The major locus for mouse adenovirus susceptibility maps to genes of the hematopoietic cell surface-expressed LY6 family

Abstract

Susceptibility to mouse adenovirus type 1 is associated with the major quantitative trait locus Msq1. Msq1 was originally mapped to a 13-Mb region of mouse chromosome (Chr) 15 in crosses between SJL/J and BALB/cJ inbred mice. We have now narrowed Msq1 to a 0.75-Mb interval from 74.68 to 75.43 Mb, defined by two anonymous markers, rs8259436 and D15Spn14, using data from 1396 backcross mice. The critical interval includes 14 Ly6 or Ly6-related genes, including Ly6a (encoding Sca-1/TAP), Ly6e (Sca-2/Tsa1), Ly6g (Gr-1), and gpihbp1 (GPI-anchored high-density lipoprotein-binding protein 1), as well as the gene encoding an aldosterone synthase (Cyp11b2). The Ly6 family members are attractive candidates for virus susceptibility genes because their products are GPI-anchored membrane proteins expressed on lymphoid and myeloid cells, with proposed functions in cell adhesion and cell signaling. To determine interstrain variation in susceptibility and produce additional resources for cloning Msq1, we assayed the susceptibility phenotype of four previously untested inbred mouse strains. Susceptibility of strain 129S6/SvEvTac was subsequently localized to the Ly6 complex region, using polymorphic genetic markers on Chr 15 in a population of 271 (129S6/SvEvTac x BALB/cJ)F(1) x BALB/cJ backcross mice. We identified a major 129S6/SvEvTac susceptibility allele, Msq1(129S6), on Chr 15 in the same region as Msq1(SJL). The results indicate that a major host factor in mouse adenovirus type 1 susceptibility is likely to be a member of the Ly6 gene family.

Figure 1

Genetic mapping of Msq1. The top line shows SSLP and SNP markers used in fine mapping (BALB/cJ x SJL/J)F₁ x BALB/cJ backcross progeny in the Chr 15 interval between 72.56 and 75.85 Mb; physical positions of each marker are indicated in parentheses. The X symbols indicate the number of mice with genotypic recombination within each subinterval. The lower line is an expansion of the deduced critical interval with predicted candidate genes. Ly6 genes are indicated by black triangles, Ly6-related genes by gray triangles, and the other gene by a white triangle. Genbank transcript designations for the Ly6-related genes (Ly6R1 – 5) are given in Table II. Genes transcribed from the top (+) strand point to the right and genes transcribed from the bottom (−) strand point to the left. Numbers below the line indicate the physical map position in Mb.

Figure 2

MAV-1 susceptibility of inbred strains of mice. Brain viral loads were determined by capture ELISA. Each brain homogenate was assayed in triplicate and each bar represents the average of the background-subtracted triplicate measurements per homogenate with standard deviation. Samples were standardized to a virus stock positive control included in each assay. OD450, optical density at 450 nm. Strain abbreviations: SJL, SJL/J; SWR, SWR/J; 129S6, 129S6/SvEvTac; FVB, FVB/NJ; NOD, NOD/ShiLtJ; B6, C57BL/6J; C3H, C3H/HeJ; 129P3, 129P3/J; BALB, BALB/cJ.

Figure 3

MAV-1 susceptibility phenotypes in backcross mice. Viral loads in 271 (129S6 x BALB/cJ)F₁ x BALB/cJ and (BALB/cJ x 129S6)F₁ x BALB/cJ backcross mice were determined by ELISA assay as in Fig. 2 and plotted in rank order. Each bar represents the mean value for an individual mouse brain homogenate assayed in triplicate; for clarity standard deviations are not shown but are comparable to those in Fig. 2. Genotypes at D15Spn101 are indicated by the bar colors: black, homozygous BALB/cJ; light gray, heterozygous, BALB/cJ/129S6; and four medium-gray bars marked with dots, undetermined. Inset, the frequency of phenotypic classes of the same population.