Of Mice and Men: Divergence of Gene Expression Patterns in Kidney

Abstract

Since the development of methods for homologous gene recombination, mouse models have played a central role in research in renal pathophysiology. However, many published and unpublished results show that mice with genetic changes mimicking human pathogenic mutations do not display the human phenotype. These functional differences may stem from differences in gene expression between mouse and human kidneys. However, large scale comparison of gene expression networks revealed conservation of gene expression among a large panel of human and mouse tissues including kidneys. Because renal functions result from the spatial integration of elementary processes originating in the glomerulus and the successive segments constituting the nephron, we hypothesized that differences in gene expression profiles along the human and mouse nephron might account for different behaviors. Analysis of SAGE libraries generated from the glomerulus and seven anatomically defined nephron segments from human and mouse kidneys allowed us to identify 4644 pairs of gene orthologs expressed in either one or both species. Quantitative analysis shows that many transcripts are present at different levels in the two species. It also shows poor conservation of gene expression profiles, with less than 10% of the 4644 gene orthologs displaying a higher conservation of expression profiles than the neutral expectation (p<0.05). Accordingly, hierarchical clustering reveals a higher degree of conservation of gene expression patterns between functionally unrelated kidney structures within a given species than between cognate structures from the two species. Similar findings were obtained for sub-groups of genes with either kidney-specific or housekeeping functions. Conservation of gene expression at the scale of the whole organ and divergence at the level of its constituting sub-structures likely account for the fact that although kidneys assume the same global function in the two species, many mouse “models” of human pathologies do not display the expected phenotype.

Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma

“…Clear cell RCC is thought to arise from cells in the proximal convoluted tubule, while chromophobe RCC is thought to arise from intercalated cells in the distal convoluted tubule of the nephron (Prasad et al, 2007). This theory is supported by TCGA’s analysis of clear cell RCC and chromophobe RCC gene expression profiles in the context of an external expression data set of normal tissue microdissected from various regions of the nephron (Cheval et al, 2012; Davis et al, 2014). We re-examined this model using this combined set of 888 cases, and confirmed that clear cell RCC cases had expression profiles most similar to the glomerulus and proximal nephron, chromophobe RCC cases were most similar in expression to the distal nephron, while papillary RCC cases were in general most similar in expression to the proximal nephron (Figure 1B).…”

The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

“…We examined our gene expression data in the context of an external gene expression dataset of normal tissue microdissected from various regions of the nephron (Cheval et al, 2012). Supervised analysis, globally comparing each TCGA ChRCC or ccRCC tumor expression profile (n=66 and n=417, respectively) to that of each sample in the nephron atlas, showed high mRNA expression correlations for ChRCC with distal regions of the nephron.…”

“…Exon 1a expression corresponds to p16INK4a isoform. (C) A cartoon of nephron (left) and heatmaps showing inter-sample correlations (red, positive) between profiles of kidney tumors (columns; TCGA data, arranged by subtype) and profiles of kidney nephon sites (rows; data set from Cheval et al , 2012). Glom, Kidney Glomerulus; S1/S2, Kidney Proximal Tubule; MTAL, Kidney Medullary Thick Ascending Limb of Henle's Loop; CTAL, Kidney cortical Thick Ascending Limb of Henle's Loop; DCT, Kidney Distal Convoluted Tubule; CNT, Kidney Connecting Tubule; CCD, Kidney Cortical Collecting Duct; OMCD, Kidney Outer Medullary Collecting Duct.…”

Common Variants in UMOD Associate with Urinary Uromodulin Levels

“…[44][45][46] Each gene was queried in the metaanalysis results, by extracting all variants within that gene (including the promoter and the 59 region around it). For each gene, we accounted for region-specific multiple testing using a gene-specific threshold (0.05 divided by the number of found LD blocks at R 2 =0.2).…”