Linkage analysis was performed on a population of male BALB/cSim x (BALB/cSim x B10.D2/oSnJ)F1 backcross animals to identify QTL associated with resistance to the parasite Leishmania major. Parental strain B10.D2/oSnJ is resistant to subcutaneous infection with L. major whereas parental strain BALB/cSim is susceptible. F1 hybrids are fully resistant to L. major infection. 98 microsatellite markers covering 97% of the mouse genome with an average spacing of 10 cM were used for the genome scan.
Linkage toLeishmania resistance mapped to mouse Chromosomes 6, 7, 10, 11, 15, and 16 with statistical significance of p<0.0001. These loci are named Lmrq1 (Leishmania resistance QTL 1), Lmrq2, Lmrq3, Lmrq4, Lmrq5, and Lmrq6, respectively. The resistance QTL appearto interact epistatically. Male backcross animals heterozygous for only one or two resistance loci have significant protection against infection with L. major compared to BALB/cSim parentals.
The Lmrq1 interval on mouse Chromosome 6 spans 21 cM long. A potential candidate gene for Lmrq1 is Klrb1c (62.1 cM).
The Lmrq2 interval on mouse Chromosome 7 spans 7 cM long.
The Lmrq3 interval on mouse Chromosome 10 spans 5 cM long. Potential candidate genes for Lmrq3 are Ifng (67 cM) and Stat6 (70 cM).
Lmrq4 on mouse Chromosome 11 was confirmed in a congenic line homozygous for B10.D2/oSnJ-derived alleles between D11Mit2 (2.4 cM) and D11Mit29 (40 cM) on a BALB/cSim genetic background. Male mice of this congenic line were either fully resistant or intermediate with respect to footpad swelling after subcutaneous infection with L. major. Potential candidate genes mapping near Lmrq4 include Scl1, Lif (0.25 cM), Osm (1 cM), Igfbp1 (1.3 cM), Igfbp2 (36.1 cM), Zfpn1a1 (6 cM), Il4 (29 cM), and Il12b (19 cM).
The Lmrq5 interval on mouse Chromosome 15 spans 10 cM long. Potential candidate genes for Lmrp5 include Il7r (4.6 cM), Lifr (4.6 cM), C6 (3 cM), and C7 (3 cM).
The Lmrq6 interval on mouse Chromosome 16 spans 2 cM long. A previously identified QTL named Eae2 (15.5 cM) maps near Lmrq6. Potential candidate genes for Lmrq6 include Ifngr2 (63.3 cM), Ifnar1 (63.2 cM), and Ifnar2 (63.1 cM).