News Release

New findings represent the first aerobic capacity QTLs identified in genetic models

Chromosomal intervals showing statistical evidence for suggestive or significant linkage to aerobic running capacity to be discussed by researchers at upcoming meeting

Peer-Reviewed Publication

American Physiological Society

New Orleans, LA – It is not by the pure chance of nature that some individuals have enhanced aerobic capacity. The ability to sustain efficient oxygen utilization is a quantitative trait influenced by the interaction of multiple genetic and environmental factors. This has been evidenced by previous studies on the genetic nature of aerobic endurance capacity in humans that suggest that between 70-90 percent of the total phenotypic (characteristics devolved from the interaction of genes to the environment) variance can be attributed to an inherited genetic component.

Background

Fitness tests of aerobic capacity are used to assess cardio-respiratory function and as a general test of overall physical health status. It has been readily accepted that certain levels of physical fitness are strong predictors of cardiovascular disease and overall rate of death. Despite evidence and evolutionary support that aerobic exercise capacity is an inherited trait of primary importance, the underlying genes remain undefined.

The most important environmental factor contributing to aerobic capacity is exercise, activity known to moderate the effect of numerous diseases such as cardiovascular disease, hypertension, diabetes mellitus, obesity, and lipid abnormalities. Most genomic research on aerobic capacity has focused on exercise as a proactive action that affects quantitative measures such as body composition, muscle mass, blood pressure, or disease outcomes such as hypertension or diabetes. For example, a recent genomic scan for maximal oxygen consumption (VO2 max) in humans revealed that chromosomal regions linked to VO2 max in the untrained (sedentary) state were different from those linked to VO2 max in response to exercise training.

Such results imply that there is a set of genes that determine levels of intrinsic aerobic capacity in the untrained state and apparently another set of genes that dictate the response to aerobic exercise training.

The Study

Researchers believe that genes for both inherited aerobic capacity and the adaptational response to aerobic exercise must be resolved in order to understand the role that aerobic capacity plays in defining the entire relationship between health and disease. Accordingly, Lauren Gerard Koch, Justin A. Ways, George T. Cicila, Michael R. Garrett, and Steven L. Britton, all from the Functional Genomics Laboratory, Department of Physiology and Molecular Medicine, Medical College of Ohio, Toledo, Ohio, have conducted a study entitled “A Genome Scan for Loci Associated with Aerobic Running Capacity in Rats.” Their long-term goal is to use these inbred model systems to identify genes, proteins, and intermediate phenotypes that collectively cause differences between low and high aerobic capacity.

The researchers will present their findings in full during the American Physiological Society’s (APS) annual meeting, part of the "Experimental Biology 2002” conference. More than 12,000 will attend the conference being held at the Ernest N. Morial Convention Center, New Orleans, LA from April 20-24, 2002.

Methodology

Their scan for intrinsic aerobic exercise capacity quantitative trait loci (QTLs) in rats was based on 210 polymorphic microsatellite markers and an F2 intercross population (n = 224) derived from Copenhagen (COP) and DA strains. (In previous experiments, the researchers tested maximal treadmill running capacity in a panel of eleven different inbred rat strains to evaluate the genetic variance that exists for intrinsic (untrained) aerobic capacity. At the extremes, DA inbred rats showed the highest capacity and ran 810 meters to exhaustion whereas Copenhagen (COP) rats were the lowest performers and became exhausted by 300 meters. This wide difference in phenotypic values suggested that the COP and DA rats could serve as parental strains for a genetic cross to test for an association between allelic variation (alternative forms of the same gene) and aerobic running capacity.)

Results

The most significant linkage for an aerobic running capacity QTL was found on chromosome RNO16. Although the location of the peak in the LOD plot (used to measure genetic linkage) gives the best estimate of the map position for the QTL, confidence intervals constructed on either a one-LOD support interval or an interval showing a two-LOD difference, have a high probability of containing a QTL. Almost 90 percent of the LOD plot for RNO16 was above the suggestive threshold of linkage for a QTL. This broad plateau in the LOD plot on RNO16 between D16Rat32 and D16Arb3 may be the result of multiple aerobic running capacity QTLs that are in relatively close proximity. A suggestive linkage was also found near the p-terminus of chromosome RNO3 with evidence of an interaction between a QTL on RNO16.

The study also revealed that other cardiac trait differences may also contribute to the genetic differences in running capacity. Heart weight and relative heart weight were significantly greater in the DA strain compared to the COP strain From genetic analysis in the population, a heart weight QTL was identified on chromosome RNO8 and relative heart weight QTL on RNO7. Both of these QTL regions co-localized to markers, D7Rat74 and D8Rat23 near putative aerobic running capacity QTLs identified using selective genotyping.

The parental COP and DA strains were not significantly different in body weight; data, however, showed a small but significant negative correlation between body weight and running capacity in the F2 (COP x DA) population; i.e., rats with lower body weights tended to run further. The researchers also identified a body weight QTL located in the same region of RNO8 that contained aerobic capacity and heart weight QTLs whose effects approached the threshold for suggestive linkage. The genetic component of these correlations are likely to stem from either a gene that has a pleiotropic or multiple effect on both running capacity and body weight and/or represents linkage disequilibrium between distinct loci that affect both traits.

Conclusions

These findings represent the first aerobic capacity QTLs identified in genetic models. Chromosomal intervals showing statistical evidence for suggestive or significant linkage to aerobic running capacity are suitable candidates for the construction of congenic strains and substrains. This is accomplished by systematically introgressing chromosomal intervals from donor strains containing either high or low aerobic capacity QTL alleles into recipient strains having the reciprocal genetic backgrounds from the contrasting strain. Congenic strains can be used to confirm the presence of aerobic capacity QTLs and to delimit the chromosomal regions containing allele(s) responsible for the QTL. Construction of “double” congenic strains is another strategy, where the chromosomal regions in the donor strain containing two QTLs on separate chromosomes are introgressed into the same recipient strain to test whether there is such an interaction.

The researchers suggest such an approach may be necessary to study the effects of the aerobic running capacity QTLs located near D16Rat55 and D3Rat56 if these two loci interact in a congenic strain derived from COP and DA rats as they did in the F2 segregating population.

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The American Physiological Society (APS) is one of the world’s most prestigious organizations for physiological scientists. These researchers specialize in understanding the processes and functions underlying human health and disease. Founded in 1887 the Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals each year.

APS Newsroom: April 20-24, 2002
Morial Convention Center, New Orleans
Room: Level 2, Room B211
Telephone: 504.670.6534


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