Genetic analysis of albuminuria in collaborative cross and multiple mouse intercross populations

Albuminuria is an important marker of nephropathy that increases the risk of progressive renal and chronic cardiovascular diseases. The genetic basis of kidney disease is well-established in humans and rodent models, but the causal genes remain to be identified. We applied several genetic strategies to map and refine genetic loci affecting albuminuria in mice and translated the findings to human kidney disease. First, we measured albuminuria in mice from 33 inbred strains, used the data for haplotype association mapping (HAM), and detected 10 genomic regions associated with albuminuria. Second, we performed eight F2 intercrosses between genetically diverse strains to identify six loci underlying albuminuria, each of which was concordant to kidney disease loci in humans. Third, we used the Oak Ridge National Laboratory incipient Collaborative Cross subpopulation to detect an additional novel quantitative trait loci (QTL) underlying albuminuria. We also performed a ninth intercross, between genetically similar strains, that substantially narrowed an albuminuria QTL on Chromosome 17 to a region containing four known genes. Finally, we measured renal gene expression in inbred mice to detect pathways highly correlated with albuminuria. Expression analysis also identified Glcci1, a gene known to affect podocyte structure and function in zebrafish, as a strong candidate gene for the albuminuria QTL on Chromosome 6. Overall, these findings greatly enhance our understanding of the genetic basis of albuminuria in mice and may guide future studies into the genetic basis of kidney disease in humans.

Download Full-text

H-2 mutation affecting immune response to Thy-1.1 antigen

Journal of Experimental Medicine ◽

10.1084/jem.145.6.1602 ◽

1977 ◽

Vol 145 (6) ◽

pp. 1602-1606 ◽

Cited By ~ 13

Author(s):

M Zaleski ◽

J Klein

Keyword(s):

Immune Response ◽

Inbred Mice ◽

Serum Antibody ◽

Inbred Strains ◽

Antibody Responses ◽

Chromosome 9 ◽

Chromosome 17 ◽

Target Cells ◽

Histocompatibility Complex ◽

The Right

Mouse thymus, thymus-derived lymphocytes, and brain share an antigen determined by gene at the Thy-1 locus in chromosome 9 (1). Two alleles have been identified at this locus: Thy-1(a), coding for antigen Thy-1.1 (or θ-AKR) present in AKR and seven other strains; and Thy-1(b), coding for antigen Thy-1.2 (or{teta}-C3H) and present in C3H and all the remaining inbred strains. Injection of AKR thymocytes into inbred mice carrying the Thy-1(b) allele results in an immune response that can be measured either serologically by determining the level of antibodies in the recipients serum (1) or by counting plaque- forming cells (PFC) detectable in spleens of the recipients by means of an assay, with AKR thymocytes as target cells(2). The magnitude of PFC and serum antibody responses after a single thymocyte injection depends on the genetic make-up of the recipient. Three genes controlling the PFC response to the Thy- 1.1 antigen have been identified: Ir-Thy-1A and Ir-Thy-1B, which are closely linked to the major histocompatibility complex (H-2) of the mouse (3-6), and Ir-5, which is located at a distance of 17 cm to the right of the H-2 complex on chromosome 17 (6). Previous genetic mapping with H-2 recombinant strains has indicated that the two Ir-Thy-1 loci are located to the left of the IC subregion (7). Further experiments strongly suggested that either one or both Ir-Thy-1 loci map to the K rather than the I region of the H-2 complex (8). In this report, the study of an H- 2 mutant, CBA-H-2(ka) (M523) (9), and its parental strain, CBA/LacStoY (CBA) provided further evidence that one of these loci apparently resides in the K region and might even be identical with the H-2K locus in that region.

Download Full-text

The Putative Oncogene Pim-1 in the Mouse: Its Linkage and Variation Among t Haplotypes

Genetics ◽

10.1093/genetics/117.3.533 ◽

1987 ◽

Vol 117 (3) ◽

pp. 533-541

Author(s):

Joseph H Nadeau ◽

Sandra J Phillips

Keyword(s):

Restriction Fragment ◽

Inbred Mice ◽

Globin Gene ◽

Inbred Strains ◽

Chromosome 17 ◽

Wild Type ◽

Alpha Crystallin ◽

T Complex ◽

Variant Alleles ◽

Apparent Association

ABSTRACT Pim-1, a putative oncogene involved in T-cell lymphomagenesis, was mapped between the pseudoalpha globin gene Hba-4ps and the alpha-crystallin gene Crya-1 on mouse chromosome 17 and therefore within the t complex. Pim-1 restriction fragment variants were identified among t haplotypes. Analysis of restriction fragment sizes obtained with 12 endonucleases demonstrated that the Pim-1 genes in some t haplotypes were indistinguishable from the sizes for the Pim-1b allele in BALB/c inbred mice. There are now three genes, Pim-1, Crya-1 and H-2 I-E, that vary among independently derived t haplotypes and that have indistinguishable alleles in t haplotypes and inbred strains. These genes are closely linked within the distal inversion of the t complex. Because it is unlikely that these variants arose independently in t haplotypes and their wild-type homologues, we propose that an exchange of chromosomal segments, probably through double crossingover, was responsible for indistinguishable Pim-1 genes shared by certain t haplotypes and their wild-type homologues. There was, however, no apparent association between variant alleles of these three genes among t haplotypes as would be expected if a single exchange introduced these alleles into t haplotypes. If these variant alleles can be shown to be identical to the wild-type allele, then lack of association suggests that multiple exchanges have occurred during the evolution of the t complex.

Download Full-text

The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics

Mammalian Genome ◽

10.1007/s00335-008-9135-8 ◽

2008 ◽

Vol 19 (6) ◽

pp. 382-389 ◽

Cited By ~ 171

Author(s):

Elissa J. Chesler ◽

Darla R. Miller ◽

Lisa R. Branstetter ◽

Leslie D. Galloway ◽

Barbara L. Jackson ◽

...

Keyword(s):

National Laboratory ◽

Collaborative Cross ◽

Systems Genetics ◽

Oak Ridge ◽

Oak Ridge National Laboratory

Download Full-text

Plug-in scripts for EFTEM automation

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100165197 ◽

1996 ◽

Vol 54 ◽

pp. 546-547

Author(s):

N. D. Evans ◽

M. K. Kundmann

Keyword(s):

Electron Microscopy ◽

National Laboratory ◽

Oak Ridge ◽

Multiple User ◽

Transmission Electron ◽

Short Period ◽

User Facility ◽

Instrument Control ◽

And Control ◽

Research Equipment

Post-column energy-filtered transmission electron microscopy (EFTEM) is inherently challenging as it requires the researcher to setup, align, and control both the microscope and the energy-filter. The software behind an EFTEM system is therefore critical to efficient, day-to-day application of this technique. This is particularly the case in a multiple-user environment such as at the Shared Research Equipment (SHaRE) User Facility at Oak Ridge National Laboratory. Here, visiting researchers, who may oe unfamiliar with the details of EFTEM, need to accomplish as much as possible in a relatively short period of time.We describe here our work in extending the base software of a commercially available EFTEM system in order to automate and streamline particular EFTEM tasks. The EFTEM system used is a Philips CM30 fitted with a Gatan Imaging Filter (GIF). The base software supplied with this system consists primarily of two Macintosh programs and a collection of add-ons (plug-ins) which provide instrument control, imaging, and data analysis facilities needed to perform EFTEM.

Download Full-text