Spp1^Ric-s
QTL Variant Detail

Summary

• QTL variant: Spp1^Ric-s
• Name: secreted phosphoprotein 1; rickettsia tsutsugamushi susceptible
• MGI ID: MGI:2663655
• Synonyms: Ric^S
• QTL: Spp1 Location: Chr5:104582984-104588916 bp, + strand Genetic Position: Chr5, 50.68 cM

Variant origin

• Strain of Specimen: multiple strains

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele determines susceptibility to Rickettsia tsutsugamushi and occurs in strains A/He, C3H/He, CBA/J, DBA/1, DBA/2, and SJL. (J:9889)
• Inheritance: Recessive

Notes

This allele determines susceptibility to the lethal effects of intraperitoneal injection of the Gilliam strain of Rickettsia tsutsugamushi. Susceptible strains include A/He, C3H/He, CBA/J, DBA/1, DBA/2 and SJL. Spp1^Ric-r/Spp1^Ric-s heterozygotes are resistant (J:5949, J:6505).

Mapping and Phenotype information for this QTL, its variants and associated markers

J:75894

26 C57BL/6J x DBA/2J (BXD) recombinant inbred (RI) strains were analyzed for loci linked to spatial abilities during the Morris navigation task. 118 polymorphic markers at an average spacing of 25 cM were screened in 6 animals of each RI strain. A locus with significant linkage to escape latencies during the Morris navigation task, Elnt, mapped to mouse Chromosome 1 with a maximun LOD = 6.23 between 90 cM (D1Mit106) - 98 cM (D1Mit155). A locus linked to spacial bias during the Morris navigation task, Sbnt1, mapped to mouse Chromosome 5 with a LOD peak of 3.72 at 61 cM between Spp1 (56 cM) and D5Byu4 (68 cM). Two other loci affecting spacial bias were shown to interact with Sbnt1, one of which reached statistcal significance on mouse Chromosome 13 with LOD = 3.41 between 23 cM (D13Byu1) - 35 cM (D13Mit13) and was named Sbnt2. The other locus reached suggestive significance on mouse Chromosome 2 with LOD = 2.9 at 49 cM between D2Mc2 (48 cM) and D2Byu3 (69 cM).

J:97786

Linkage analysis was performed on 527 animals from a (MRL/MpJ-Fas^lpr x C3H/HeJ-Fas^lpr)F2 intercross to identify loci associated with susceptibility to systemic lupus erythrematosus (SLE). 106 polymorphic microsatellite markers at an average spacing of 12 cM were used for the genome scan. Glomerulonephritis incidence was used to measure SLE susceptibility. Parental strain MRL/MpJ-Fas^lpr is susceptible to SLE (68.2% incidence) whereas parental strain C3H/HeJ-Fas^lpr is resistant (5.1% incidence). F1hybrids and F2 intercross animals exhibit intermediate SLE resistance with 24% and 28.8% disease incidence, respectively.

Significant linkage to SLE susceptibility mapped to 2 different loci on mouse Chromosome 4. The first QTL, named Agnm1 (autoimmuneglomerulonephritis in MRL 1), is located between D4Mit89 (19.8 cM) and D4Mit241 (24.1 cM). MRL/MpJ-derived alleles at Agnm1 confer recessive susceptibility to SLE, or increased glomerulonephritis, with LOD=8.2. The second QTL, named Agnm2 (autoimmune glomerulonephritis in MRL 2), is located between D4Mit187 (49 cM) and D4Mit147 (57.6 cM). MRL/MpJ-derived alleles at Agnm2 confer additive susceptibility to SLE, or increased glomerulonephritis, with LOD=5.5. These loci colocalize with previously identified QTLs Arvm1 (19.8 cM) and Arvm2 (58 cM) and are suspected to harbor the same underlying genes.

Significant linkage to SLE susceptibility mapped to 56 cM on mouse Chromosome 5 near D5Mit115 (LOD=4.0). This locus is named Agnm3 (autoimmune glomerulonephritis in MRL 3) and was confirmed by composite interval mapping. MRL/MpJ-derived alleles at Agnm3 confer additive susceptibility to SLE (as measured by increased glomerulonephritis). The Agnm3 interval spans approximately 54 cM - 65 cM on chromosome 5. Previously identified loci mapping near Agnm3 are Lprm4 (54 cM) and Tsz1 (56 cM). A range between D5Mit23 and D5Mit136 can be outlined for Agnm3.

