Genome-wide isolation of growth and obesity QTL using mouse speed congenic strains

Linkage studies suggested that a quantitative trait locus (QTL) for blood pressure (BP) was present in a region on chromosome 17 (Chr 17) of Dahl salt-sensitive (DSS) rats. A subsequent congenic strain targeting this QTL, however, could not confirm it. These conflicting results called into question the validity of localization of a QTL by linkage followed by the use of a congenic strain made with an incomplete chromosome coverage. To resolve this issue, we constructed five new congenic strains, designated C17S.L1 to C17S.L5, that completely spanned the ±2 LOD confidence interval supposedly containing the QTL. Each congenic strain was made by replacing a segment of the DSS rat by that of the normotensive Lewis (LEW) rat. The only section to be LL homozygous is the region on Chr 17 specified in a congenic strain, as evidenced by a total genome scan. The results showed that BPs of C17S.L1 and C17S.L2 were lower ( P < 0.04) than that of DSS rats. In contrast, BPs of C17S.L3, C17S.L4, and C17S.L5 were not different ( P > 0.6) from that of DSS rats. Consequently, a BP QTL must be located in an interval of ∼15 cM shared between C17S.L1 and C17S.L2 and unique to them both, as opposed to C17S.L3, C17S.L4, and C17S.L5. The present study illustrates the importance of thorough chromosome coverage, the necessity for a genome-wide screening, and the use of “negative” controls in physically mapping a QTL by congenic strains.

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Genome-Tagged Mice (GTM): Two Sets of Genome-wide Congenic Strains

Genomics ◽

10.1006/geno.2000.6497 ◽

2001 ◽

Vol 74 (1) ◽

pp. 89-104 ◽

Cited By ~ 60

Author(s):

Olga A. Iakoubova ◽

Christine L. Olsson ◽

Katherine M. Dains ◽

David A. Ross ◽

Ali Andalibi ◽

...

Keyword(s):

Congenic Strains ◽

Genome Wide

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Quantitative trait loci with opposing blood pressure effects demonstrating epistasis on Dahl rat chromosome 3

Physiological Genomics ◽

10.1152/physiolgenomics.00084.2003 ◽

2003 ◽

Vol 15 (1) ◽

pp. 1-8 ◽

Cited By ~ 39

Author(s):

Ana Palijan ◽

Julie Dutil ◽

Alan Y. Deng

Keyword(s):

Blood Pressure ◽

Quantitative Trait ◽

Pressure Effects ◽

Chromosome 3 ◽

Screening Process ◽

Congenic Strains ◽

Genome Wide ◽

A Genome ◽

Blood Pressure Effects ◽

Trait Locus

Our previous linkage studies indicated that there might be a blood pressure (BP) quantitative trait locus (QTL) on chromosome 3 (Chr 3) contrasting between the Dahl salt-sensitive (S) strain and the Lewis (LEW) strain. To prove and then to narrow down the segment containing this QTL, five congenic strains have been generated by replacing various segments of the S rats with the homologous segments of the LEW rats. They are designated as S.L1, S.L2, S.L3, S.L4, and S.L5, respectively. S.L2, S.L3, S.L4, and S.L5 are substrains of S.L1, i.e., they contain substitutions of smaller sections within the large fragment defined by S.L1. The construction of these congenic strains was facilitated by a genome-wide marker screening process. BPs of the rats were measured by telemetry. S.L2 and S.L3 shared a fragment of Chr 3 in common and both showed a BP-lowering effect, indicating the existence of “−BP” QTL alleles from LEW compared with S. In contrast, S.L4 involves a section with no overlap with either S.L2 or S.L3, and S.L4 showed a BP significantly higher than that of S rats, indicating the presence of “+BP” QTL alleles from LEW compared with S. Interestingly, the combined effect of the −BP QTL and +BP QTL alleles was “−” in S.L1, implying that the “−” QTL is epistatic to “+” QTL.

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Chromosome 2 Reciprocal Congenics to Evaluate the Effect of the Genetic Background on Blood Pressure

Hypertension ◽

10.1161/hyp.36.suppl_1.687-c ◽

2000 ◽

Vol 36 (suppl_1) ◽

pp. 687-687

Author(s):

Cervantes D Negrin ◽

Delyth Graham ◽

James S Clark ◽

Martin W McBride ◽

Fiona J Carr ◽

...

Keyword(s):

Blood Pressure ◽

Parental Strain ◽

Genetic Background ◽

Congenic Strain ◽

Chromosome 2 ◽

Night Time ◽

Congenic Strains ◽

Genome Wide ◽

A Genome ◽

Additional Qtls

54 Background Localisation of QTL using a genome wide scan strategy is the first step towards gene identification. This is followed by the construction of congenics by which the existence of the QTL can be verified. Congenic strains for chromosome 2 using the Dahl S as the recipient and WKY and MNS as donors, showed variable blood pressure (BP) depending on the donor alleles 1 . Methods We used a speed congenic approach to produce several congenic strains of chromosome 2 using the SHRSP Gla and the WKY Gla as recipients to test the effect of the genetic background of a given congenic on BP. In some strains, the region introgressed was identical to avoid confounding effects of additional QTLs. Two reciprocal control congenic strains were also produced to determine the presence of any passenger loci. Baseline systolic BP was measured by radiotelemetry. Results Four congenic and 2 parental strains were phenotyped (n=3-6). Transfer of the region of rat chromosome 2 from the WKY into a SHRSP background significantly lowered both day and night-time systolic BP by approximately 16 and 20 mm Hg respectively in male congenic rats compared to the SHRSP parental strains (p<0.005, 95%CI: 8.6-21.0 mm Hg; and p<0.005, 95%CI: 16.7-24.7 mm Hg). In contrast, transfer of the same region from the SHRSP into a WKY background significantly increased both day and night-time systolic BP by approximately 25 and 28 mm Hg, respectively in male congenic rats compared to the WKY parental strains (p<0.05, 95%CI: -49.2-2.0 mmHg; and p<0.05%, 95%CI: -61.2-6.1 mm Hg, respectively). Reciprocal control congenic strain showed no deviation from the BP recorded in the parental strain (Strain WKY.SPGla2b vs. WKY parental strain, 128.8±5.2 mm Hg vs. 139.7±5.7 mm Hg, p= ns; and strain SP.WKYGla2b vs. SHRSP parental strain, 178.0±5.0 mm Hg vs. 179.9±2.1 mm Hg, p= ns). Conclusions The results show the effect of a permissive background on BP and confirm that the genetic background chosen for a congenic strain has a significant effect on the BP phenotype. Moreover, this work sheds new light on the different epistatic or pleiotropic effects according to the genetic background chosen. 1. Deng AY et al . Hypertension 1997;30:199-202

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