Limits to the evidence that DNA sequence differences contribute to variability in fitness and trainability

Abstract

Introduction In this contrasting perspective, I argue that the evidence a genetic explanation accounts for the variability seen in human cardiorespiratory fitness and its trainability is limited. To make my argument, I first outline key steps in the oxygen transport cascade central to cardiorespiratory fitness. I then define genetic causation and ask how much variation in DNA sequence influences key traits relevant to oxygen transport. Finally, I highlight ongoing issues relevant to the current narrative about genetic causation and complex human phenotypes. The Oxygen Transport Cascade and Cardiorespiratory Fitness The oxygen transport cascade describes the steps involved in oxygen transport from the air to the tissues. In the case of endurance exercise, the tissue of interest is skeletal muscle because that is where the vast majority of oxygen consumption occurs. The major steps in the cascade include: 1) pulmonary ventilation, 2) diffusion of O2 across the alveolar capillary membrane, 3) delivery of O2 to peripheral tissues via a combination of cardiac output and hemoglobin in red blood cells, 4) distribution of a high fraction of cardiac output (e.g., blood flow) to the contracting muscles, and 5) diffusion of O2 from the microcirculation to the tissues and oxidative metabolism in the mitochondria. Importantly, acquired or rare inborn defects in one or more of these steps can result in reduced cardiorespiratory fitness and blunted responses to endurance exercise training (1,2). However, in large populations of healthy humans (including elite endurance athletes), a combination of peak cardiac output and red cell mass is the deterministic element of the oxygen transport cascade that dominate cardiorespiratory fitness (3). This is shown via the tight linkage between V˙O2max values ranging from 2 to 8 L·min−1 and cardiac output shown in Figure 1. Thus, any “causal” explanations for cardiorespiratory fitness at the level of DNA variation must explain the range in cardiac output and related physiological parameters.FIGURE 1: V˙O2max is linearly related to cardiac output (Q˙) across a wide range of values in humans. The vast majority of this relationship is explained by differences in stroke volume. To date, there is no clear genetic explanation for this variability in stroke volume or the wide range of increases in stroke volume that can occur in response to endurance exercise training. Data courtesy of C. Lundby, Ph.D.Genetic Causation Defined With modern DNA sequencing technology, it is possible to search for variation at the level of DNA sequence and link any variation with phenotypic variation and make a causal argument that variation in gene X explains some of the variation in phenotypic trait Y. This approach has superseded statistical techniques relating phenotypes of interest with assumptions about the magnitude of shared genetic influences in monozygotic or dizygotic twins or other forms of family or population studies. Concurrently, there has been a shift in the definition of “what is a gene” from a phenotypically derived unit of inheritance to something embedded in DNA sequence (4). The epistemology behind this shift and its implications for biological theory are beyond the scope of this essay, but excellent resources are available for those interested. (5) Along these lines, five key criteria for claims about genetic causation at the level of DNA variation are required to explain complex phenotypes like cardiorespiratory fitness: identification of potentially causal variants, linkage of these variants to deterministic physiological mechanisms, explanation by these variants of more than a small fraction of the phenotypic trait of interest, demonstration that the gene or pathway is obligatory for an adaptive response, applicability of criteria 1 to 4 when a “maximal” adaptive stimulus has been applied. Using this general framework, I now ask how much variation in key traits relevant to oxygen transport can be accounted for by variation in DNA sequence. DNA Sequence and Key Traits Relevant to Oxygen Transport Before deconstructing the relationship between the oxygen transport cascade and DNA variation, it is important to realize that with the advent of the Human Genome Project and related initiatives, it was widely believed that a few gene variants (~10) would explain the vast majority of phenotypic variation. For noncommunicable diseases, this was known as the Common Disease/Common Variant hypothesis. It was summarized by Francis Collins for Type 2 diabetes in a 2006 Wall Street Journal interview (6): “I expect there are about 12 genes involved, and that all of them will be discovered in the next two years.” That having been said, it now appears that tens if not hundreds of gene variants with tiny effect sizes contribute to human phenotypic variability. Of note, many of these effect sizes are typically reported in increments (like a fraction of a millimeter of mercury of blood pressure) that are not