Hui-Chen Hsu

Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function.

Patterns of gene expression in the central nervous system are highly variable and heritable. This genetic variation among normal individuals leads to considerable structural, functional and behavioral differences. We devised a general approach to dissect genetic networks systematically across biological scale, from base pairs to behavior, using a reference population of recombinant inbred strains. We profiled gene expression using Affymetrix oligonucleotide arrays in the BXD recombinant inbred strains, for which we have extensive SNP and haplotype data. We integrated a complementary database comprising 25 years of legacy phenotypic data on these strains. Covariance among gene expression and pharmacological and behavioral traits is often highly significant, corroborates known functional relations and is often generated by common quantitative trait loci. We found that a small number of major-effect quantitative trait loci jointly modulated large sets of transcripts and classical neural phenotypes in patterns specific to each tissue. We developed new analytic and graph theoretical approaches to study shared genetic modulation of networks of traits using gene sets involved in neural synapse function as an example. We built these tools into an open web resource called WebQTL that can be used to test a broad array of hypotheses.

The nature and identification of quantitative trait loci: a community’s view

This white paper by eighty members of the Complex Trait Consortium presents a communitys view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?

The Dynamic Duo-Inflammatory M1 macrophages and Th17 cells in Rheumatic Diseases.

The synovial tissue of Rheumatoid Arthritis (RA) patients is enriched with macrophages and T lymphocytes which are two central players in the pathogenesis of RA. Interaction between myeloid cells and T cells are essential for the initiation and progression of the inflammatory processes in the synovium. With the rapid evolution of our understanding of how these two cell types are involved in the regulation of immune responses, RA is emerging as an ideal disease model for investigating the cell-cell interactions and consequently introducing novel biologic agents that are designed to disrupt these processes. This review will discuss the bidirectional interaction between the IL-23+ inflammatory macrophages and IL-17+ GM-CSF+ CD4 T cells in rheumatic diseases as well as potential antirheumatic strategies via apoptosis induction in this context.

Management of Murine Lupus by Correction of Fas and Fas Ligand-Induced Apoptosis

Identification of mutations of fas and fas ligand (fasL) genes in murine models of autoimmune disease has provided an important experimental tool for the analysis of tolerance and autoimmune disease. Mutations of fasL and fas genes are not a common cause of autoimmune disease in humans, although a mutation of the fas gene has been associated with autoimmune lymphoproliferative syndrome (1–5), and we have described a mutation of the fasL gene in one patient with SLE (6). Furthermore, accumulating evidence suggests that dysregulation of apoptosis or altered levels of expression of FasL and Fas plays an important role in the pathogenesis of diseases associated with immune regulation (6–11). Fas apoptosis appears to be the primary mechanism for elimination of autoreactive T cells outside the thymus. FasL regulation is tightly controlled, and specific cells and transcription factors have been identified that play a role in this process. Further investigations of Fas/FasL regulation should allow development of strategies to restore T-cell tolerance in autoimmune situations. The first part of this chapter uses Fas/FasL as an example to demonstrate the importance of apoptosis in the regulation of immune homeostasis. The second part of this chapter follows the footsteps of investigators in this field to understand how one can apply modern technology to understand mechanisms associated with genetic defect-related autoimmune disease and to develop strategies to overcome these defects.