Acads^{Hdlq8-C57BL/6J}
QTL Variant Detail

Summary

• QTL variant: Acads^{Hdlq8-C57BL/6J}
• Name: acyl-Coenzyme A dehydrogenase, short chain; C57BL/6J
• MGI ID: MGI:3038140
• QTL: Acads Location: Chr5:115248358-115257405 bp, - strand Genetic Position: Chr5, 55.99 cM

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers decreased HDL cholesterol compared to NZB/BlNJ. Sequencing revealed some splice site variants and one polymorphism changing the amino acid from aspartic acid to glycine at amino acid 94. This polymorphism changes both the charge and polarity of the amino acid and is in a highly conserved region of the protein. (J:164460)
• Inheritance: Not Specified

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

This allele is associted with HDL cholesterol levels on an atherogenic diet.

Candidate Genes

J:133501

SNP analysis, mRNA microarray analysis and protein expression difference analysis were used to narrow the QTL intervals of 9 previously identified QTLs for HDL cholesterol (Hdlq1, Hdlq20, Hdlq24), gallstone susceptibility (Lith17, Lith19, Lith21) and obesity (Obwq3, Obwq4, Obwq5). This methodology identified a manageable list of potential candidate genes for each QTL.

A panel of 130,000 SNPs for SM/J and NZB/BlNJ reduced the QTL intervals by 40%-72%. Liver mRNA analysis identified 10 genes differentially expressed between SM/J and NZB/BlNJ strains and this finding was confirmed using TaqMan RT-PCR assays. Mass spectrometry analysis of liver proteins identified 45 proteins displaying differential expression between SM/J andNZB/BlNJ.

On mouse Chromosome 1, Apoa2 (92.6 cM), Fh1, and Hsd11b1 were identified as potential candidate genes for Hdlq20 at 96 cM. Apoa2 was identified based on protein expression and SNP coding sequence differences. Apoa2 displays up-regulation in NZB/BlNJ liver proteins comparedto SM/J. Fh1 displays gene coding sequence differences and decreased protein expression in NZB/BlNJ livers compared to SM/J. Hsd11b1 was identified based on decreased protein expression in NZB/BlNJ.

On mouse Chromosome 5, Acads (65 cM) and Scarb1 (68 cM)were identified as potential candidate genes for Hdlq1 (70 cM) and Lith17 (60 cM). Acads was identified on the basis of decreased protein expression in NZB/BlNJ livers compared to SM/J, as well as coding sequence differences. Scarb1 displays coding regionsequence differences and decreased liver mRNA expression in NZB/BlNJ. Scarb1 is located more closely to Hdlq1 and decreased Scarb1 mRNA expression was observed for this QTL.

On mouse Chromosome 6, Pparg (52.7 cM), Rassf4 and Adipor2 (60.7 cM) were identified as potential candidate genes for Hdlq24 (66 cM) and Obwq3 (42 cM). Pparg displays coding sequences differences between NZB/BlNJ and SM/J while Rassf4 displays decreased liver mRNA expression in NZB/BlNJ animals. Adipor2 displays increased liver mRNAexpression in NZB/BlNJ and gene coding sequence differences. Ndufa9 was identified as a QTL for Hdlq24 on the basis of decreased liver protein expression in NZB/BlNJ and coding sequence differences.

On mouse Chromosome 8,Slc10a2 (2 cM) was identifiedasa potential candidate gene for Lith19 (0 cM) on the basis of increased liver mRNA expression in NZB/BlNJ animals compared to SM/J.

On mouse Chromosome 10, Ctgf (17 cM) was identified as a potential candidate gene for Lith21 (24 cM)on the basis of decreased liver mRNA expression in NZB/BlNJ animals compared to SM/J and gene coding sequences differences.

On mouse Chromosome 17, Pgc (30 cM) was identified as a potential candidate for Obwq4 (32 cM).Pgc displays coding sequence differences between NZB/BlNJand SM/J.

