The need for locus-specific P-values.

<p>The 95% LOD score (the LOD score equivalent to a locus-specific P = 0.05) was calculated using 10,000 permutations for markers on Chr. 1 for body weight in several different populations. Each marker is indicated by a dot with connecting lines interpolated between adjacent markers. TJL BXD are BXD strains available from The Jackson Laboratory (The BXD strains developed by Taylor and colleagues <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001036#pone.0001036-Taylor1" target="_blank">[26]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001036#pone.0001036-Taylor2" target="_blank">[27]</a>). New BXD are the recently developed BXD strains currently resident at UTHSC. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001036#pone.0001036-Peirce2" target="_blank">[18]</a> Note that the maximum and minimum values of the 95^th percentile LOD score vary considerably for the AIL population, somewhat for the RI (New BXD and TJL BXD) populations, (predicted by missing data pattern) and very little for the 183 member F2 population tested. (There are only three widely spaced markers genotyped for the F2 population on Chr. 1, so the interpolation between points should not be interpreted as a meaningful line. However, markers on all chromosomes were very similar, between a 95% LOD of 1.2 and 1.4.)</p

List of Microsatellite Markers and Mendelian Correlations.

<p>List of Microsatellite Markers and Mendelian Correlations.</p

Combined mapping for <i>Hipp1a</i> and <i>Hipp9a.</i>

<p>This figure shows mapping data for the hippocampus weight loci <i>Hipp1a</i> and <i>Hipp9a</i> using 34 BXD strains (BXD; shaded line) and 679 advanced intercross animals (AIL, thin solid line) as well as the composite map using the described method (thick solid line). The genome-wide adjusted composite P = 0.05 threshold is −log P = 3.5 (dark solid horizontal line). Since 5000 permutations were used for each data set, the maximum −log P<3.7 (graphed as −log P = 3.7 for convenience) for each individual data set, so increasing the number of permutations might increase the peak combined value and slightly improve the range of the combined interval. Bars underneath the peaks are labeled AIL, BXD, and combined to indicate the l-LOD support interval of these mapping populations.</p

A Forward Phenotypically Driven Unbiased Genetic Analysis of Host Genes That Moderate Herpes Simplex Virus Virulence and Stromal Keratitis in Mice

<div><p>Both viral and host genetics affect the outcome of herpes simplex virus type 1 (HSV-1) infection in humans and experimental models. Little is known about specific host gene variants and molecular networks that influence herpetic disease progression, severity, and episodic reactivation. To identify such host gene variants we have initiated a forward genetic analysis using the expanded family of BXD strains, all derived from crosses between C57BL/6J and DBA/2J strains of mice. One parent is highly resistant and one highly susceptible to HSV-1. Both strains have also been fully sequenced, greatly facilitating the search for genetic modifiers that contribute to differences in HSV-1 infection. We monitored diverse disease phenotypes following infection with HSV-1 strain 17syn+ including percent mortality (herpes simplex encephalitis, HSE), body weight loss, severity of herpetic stromal keratitis (HSK), spleen weight, serum neutralizing antibody titers, and viral titers in tear films in BXD strains. A significant quantitative trait locus (QTL) on chromosome (Chr) 16 was found to associate with both percent mortality and HSK severity. Importantly, this QTL maps close to a human QTL and the gene proposed to be associated with the frequency of recurrent herpetic labialis (cold sores). This suggests that a single host locus may influence these seemingly diverse HSV-1 pathogenic phenotypes by as yet unknown mechanisms. Additional suggestive QTLs for percent mortality were identified—one on Chr X that is epistatically associated with that on Chr 16. As would be anticipated the Chr 16 QTL also modulated weight loss, reaching significance in females. A second significant QTL for maximum weight loss in male and female mice was mapped to Chr 12. To our knowledge this is the first report of a host genetic locus that modulates the severity of both herpetic disease in the nervous system and herpetic stromal keratitis.</p></div

Chromosomal maps showing the identified QTL regions.

<p>A 20 cM region (red box) on the distal are of mCHr 5 and the proximal arm of mChr14 were identified by QTL analysis.</p

Syndromes involving an abnormal corpus callosum (ACC).

<p>Syndromes involving an abnormal corpus callosum (ACC).</p

Genetic mapping of corpus callosum volume in the BXD mouse genetic reference panel.

<p>Likelihood ratio (LRS; ordinate) of the association or linkage between differences in corpus callosum volume and natural genetic variation as a function of position in the mouse genome (chromosome number and coordinates in megabses given; abscissa). Note the single genome-wide significant peak in mouse chromosome 7 (A). Overlapping deletions in genomic region 1q44 in patients with an ACC (B). Black bars and arrows indicate hemizygously deleted regions. Grey bars and arrows indicate hemizygous deletions found in subject with a normal corpus callosum. Vertical lines indicate the region that is hemizygous in 32 out of 41 cases, and overlaps with the mouse QTL.</p

Correlations between phenotypes that map to the distal end of Chr 16.

<p>Spearman Rank correlations were performed bewteen percent mortality and herpetic stromal keratitis datasets (left panel, p = 1.52×10⁻⁰⁵) or percent maximum weight loss of both male and female mice combined and percent mortality of male and female mice combined (right panel, p =  1.75×10⁻⁰⁶).</p

Representitive results with several BXD strains.

<p>Shown are representitive data from four different BXD lines. The top Y axis in each panel is the percent survival and the bottom Y axis is the percent weight loss. The X axis is the time in Days post infection (p.i.). The scattergrams on the right show the tear film titers of individual mouse eyes at 4 days p.i. Red circles and dashed lines  =  female; Black squares and solid lines =  male. In the experiment shown, which is a small subset of the data generated, four male and four female mice of each BXD strain were employed.</p

Quantitative trait loci associated with herpetic stromal keratitis.

<p>BXD strains of mice were infected via the cornea and the severity of stromal keratitis in male and female mice combined determined by two independent observers using a 5 point scale (0 =  no disease, 5 =  penetrating stromal keratitis). Analysis tools in genenetwork available at <a href="http://www.genenetwork.org" target="_blank">www.genenetwork.org</a> were employed to search for possible quantitative trait loci (QTL). See the legend for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092342#pone-0092342-g002" target="_blank">fig. 2</a> for an explanation of the lines in the figure. A significant quantitative trait locus (QTL) for severity of herpetic stromal keratitis was identified on Ch 16. A fully functional interactive analysis and graphic interface is available on GN for trait ID:16186.</p