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A Genome Scan for Aerobic Running Capacity QTLs in Rats. Lauren Gerard Koch Functional Genomics Laboratory Medical College of Ohio Toledo, Ohio. Rat Genetic Models of Aerobic Running Capacity “A Parallel Strategy”

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slide1

A Genome Scan for Aerobic Running Capacity QTLs in Rats

Lauren Gerard Koch

Functional Genomics Laboratory

Medical College of Ohio

Toledo, Ohio

slide2

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.

slide3

Aerobic Capacity was Assessed By Treadmill Running To Exhaustion In 11 Inbred Rat Strains

DA and COP showed the widest divergence

DISTANCE RUN (meters)

[Barbato et al, J. Appl. Physiol., 1998]

slide4

Cardiac Performance as a Likely Determinant Phenotype for Differences in Aerobic Capacity

AFTER-LOAD

70 mm Hg

70 mm Hg

PRE-LOAD

15 mm Hg

Langendorff-Neely Working Heart Preparation

slide5

Cardiac Output Versus Distance Run

900

DA

y = 19.03X - 290.39

800

r = 0.868

PVG

AUG

700

600

SR

DISTANCE RUN (METERS)

500

F344

ACI

LEW

WKY

400

BUF

MNS

300

COP

200

30

35

40

45

50

55

60

ISOLATED CARDIAC OUTPUT (ml/min/g Heart Weight)

[Barbato et al, J. Appl. Physiol., 1998]

slide6

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.

slide7

DA

COP

slide8

COP

F1

DA

slide9

DA

F1

F2

COP

slide10

Genome-Wide Scan for Aerobic Capacity QTLs.

Phase I: Selective Genotyping of F2 (COP X DA) Population

slide11

LOD Plot for Chromosome 16

Phase II: Entire F2 (COP X DA) Population

Significant QTL

slide12

LOD Plot for Chromosome 3

Phase II: Entire F2 (COP X DA) Population

slide14

Additional interval mapping was done to determine whether heart weight and body weight QTLs co-localize to aerobic capacity regions.

slide15

Relative Heart Weight QTL

Chromosome 7

Aerobic Capacity-Phase I

slide16

Total Heart Weight QTL

Chromosome 8

Aerobic Capacity-Phase I

slide17

Body Weight QTL

Chromosome 8

Aerobic Capacity-Phase I

slide18

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 3
    • Carboxyl Ester Lipase (Cel)
    • Retinoid X Receptor (Rxra)
  • Chromosome 8
    • Apolipoprotein
    • (Apoc3, Apoa1, APoa4)
    • Hepatic Lipase (Lipc)
    • 5´Nucleotidase (Nt5)
  • Chromosome 7
    • Peroxisome Proliferator-
    • Activated Receptors (Ppara)
slide19

Summary

  • 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.
slide20

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.

slide23

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).