Atrnl1 was identified as a candidate for Obwq5 (52 cM) on chromosome 19. Atrnl1 displays increased liver mRNA expression in NZB/BlNJ animals compared to SM/J.

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

J:83735

Genome scan was performed on 100 male NZO/HlBom x (SJL/NBom x NZO/HlBom)F1 backcross animals to identify QTLs associated with diet-induced obesity and hypercholesterolemia. Parental strain NZO/HlBom exhibits 2-fold increased body weight and plasma cholesterol at 22 weeks of age on a high fat diet compared to lean parental strain SJL/NBom. A single QTL at 72 cM on mouse Chromosome 5, Hypch, was identified in association with elevated serum cholesterol, but not elevated body weight. Hypch gives peak linkage at D5Mit244 with LOD=7.3 on a standard diet and LOD=13.5 on a high fat diet. NZO/HlBom-derived alleles confer elevated serum cholesterol at this locus. The QTL interval spans approximately 59 cM to 79 cM with markers D5Mit240 and D5Mit374 flanking the region, respectively. Hypch maps near previously identified cholesterol QTLs Hdlq1 and Hdl2, and obesity QTL Nob1.

J:84430

Genome scan was performed on 104 female (C57BL/6J x NZB/BlNJ)F1 x C57BL/6J backcross animals to identify QTLs associated with CHOW- and atherogenic-fed HDL cholesterol levels. 97 polymorphic markers were typed and statistically significant loci were confirmed and resolved using (C57BL/6J x NZB/BlNJ)F11 advanced intercross lines (AIL). Parental strain C57BL/6J exhibits decreased HDL cholesterol levels and susceptibility to atherosclerosis compared to parental strain NZB/BlNJ. 6 weeks on an atherogenic diet results in increased HDL levels in NZB/BlNJ but not in C57BL/6J.

Significant linkage was detected at 96 cM on mouse Chromosome 1 near D1Mit206 (LOD=5.5) in the backcross population. This locus, named Hdlq5, is associated with CHOW- and atherogenic-fed HDL levels. Using AILs, the Hdlq5 locus was resolved to a 6 cM interval (87 cM - 93 cM) and a second QTL is named Hdlq6 was discovered. Hdlq6 maps to 102 cM near D1Mit291 (LOD=5.8) and is associated with atherogenic-fed HDL levels. The confidence intervalof Hdlq6 spans 87 cM - 110 cM. Homozygosity for C57BL/6J-derived alleles at Hdlq5 and Hdlq6 confers decreased HDL level whereas homozygosity for NZB/BlNJ-derived alleles confers increased HDL levels. Heterozygous animals exhibit an intermediate phenotype. Three candidate genes for Hdlq5 show differential expression between C57BL/6J and NZB/BlNJ: Nr1i3, Apoa2, and Apcs (Sap). Tgfb2 is a candidate gene for Hdlq6 exhibiting differential expression between the two parental strains.

Significant linkage was also detected at 38 cM on mouse Chromosome 5 near D5Mit200 (LOD=4.7 on the atherogenic diet). Using AILs this locus was resolved into 3 separate QTLs: Hdlq7, Hdlq8, and Hdlq1. Hdlq7 maps to 29 cM and is associated with HDL levels on both CHOW and atherogenic diets (LOD=12 at D5Mit233). The confidence interval of Hdlq7 spans 25 cM - 32 cM. Hdlq8 maps to 60 cM and is associated with HDL levels on an atherogenic diet (LOD=3.6 at D5Mit155). The confidence interval of Hdlq8 spans 58 cM - 63 cM. Hdlq1 (identified in a previous study) maps to 69 cM and is associated with HDL levels on both CHOW and atherogenic diets (LOD=7.1 at D5Mit242.) The confidence interval of Hdlq1 spans 66 cM - 77 cM. Homozygosity for C57BL/6J-derived alleles at Hdlq7, Hdlq8, and Hdlq1 confers decreased HDL level whereas homozygosity for NZB/BlNJ-derived alleles confers increased HDL levels. Heterozygous animals exhibit an intermediate phenotype. Several candidate genes exhibiting differential expression between C57BL/6J and NZB/BlNJ map to the region containing Hdlq7, Hdlq8, and Hdlq1: Fgfbp1, Prom1, Ppargc1a, Tcf1, Ncor2, Scarb1 (Srb1).

