Scpro6^DBA/2J
QTL Variant Detail

Summary

• QTL variant: Scpro6^DBA/2J
• Name: Stem cell proliferation 6; DBA/2J
• MGI ID: MGI:3578844
• QTL: Scpro6 Location: unknown Genetic Position: Chr3, cM position of peak correlated region/allele: 21.81 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: DBA/2J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased hematopoietic stem cell numbers in young animals compared to C57BL/6J. (J:98123)

Notes

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

J:98123

Linkage analysis was performed on animals from 26 BXD (B=C57BL/6J; D=DBA/2J) recombinant inbred (RI) strains to identify QTLs associated with age-dependent hematopoietic stem cell proliferation. A panel of 319 markers at a resolution of 3.75 cM was used for linkage analysis. Aged animals of progenitor strain C57BL/6J exhibit increased stem cell proliferation and bone marrow repopulation capability compared to aged animals of progenitor strain DBA/2J.

Significant linkage to early hematopoietic progenitorcell (eHPC) numbers and hematopoietic stem cell (HSC) numbers in young animals mapped to 38 cM on mouse Chromosome 1 near D1Mit282. This locus is named Scpro4 (stem cell proliferation 4.) C57BL/6J-derived alleles at Scrpo4 confer increased eHPCs and HSCsin young animals and shows interaction with Scpro7 on mouse Chromosome 5. (The C57BL/6J allele at Scpro4 appears to suppress the effect of the DBA/2J allele at Scpro7.) This locus shows synteny to a region on human Chromosome 2q33-q35. Potential candidate genes for Scpro4 are Igfbp2 (36.1 cM), Igfbp5 (36.1 cM), Wdt2, and Il8rb (40 cM). Suggestive linkage to HSCs in young animals mapped to 100 cM near D1Mit150. DBA/2J-derived alleles at D1Mit150 confer increased HSCs at the suggestive locus.

Linkage to early hematopoietic progenitor cell (eHPC) numbers and hematopoietic stem cell (HSC) numbers in old animals mapped to 72 cM on mouse Chromosome 2 near D2Mit423. This locus is named Scpro5 (stem cell proliferation 5) and is believed to also be involved in aging. C57BL/6J-derived alleles at Scrpo5 confer increased eHPCs and HSCs in old animals. Potential candidate genes mapping near Scrpo5 are Il1a (73 cM), Il1b (73 cM), Fgf7, Dll4, and Bmp2 (76.1 cM). This locus shows synteny to regions on human Chromosomes15p13-p22 and 20p12-p13.

Linkage to hematopoietic stem cell (HSC) number in young animals mapped to

24 cM on mouse Chromosome 3 near D3Mit6. This locus is named Scpro6 (stem cell proliferation 6.) DBA/2J-derived alleles at Scpro6 confer increased HSCs in young animals. Potential candidate genes for Scpro6 are Il2 (19.2 cM) and Fgf2 (19.3 cM). This locus shows synteny to regions on human Chromosome 3q25-p27 and 4q26-p28.

Linkage to hematopoietic stem cell (HSC) number in young animals mapped to

20 cM onmouse Chromosome 5 near D5Mit352. This locus is named Scpro7 (stem cell proliferation 7.) DBA/2J-derived alleles at Scpro7 confer increased HSCs in young animals. Scpro4 on mouse Chromosome 1 shows interaction with Scpro7. (The C57BL/6J allele at Scpro4 appears to suppress the effect of the DBA/2J allele at Scpro7.) Potential candidate genes mapping near Scpro7 are Il6 (17 cM), Fgfr3 (20 cM), Hmx1 (18 cM), and Msx1 (21 cM). This locus shows synteny to regions on human Chromosome 3q25-p27 and 4q26-p28.

Linkage to early hematopoietic progenitor cell (eHPC) number in young and old animals mapped to 50 cM on mouse Chromosome 7 with LOD=10.1 near Hbb (50 cM). This locus is named Scrpo8 (stem cell proliferation 8.) DBA/2J-derived alleles at Scpro8 confer increased eHPCs in young and old animals. Scpro8 was confirmed using congenic lines derived from DBA/2J and C57BL/6J. Potential candidate genes mapping near Scrpo8 are Eed (47 cM) and Stim1 (50 cM.) This locus shows synteny to regions on human Chromosome 11q13-q11.5 and 11p15-p15.5. Suggestive linkage to eHPCs in young animals was also detected on mouse Chromosome 7 at 8 cM and 25 cM.

Linkage to early hematopoietic progenitor cell (eHPC) number in old animals mapped to 13 cM on mouse Chromosome 14 near D14Mit45.This locus is named Scpro9 (stem cell proliferation 9.) DBA/2J-derived alleles at Scpro9 confer increased eHPCs in old animals. This locus shows synteny to regions on human Chromosome 3, 10q22, and 14q11-q12. Potential candidate genes for Scrpo9 are Prkcd (11 cM), Bmpr1a (13 cM), Tep1 (13.5 cM), Bmp4 (15 cM.)

