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Lauren Gerard Koch
Functional Genomics Laboratory
Medical College of Ohio
Toledo, Ohio
A Genome Scan for Aerobic Running Capacity QTLs in Rats
Rat Genetic Models of Aerobic Running Capacity
“A Parallel Strategy”
Identify already-available inbred strains that widely differ in aerobic capacity to serve as genetic models.
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DA PVG AUG SR F344 ACI LEW WKY BUF MNS COP
STRAIN
*
*
*
*
Aerobic Capacity was Assessed By Treadmill Running To Exhaustion In 11 Inbred Rat Strains
DA and COP showed the widest divergence
[Barbato et al, J. Appl. Physiol., 1998]
DIS
TA
NC
E R
UN
(m
eter
s)
70 mm Hg
Langendorff-Neely Working Heart Preparation
Cardiac Performance as a Likely Determinant Phenotype for Differences in Aerobic Capacity
PRE-LOAD
15 mm Hg
AFTER-LOAD
70 mm Hg
Cardiac Output Versus Distance Run
y = 19.03X - 290.39r = 0.868
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30 35 40 45 50 55 60
ISOLATED CARDIAC OUTPUT (ml/min/g Heart Weight)
DIS
TA
NC
E R
UN
(M
ET
ER
S)
PVG
DA
AUG
SR
F344ACILEW
WKYBUF
MNS
COP
[Barbato et al, J. Appl. Physiol., 1998]
Based on these data, we propose that COP and DA strains could serve as parentals for developing a segregating population for the evaluation of the genetic basis of low and high exercise capacity.
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Distance Run to Exhaustion (m)
Tim
e (
min
)
Test for Aerobic Running Capacity
Time
COPDA
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Distance Run to Exhaustion (m)
Tim
e (
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Test for Aerobic Running Capacity
Time
COP F1 DA
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Distance Run to Exhaustion (m)
Tim
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Test for Aerobic Running Capacity
Time
COP F2 F1 DA
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Position (cM)
LO
D s
core
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 X
D3Rat56
D7Rat74D8Rat23
D16Rat17 D16Rat55
D20Rat5
Significant linkage
Suggestive linkage
Genome-Wide Scan for Aerobic Capacity QTLs.Phase I: Selective Genotyping of F2 (COP X DA) Population
D16Rat90
D16Rat48D16Rat13
D16Rat55D16Rat36
D16Rat16
D16Rat56
D16Rat42
D16Arb3
D16Rat109
D16Rat12
D16Rat32
D16Rat19
D16Rat17
D16Rat95
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0 10 20 30 40 50 60 70Position (cM)
LO
D s
core
Lpl Npy5r Cpe Adrb3
LOD Plot for Chromosome 16Phase II: Entire F2 (COP X DA) Population
Significant QTL
D3Rat132D3Rat114
D3Rat61
D3Rat150
D3Rat21D3Rat25D3Rat31
D3Rat42D3Rat44
D3Rat98
D3Rat277
D3Rat56
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0 20 40 60 80 100Position (cM)
LO
D s
co
re
Cel Rxra
Suggestive QTL
LOD Plot for Chromosome 3Phase II: Entire F2 (COP X DA) Population
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COP/COP COP/DA DA/DA
D16Rat55
Dis
tan
ce R
un
(m
)
D3Rat56
DA/DA
COP/COP
COP/DA
Interaction Effect Between Markers D16Rat55 and D3Rat56 on Distance Run
Additional interval mapping was done to determine whether heart weight and body weight QTLs co-localize to aerobic capacity regions.
D7Rat66D7Rat34
D7Rat27
D7Rat147D7Rat51
D7Rat69
D7Rat74
D7Rat86
D7Rat100D7Rat67D7Rat11
D7Rat123D7Rat81 D7Rat101
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Position (cM)
LO
D s
co
reRelative Heart Weight QTL
Chromosome 7
Aerobic Capacity-
Phase I
D8Rat71D8Rat5D8Rat59D8Rat16
D8Rat23
D8Rat158
D8Rat99
D8Rat49D8Rat54D8Rat77
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Position (cM)
LO
D s
co
re
Aerobic Capacity-
Phase I
Total Heart Weight QTLChromosome 8
D8Rat71
D8Rat5
D8Rat59
D8Rat16
D8Rat23
D8Rat158
D8Rat99
D8Rat49
D8Rat54D8Rat77
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Position (cM)
LO
D s
co
re
Body Weight QTLChromosome 8
Aerobic Capacity-Phase I
QTL Regions contain genes related to Lipid Metabolism and Energy Homeostasis
Chromosome 16
• Lipoprotein Lipase (Lpl)
• Neuropeptide Y5 (Npy5r)
• Adrenergic Beta 3 (Adrb3)
• Carboxypeptidase E (Cpe)
Chromosome 7
• Peroxisome Proliferator- Activated Receptors (Ppara)
Chromosome 3
• Carboxyl Ester Lipase (Cel)
• Retinoid X Receptor (Rxra)
Chromosome 8
• Apolipoprotein
(Apoc3, Apoa1, APoa4)
• Hepatic Lipase (Lipc)
• 5´Nucleotidase (Nt5)
• There are at least two aerobic capacity QTLs present on rat chromosome 16. A QTL near D16Rat17 had effects on running capacity independent of other putative QTLs whereas the aerobic capacity QTL located near D16Rat55 interacted with a QTL located near D3Rat56.
• Possible associated relative heart weight, total heart weight, and average body weight QTLs were found on chromosomes 7 (D7Rat74) and 8 (D8Rat23) respectively.
• Candidate genes within the identified QTL regions include enzymes and transcription factors involved in energy balance and lipid metabolism.
Summary
Significance
• These findings represent the first known identification of aerobic capacity QTLs in animal genetic models.
This work will be appear as the cover article in the June issue of Genomics.
END
Phenotype by Genotype(meters run)
Chromosome Locus Model COP/COP COP/DA DA/DA LOD
Score
P Value
(ANOVA)
3 D3Rat56 Dominant 486 18 560 13 592 19 2.2* 0.008
7 D7Rat74 Dominant 493 20 562 14 572 20 1.6 0.035
8 D8Rat23 Additive 588 24 549 18 505 25 1.5 0.041
16 D16Rat17 Dominant 466 19 568 14 601 22 4.0** <0.0001
16 D16Rat55 Dominant 488 19 567 15 597 23 2.9* 0.0007
20 D20Rat5 Recessive 570 29 565 18 494 28 1.6 0.032
* markers above the suggestive LOD threshold for respective models
** markers above the significant LOD threshold for respective models
Putative Aerobic Capacity QTLs for F2 (COP x DA) Population
We found other Likely Determinant Phenotypes where DA is Significantly Greater than COP:
1. Maximal developed tension in isolated papillary muscles (38%) (Chen et al., J. Physiol., 2001).
2. Fractional Shortening (50%) and amplitude of calcium transients (78%) in ventricular myocytes (Chen et al., J.
Physiol., 2001).
3. Wider range for sympathetic and parasympathetic control of heart rate and blood pressure (Koch et al., Physiol.
Genomics, 1999).
4. Heart weight to body weight ratio (27%) (Koch et al., Physiol.
Genomics, 1999).
5. Cardiac adenosine production (46%) (Walker et al., Am J.
Physiol., 2002).
Sensorimotor Capacity in 11 Inbred Rat Strains Assessed by Rotarod Performance
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PVG BUF SR/Jr ACI WKY F344 AUG LEW COP DA MNS
SE
CO
ND
S
PVG and MNS showed the widest divergence
Biesiadecki et al., Am J. Physiol.,1999
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