Hdlq9 mapped to 59 cM on mouse Chromosome 16 near D16Mit227 (LOD=1.3 on CHOW diet). The confidence interval of Hdlq9 spans 50 cM - 60 cM. This locus was found to interact with Hdlq7 on mouse Chromosome 5. Animals homozygous for C57BL/6J-derived alleles at both Hdlq7 and Hdlq9 exhibit the lowest HDL cholesterol levels on a CHOW diet. Candidate genes for Hdlq9 showing differential expression between the parental strains are App and Ifnar1.

J:154142

A backcross (NZO/HlLt x NON/LtJ) x NON/LtJ, and three intercrosses, (C57BL/6J x DBA/2J), (C57BL/6J x C3H/HeJ), and (NZB/B1NJ x NZW/LacJ) were informative in mapping QTL loci controlling plasma HDL , total cholesterol and triglyceride levels.

In the (C57BL/6J x DBA/2J) cross QTL results presented here by Phenotype, Chr, Marker, cM location , LOD, High strain

Plasma HDL , Chr 1 , Hdlq15 , 85cM , 2.8 , DBA/2J

Plasma HDL , Chr 3 , Hdlq21 , 64cM , 3.0 , C57BL/6J

Plasma HDL , Chr 4 , Hdlq64 , 3cM , 2.2 , C57BL/6J

Plasma HDL , Chr 6 , Hdlq11 , 37cM , 2.8 , DBA/2J

Plasma HDL , Chr 8 , Hdlq16 , 56cM , 4.6 , DBA/2J

Plasma HDL , Chr 12, Hdlq63 , 42cM , 2.2 , C57BL/6J

12.09.2014 Curator Note:

Because Hdlq15 was was originally mapped in J:88486 in 2004 using an (C57BL/6J x 129S1/SvImJ)F2 intercross, which differs from the cross used here, we consider the current study a separate mapping experiment and have named this QTL Hdlq87.

Because Hdlq21 was originally mapped inJ:89309 in 2004 using an (SM/J x NZB/BlNJ)F2 intercross, which differs from the cross used here, we consider the current study a separate mapping experiment and have named this QTL Hdlq93.

Because Hdlq64 was originally mapped in J:142770 in 2008 using (DBA/1J x DBA/2J) crosses, which differs from the cross used here, we consider the current study a separate mapping experiment and have named this QTL Hdlq98.

Because Hdlq11 was originally mapped in J:83460 in 2003 using a (CAST/Ei x DBA/2J)F2 cross, which differs from the cross used here, we consider the current study a separate mapping experiment and have named this QTL Hdlq85.

Because Hdlq16 was originally mapped in J:88486 in 2004 using an (C57BL/6J x 129S1/SvImJ)F2 intercross, which differs from the cross used here, we consider the current study a separate mapping experiment and have named this QTL Hdlq88.

Because Hdlq63 was originally mapped in J:142770 in 2008 using (DBA/1J xDBA/2J)crosses, which differs from the cross used here, we consider the current study a separate mapping experiment and have named the QTL Hdlq97.