Linkage to hematopoietic stem cell (HSC) and early hematopoietic progenitor cell (eHPC) numbers in old animals mapped to 27 cM on mouse Chromosome 18 near D18Mit53 (LOD=7.5). This locus is named Scpro10 (stem cell proliferation 10.) DBA/2J-derived alleles at Scpro10 confer increased HSCs and eHPCs in old animals. Scpro10 also shows suggestive linkage to HSCs in young animals with DBA/2J-derived alleles conferring increased HSCs in this group. Potential candidate genes mapping near Scrpo10 are Fgf1 (19 cM), Csf1r (30 cM), Pdgfrb (30 cM), and Cdx1 (30 cM). This locus shows synteny to a region on human Chromosome 5q31-q33.

Linkage to hematopoietic stem cell (HSC) numbers in young animals mapped to 51 cM on mouse Chromosome X near DXMit38. This locus is named Scpro11 (stem cell proliferation 11.) C57BL/6J-derived alleles at Scpro11 confer increased HSCs in young animals. No candidate genes for Scpro11 have been identified thus far. This locus shows synteny to human Chromosome Xq21-q27.

Suggestive linkage to early hematopoietic progenitor cell (eHPC) numbers in old animals mapped to 59 cM on mouse Chromosome 15 near D15Mit42. C57BL/6J-derived alleles at D15Mit42 confer increased eHPCs in old animals.Potential candidate genes mapping near this locus are Ecgf1 (51.6 cM), Hoxc (57.4 cM), Itga5 (57.4 cM), and Itgb7 (61.1 cM).

J:118331

Reciprocal congenic lines derived from DBA/2J and C57BL/6J were used to further examine Scpro6 (stem cell proliferation 6), a previously identified QTL at 24 cM on mouse Chromosome 3. Parental strain C57BL/6J exhibits increased stem cell proliferation and bone marrow repopulation capability compared to parental strain DBA/2J.

The B6.D2-Scpro6 congenic line carries DBA/2J-derived DNA on chromosome 3 from 14 cM to 33 cM on a C57BL/6J genetic background. These animals display a 2-fold increase in whole-bone marrow cobblestone area forming cell (CAFC) numbers in vitro, and a 73% increase in long-term repopulating hematopoietic stem cells (HSCs) in vivo. The reciprocal congenic D2.B6-Scpro6 carries C57BL/6J-derived DNA on chromosome 3 from 19 cM - 60 cM on aDBA/2J genetic background. These animals display the reverse trend with a 40% decrease in day 35 CAFC numbers. The findings suggest that DBA/2J-derived alleles at Scpro6 increase HSC numbers whereas C57BL/6J-derived alleles decrease HSC numbers.

The Scpro6 consensus interval was localized to a region spanning 36.5 Mb (19.2 cM) - 67.8 Mb (33 cM). The mostly highly correlated marker is D3Mit5 at 50.4 Mb (25 cM). Oligonucleotide array analysis was performed using bone marrow RNA derived from reciprocal congenic lines and progenitor strains C57BL/6J and DBA/2J to identify genes exhibiting differential expression. Lxn (31.6 cM) maps to the Scpro6 QTL interval and is upregulated in C57BL/6J and downregulated in DBA/2J. In addition an inverse correlation between Lxn expression and HSC numbers was observed in reciprocal congenic animals. B6.D2-Scpro6 congenic animals display decreased Lxn expression and increased HSC numbers while D2.B6-Scpro6 congenic animals display increased Lxn expression and decreased HSC numbers. Several SNPs were detected and confirmed in the Lxn potential upstream regulatory regions.

In vitro overexpression of Lxn in bone marrow cells derived from DBA/2J and B6.D2-Scpro6 (both high HSC strains) reduced primitivestem cell frequencies byone-thirdcompared to the level of primitive stem cells observed in bone marrow cells transfected with a control-vector.

Linkage analysis was performed using 30 BXD (B=C57BL/6J; D=DBA/2) recombinant inbred (RI) strains to identify QTLs regulating Lxn expression. A suggestive cis-acting QTL was detected at 56.9 Mb - 66.8 Mb on chromosome 3 near Lxn with C57BL/6J-derived alleles increasing Lxn expression. It is unclear whether this is a separate and distinct QTL from Scpro6.

References

• Original: J:98123 Geiger H, et al., Age- and stage-specific regulation patterns in the hematopoietic stem cell hierarchy. Blood. 2001 Nov 15;98(10):2966-72
• All: 2 reference(s)