Definition of a 1.06-Mb region linked to neuroinflammation in humans, rats and mice

Abstract

Unbiased identification of susceptibility genes might provide new insights into pathogenic mechanisms that govern complex inflammatory diseases such as multiple sclerosis. In this study we fine mapped Eae18a, a region on rat chromosome 10 that regulates experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. We utilized two independent approaches: (1) in silico mapping based on sequence similarity between human multiple sclerosis susceptibility regions and rodent EAE quantitative trait loci and (2) linkage mapping in an F10 (DA x PVG.AV1) rat advanced intercrossed line. The linkage mapping defines Eae18a to a 5-Mb region, which overlaps one intergenomic consensus region identified in silico. The combined approach confirms experimentally, for the first time, the accuracy of the in silico method. Moreover, the shared intersection between the results of both mapping techniques defines a 1.06-Mb region containing 13 candidate genes for the regulation of neuroinflammation in humans, rats, and mice.

Figure 1.—

Summary of sex distribution and clinical parameters for animals that displayed signs of EAE after immunization. In total, 224 (DA × PVG.AV1) F₁₀ animals displayed signs of EAE after MOG immunization. Number of animals in each phenotypic group is given on the y-axis. The clinical parameters are described in materials and methods.

Figure 2.—

Log-likelihood plot of Eae18a that regulates MOG–EAE in the (DA × PVG.AV1) F₁₀ advanced intercross line. Eae18a displayed significant linkage to all clinical EAE phenotypes (incidence of EAE, weight loss, and cumulative EAE score are presented). LOD score values are given on the y-axis whereas microsatellite markers and their positions are on the x-axis. The 95% confidence interval is indicated by the shaded horizontal bar.

Figure 3.—

Schematic of the 1.06-Mb intergenomic consensus region defined by in silico and AIL mapping. The vertical solid bars represent 95% confidence intervals of Eae18a identified by AIL mapping in F₇ and F₁₀ generations. The vertical shaded bar represents the intergenomic consensus region defined by in silico analysis in rats, mice, and humans, comprising 22 genes. The number of genes is reduced to 13, listed at the right with their IDs for human genes for the combined 1.06-Mb region that is common for the F₁₀ confidence interval and the intergenomic consensus region. Boldface type indicates genes identified and described in humans, rats, and mice. Italics indicate genes identified in humans and predicted in rats and mice by sequence homology. Boldface italic type indicates genes identified in rats, mice, and humans but described only in humans and mice. Roman type indicates genes identified in rats, mice, and humans but described in humans alone.