In the (C57BL/6J x C3H/HeJ) cross

Plasma HDL , Chr 1 , Hdlq15 , 6.0cM 9.1, C3H/HeJ

Plasma HDL , Chr 11 , Hdlq74 , 42cM ,3.2, C3H/HeJ

Plasma HDL , Chr 18 , Hdlq76,37cM ,2.1, C3H/HeJ

Plasma HDL , Chr 19 , Hdlq48 , 4cM ,2.1, C57BL/6J

In the (NZO/HlLt x NON/LtJ) x NON/LtJ cross

PlaDL , Chr1 ,Hdlq69 , 92cM , 2.4 , NON/LtJ

Plasma HDL , Chr 5 , Hdlq73, 41cM , 3.4, Heterozygous

In the (NZB/B1NJ x NZW/LacJ) cross

Plasma HDL , Chr 1 , Hdlq68 , 49cM , 3.3 , NZW/LacJ

Plasma HDL , Chr 2 , Hdlq70 , 82cM , 2.8 , NZB/B1

PlasmaHDL , Chr3 , Hdlq71 , 26cM , 4.5 , NZB/B1NJ

Plasma HDL , Chr 4 , Hdlq72 , 25cM , 3.5 , NZW/LacJ

Plasma HDL ,Chr 5 , Hdlq7 , 26cM , 9.05 , NZW/LacJ

Plasma HDL , Chr 5 , Hdlq8 , 57cM , 12.7 , NZB/B1NJ

Plasma HDL , Chr 12 , Hdlq75 , 54cM , 4.1 , NZB/B1NJ

Plasma HDL , Chr 16 , Hdlq76 , 2cM , 3.2 , NZW/LacJ

Plasma HDL , Chr 18 , Hdlq77 , 30cM,5.1 , NZW/LacJ

12.09.2014 Curator Note: Because Hdlq7 was originally mapped in J:84430 in 2003 using a (C57BL/6J x NZB/BlNJ)F1 x C57BL/6J backcross, which differs from the cross used here, we consider the current study a separate mapping experiment and have named this QTL Hdlq66.

Also, because Hdlq76 was first mapped here to Chr 18 using the C57BL/6J x C3H/HeJ cross; we have renamed the QTL mapping to 2cM on Chr16 using the (NZB/B1NJ x NZW/LacJ) cross as Hdlq101. We consider the separate crossesasseparte map experiments, mapping novel QTL.

In the (C57BL/6J x DBA/2J) cross

Triglycerides , Chr 12 , Tgq33 , 14 cM , 3.1 , C57BL/6

In the (C57BL/6J x C3H/HeJ) cross

Triglycerides , Chr 2 , Tgq32 , 80 cM , 4.7 , C3H/HeJ

Triglycerides , Chr19 , Tgq34 , 39 cM , 3.2 , C3H/HeJ

In the (NZO/HlLt x NON/LtJ) x NON/LtJ Cross

Triglycerides , Chr 1 , Tgq30 , 89 cM , 3.5 , NON/LtJ

Triglycerides , Chr 2 , Tgq31 , 73 cM , 2.4 , NON/LtJ

In the(NZB/B1NJ x NZW/LacJ) cross

Triglycerides , Chr 7, Tgq4, 50cM ,3.1 , NZW/LacJ

Triglycerides , Chr 8 , Tgq5 , 11 cM , 3.2 , NZW/LacJ

Triglycerides , Chr 18 , Tgq6 ,34 cM,1 , NZW/LacJ

In the (C57BL/6J x C3H/HeJ) cross

Total Cholesterol , Chr 1 , Tcq3, 84 , 2.2, C3H/HeJ

In the(NZO/HlLt x NON/LtJ) x NON/LtJ cross

Total Cholesterol , Chr 8 , Tcq7 , 36 , 1.5 , Heterozygous

In the (NZB/B1NJ x NZW/Lac) cholesterol , Chr2 , Tcq4 , 83,4.0 , NZB/B1NJ

Total Cholesterol , Chr 5 , Tcq5 , 61 , 7.9 ,NZB/B1NJ

Total Cholesterol , Chr 7 , Tcq6 , 62 , 2.9 , NZW/LacJ

Total Cholesterol , Chr 9 , Tcq8 , 53 , 7.7 , NZB/B1NJ

Total Cholesterol , Chr 18 , Tcq9 , 33 , 5.8, NZB/B1NJ

References

• Original: J:84430 Wang X, et al., Using advanced intercross lines for high-resolution mapping of HDL cholesterol quantitative trait loci. Genome Res. 2003 Jul;13(7):1654-64
• All: 2 reference(s)