parsimony phylogenetics to reveal the various transcriptomic profiles of AMD’s subtypes
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