The marker of peak linkage, D5Mit115, is located in the promoter of Spp1 (formerly Opn), a possible candidate gene. Analysis of the Spp1 promoter region showed a 12 bp insertion as well as a deletion SNP in C3H/HeJ. The MRL/MpJ allele of D5Mit115 is shared among inbred strains C57BL/6J-Fas^lpr, NZW, and NZW. The C3H/HeJ allele of D5Mit115 is shared with the BXSB strain. Previous analysis of the Spp1 sequence revealed 10 amino acid differences between MRL/MpJ and C3H/HeJ. Functional analysis of MRL/MpJ-derived Spp1 protein and C3H/HeJ-derived Spp1 protein was carried out using a cell-free protein synthesis system. The MRL/MpJ-derived Spp1 protein exhibits significantly increased induction of Tnfa and Il1b in bone marrow derived macrophages, significantly increased induction of Ifng in splenocytes, and significantly higher IgG3, IgG2, and IgM secretion from splenocytes compared to the C3H/HeJ-derived Spp1 protein.

J:7417

Tsz1, a QTL affecting adult thymus size was mapped using 20 BXD (B=C57BL/6J; D=DBA/2J) and 24 AXB/BXA (B=C57BL/6J; A=A/J) recombinant inbred strains. Parental strain C57BL/6J exhibits a 2-fold increase in thymus size compared to parental strains DBA/2J and A/J. The strain distribution pattern of Tsz1 in BXD RI strains showed statistically significant correlation to Spp1 (56 cM) on mouse Chromosome 5. The genetic distance between Tsz1 and Spp1 is estimated to be approximately 8 cM. However, Tsz1 did not show linkage to Gusb (72 cM), the chromosome 5 marker in the AXB/BXA RI strains.

J:8914

Inbred strain BALB/c is susceptible to corneal infection with Pseudomonas aeruginosa whereas inbred strain DBA/2 is resistant. Approximately 30% of animals from a (DBA/2 x BALB/c)F1 x BALB/c backcross exhibit the resistant phenotype indicating that at least 2 resistance loci are involved.

Analysis of several previously established congenic lines derived from BALB/c and DBA/2 mapped one resistance locus, Pscr1 (corneal resistance to P. aeruginosa 1), to mouse Chromosome 5 near Pgm1 (38 cM) and Spp1 (56 cM). A second locus named Pscr2 mapped to mouse Chromosome 1 between Idh1 (29.8 cM) and Pepc (71 cM). A potential candidate gene for Pscr2 is Slc11a1 (39.2 cM). A third locus, Pscr3, on mouse Chromosome 12 is also implicated in resistance to corneal infection by P. aeruginosa. Pscr3 may be located near Igh-Ia (58.5 cM). DBA/2-derived alleles at Pscr1, Pscr2,and Pscr3 confer resistance.

These three resistance loci were confirmed using 26 BXD recominant inbred lines where progenitor strain C57BL/6 is susceptible and progenitor strain DBA/2 is resistant. However, the 3 BXD RI strains that were homozygous for DBA/2-derived alleles on chromosome 1, 5, and 12 exhibit partial resistance to corneal infection by P. aeruginosa.

J:252459

Quantitative trait loci mapping was used to identify candidate genes that regulate cholesterol metabolism in bone marrow-derived macrophages (BMDMs) derived from 122 (AKR/J x DBA/2J)F4 mice (70 males, 52 females). AKR/J and DBA/2J mice differ substantially in their susceptibility to atherosclerosis, where DBA/2J-Apoe^tm1Bres mice develop ~ 10 times larger aortic root lesions than AKR/J-Apoe^tm1Bres mice. Cultured BMDMs from DBA/2J (DBA/2) versus AKR/J (AKR) mice accumulate much more cholesterol ester (CE) after cholesterol loading than with acetylated LDL (acLDL). The aim was to discover genes that play causal roles in macrophage cholesterol metabolism.

The BMDMs of the 122 (AKR x DBA/2)F4 mice were acLDL loaded and their free cholesterol (FC) and CE levels normalized to cell protein were measured as well as their CE/FC ratio. After genotyping using a high-density SNP microarray using 16975 informative SNPs, QTL mapping was performed of the BMDM cholesterol phenotypes using R/qtl software. Ten distinct macrophage cholesterol metabolism QTL were identified, Table 1 (mapped locations relative to NCBI B37):

QTL Mcmm1 (macrophage cholesterol metabolism modifier 1) mapped to Chromosome 1 with the highest LOD score for FC levels (p^{0.0001) of 10.64 at peak position 155.51 Mb ; LOD=10.76 at 156.34 Mb for CE (p<0.0001) and LOD=12.46 at 156.35 for the CE/FC ratio (p<0.0001). There was strong dosage effect of Mcmm1 with the DBA/2 allele associated with lower FC and higher CE and CE/FC ratio. Mcmm1 was associated with 30% of variance in FC, 33% of the variance in CE and 31% of variance in CE/FC. Thirty four genes mapped within the Mcmm1 interval. Soat1, encoding ACAT1, was the top causal candidate gene, which was confirmed using CRISPR/Cas9 gene editing in DBA/2 ES cells. AKR mice are known to harbor a 33 amino acid N-terminal truncation in ACAT1 because of a 6.8 kb genomic deletion in Soat1.}

Because Mcmm1 had the highest LOD scores for the measured BMDM cholesterol phenotypes, CE levels for QTL Mcmm2 to Mcmm10 were determined after correcting for Mcmm1 genotype as an additive covariate.

