These findings indicate that the Rf-1 QTL directly influences renal susceptibility and autoregulation. In contrast, the Rf-4 QTL shows no direct effects, but significantly increases susceptibility to renal damage via an interaction with Rf-1.

Two 11-fold redundant bacterial artificial chromosome (BAC) libraries have been constructed to support the rat genome project. The first library was constructed using a male Brown Norway (BN/SsNHsd) rat as a DNA source long before plans for rat genome sequencing had been launched. The second library was prepared from a highly inbred female (BN/SsNHsd/MCW) rat in support of the rat genome sequencing project. The use of an inbred rat strain is essential to avoid problems with genome assembly resulting from the difficulty of distinguishing haplotype variation from variation among duplicons. We have demonstrated the suitability of the library by using a detailed quality assessment of large insert sizes, narrow size distribution, consistent redundancy for many markers, and long-range continuity of BAC contig maps. The widespread use of the two libraries as an integral part of the rat genome project has led to the database annotations for many clones, providing rat researchers with a rich resource of BAC clones that can be screened in silico for genes of interest.

The combined transfer of two renal function quantitative trait loci (QTLs), Rf-1 (rat chromosome 1) and Rf-4 (rat chromosome 14), from the Fawn-hooded hypertensive rat onto the August Copenhagen Irish genetic background significantly increases proteinuria and demonstrates an interaction between these QTLs. Because the original Rf-4 congenic region is 61.9 Mbp, it is necessary to reduce this interval to feasibly search for variants responsible for renal susceptibility in this region. Here, we generated a minimal congenic line (Rf-1a+4_a) to identify a 4.1-Mb region of the Rf-4 QTL that significantly contributes to the severity of proteinuria in the Fawn-hooded hypertensive rat. Rf-1a+4_a animals have an increased glomerular permeability to albumin without significant changes in BP, indicating that at least one genetic element in this refined region directly affects renal function. Sequence analysis revealed no variants predicted to damage protein function, implying that regulatory elements are responsible for the Rf-4 phenotype. Multiple human studies, including recent genome-wide association studies, link the homologous human region with susceptibility to renal disease, suggesting that this congenic line is an important model for studying pathways that contribute to the progression of kidney disease.