UC San Diego

Microarray-based gene expression profiling is a frequently utilized tool in the search for disease-specific molecular patterns and the development of clinically relevant panels of biomarkers. Although advances in high-throughput gene expression technology make for more reliable and interpretable studies, investigations of living humans are often limited by tissue accessibility. This is especially true for neural-based illnesses, where studies rely heavily on post-mortem brain tissue. As a result, medical researchers have focused on blood, a more easily accessible and clinically obtainable tissue. In this work I explore: 1.) the technical aspects associated with assessing peripheral whole blood gene expression via microarray; and 2.) the biological significance of blood-based gene expression patterns with respect to brain-based gene expression patterns and behavioral phenotypes in mice and humans. I describe the effects of globin reduction on blood-based gene expression in mice by comparing gene expression patterns before and after globin reduction of mouse whole blood (Chapter 2). Globin reduction was found to improve the ability to detect low abundance, biologically relevant genes. I also evaluated globin reduction in the context of human blood and two Illumina gene expression assays: (i) the IVT-based direct hybridization assay; and (ii) the WG-DASL assay (Chapter 4). As in mice, I was able to recapitulate the known benefits of globin reduction in both assays, while WG-DASL appeared to be more sensitive compared to IVT. Lastly, I characterized the correlations between blood gene expression levels and behavioral phenotypes and compared blood gene expression-trait correlations with brain gene expression-trait correlations in respect to neuropsychiatric phenotypes in mice (Chapter 3) and autism in humans (Chapter 5). In both mice and humans, blood was only able to capture a small portion of the associations identified in the brain on an individual gene level. At a pathway level, blood was able to capture a larger portion of the associated brain pathways in humans as compared to mice. I conclude blood gene expression, although it may capture a small portion of the expression patterns associated with `primary' neural insults, is more likely to capture variation due to `secondary' perturbations or other biological and environmental insults.