QTL Mcmm2 (macrophage cholesterol metabolism modifier 2) mapped to Chromosome 1 with a LOD score for CE levels (p<0.01 of 5.6 and a LOD score of 6.1 for CE/FC (p<0.01) at peak position 184.65 Mb. Mcmm2 is a very small locus at the distal end of chromosome 1 with a Bayesian credible interval of 184.65-184.89 Mb. This locus harbors only three genes; Tlr5, Susd4, and Ccdc185.

QTL Mcmm3 (macrophage cholesterol metabolism modifier 3) mapped to Chromosome 2 with a LOD score of 4.7 for CE levels (p<0.05) at peak position 118.97 Mb and a LOD score of 3.5 for CE/FC levels (p<0.02) at peak position 126.97 Mb.

QTL Mcmm4 (macrophage cholesterol metabolism modifier 4) mapped to Chromosome 5 with a LOD score of 5.7 for CE levels (p<0.01) and a LOD score of 4.6 for CE/FC levels (p<0.05) at peak position 105.44 Mb. Mcmm4 is located in the middle of chromosome 5 with a Bayesian credible interval of 68.02-107.43 Mb and harbors 428 genes. The top candidates for this locus are Mepe, Spp1, and Pkd2.

QTL Mcmm5 (macrophage cholesterol metabolism modifier 5) mapped to Chromosome 6 with a LOD score of 5.3 for CE levels (p<0.01) and a LOD score 2.4 for CE/FC levels (p0.63) at peak position 120.13 Mb. Mcmm5 is located at the distal end of chromosome 6 with a Bayesian credible interval of 118.95-122.59 Mb and harbors 64 genes. Bid and Atp6v1e1 stood out as top candidates because of their relatively strong BMDM cis-eQTL scores in prior studies.

QTL Mcmm6 (macrophage cholesterol metabolism modifier 6) mapped to Chromosome 9 with a LOD score of 5.3 for CE levels (p<0.01) at peak position 31.70 Mb and a LOD score of 3.6 for CE/FC levels (p=.15) at peak position 31.19 Mb. Mcmm6 is located at the proximal end of chromosome 9 with a Bayesian credible interval of 3.58-34.82 Mb and harbors 318 genes. Casp1 was a top candidate for this locus, Fli1 was also a candiate.

QTL Mcmm7 (macrophage cholesterol metabolism modifier 7) mapped to Chromosome 10 with a LOD score of 4.6 for CE levels (p<0.05) at peak position 127.52 Mb and a LOD score of 3.9 for CE/FC levels (p<0.10) at peak position 17.54 Mb. Os9 was a plausible cadidate for this locas, as it had a strong BMDM cis-eQTL in prior studies and was shown to be associated with lipid storage in adipocytes.

QTL Mcmm8 (macrophage cholesterol metabolism modifier 8) mapped to Chromosome 11 with a LOD score of 6.0 for CE levels (p<0.01) at peak position 7.27 Mb and a LOD score of 3.8 for CE/FC levels (p<0.10) at peak position 4.03 Mb. Mcmm8 is located at the proximal end of chromosome 11 with a Bayesian credible interval of 4.03-36.44 Mb and harbors 468 genes. Camk2b was the strongest candidate gene for this locus.

QTL Mcmm9 (macrophage cholesterol metabolism modifier 9) mapped to Chromosome 12 with a LOD score of 5.7 for CE levels (p<0.01) at peak position 95.60 Mb and a LOD score of 4.8 for CE/FC levels (p<0.05) at peak position 80.45 Mb. Mcmm9 is located at the distal end of chromosome 12 with a Bayesian credible interval of 79.09-95.60. There was no clear candidate gene.

QTL Mcmm10 (macrophage cholesterol metabolism modifier 10) mapped to Chromosome 17 with a LOD score of 5.3 for CE levels (p<0.01) at peak position 88.56 Mb and a LOD score of 3.8 for CE/FC levels (p<0.15) at peak position 77.30 Mb. Mcmm10 is located at the distal end of chromosome 17 with a Bayesian credible interval of 68.68-89.29 Mb and harbors 191 genes. The strongest candidate was Dync2li1.

References

• Original: J:5949 Groves MG, et al., Host defenses in experimental scrub typhus: genetics of natural resistance to infection. Infect Immun. 1978 Feb;19(2):583-8
• All: 8 reference(s)