Identification and analysis of renal quantitative traits loci (QTL)

Abstract

Genetic variation among normal individuals leads to significant anatomical and physiological differences accounting for predisposition to renal diseases. The fate of kidney cells in response to cellular stress may determine the progression of renal pathology. Gene expression levels in the kidney are variable and heritable. Since the copy number of many transcripts is highly heritable, it can be analyzed as a complex trait.;The present work aims to characterize the genetic loci controlling glomerular cells turnover in healthy animals and to examine the effect of kidney disease on glomerular cells densities. We defined novel quantitative kidney traits: podocytes and glomerular cells per glomerular section in DBA/2J and C57BL/6J mice and mapped the genetic loci controlling these traits in healthy animals. We also detected a significant 21% reduction of podocytes per glomerular section in DBA/2J mice (p=0.0001), but no difference in podocytes per glomerular section in C57BL/6J mice after 6 weeks of streptozotocin-induced type 1 diabetes compared to non-diabetic controls.;We mapped upstream modulators for hundreds of kidney transcripts by profiling gene expression using Affymetrix arrays in the BXD recombinant inbred panel. We identified sets of cis- and trans-acting transcription regulatory regions that control transcription of large gene networks in the normal adult mouse kidney. Through comparison of the kidney expression quantitative trait loci and QTL datasets from mouse brain we identified global regulators of transcription as well as kidney specific regulatory loci and validated these finding in the rat kidney expression QTL.;Next, we developed a new quantitative trait loci software system, named QTL MatchMaker. It combines and organizes information from public databases and publications and integrates QTL, physical, genetic and cytogenetic maps across human, mouse, and rat. We used QTL MatchMaker to search for the genes responsible for genetic variations in kidney traits. Combining multiple sources of evidence including, genetic regulation of kidney gene expression, comparative genomics, mapping of genes to renal QTL, and SNP analysis we have identified potential expression QTL genes located inside the loci controlling glomerular cells.