Athletics and genetics Personal Genetics Education Project (pgEd) Harvard Medical School - Wu Laboratory

Do Now Answer the following questions: Do you wish your parents had genetically tested you as a child to see if there is a certain sport at which you might excel or to see if you might have a special gift for music? Why or why not? What could be a benefit and what could be a disadvantage to having genetic analysis of this sort performed at an early age?

What can a genetic test for “sports ability” tell us?

How do genetic testing and athletics intersect? Genetic testing is being used to predict injury risk and to detect medical conditions with the aim of preventing harm to athletes Companies offer testing to help parents and children use genetics as part of the puzzle in deciding what sport to pursue. The role of genetic testing in sports presents a number of personal and societal questions in need of attention.

CARDIOMYOPATHY SICKLE CELL TRAIT How do we decide to screen for conditions that may put an athlete’s health at risk? How common or risky does a trait need to be before we screen everyone? Source: American Heart Association

A common version of ACTN3, the so-called “speed” gene, has been linked to sprinting ability. Most elite sprinters have at least one copy of this version. Preliminary studies have linked a common version of the APOE gene, called APOE4, to increased risk of severe effects from a concussion. On-going research is exploring link between variants in collagen-producing genes, including COL5A1 and COL5A2, and increased risk of Anterior Cruciate Ligament (ACL) tears. Genes linked to athletic performance and injury risk

Companies are currently selling tests that assess variants to try to predict a person’s risk for sports injuries and athletic abilities. Target audiences are athletes of all ages, parents, coaches and trainers. There is controversy about how predictive these tests are and what else these tests may reveal about a person’s health. For example, there is a well-established link between APOE4 and an increased risk for Alzheimer’s disease. Direct-to-consumer genetic testing for sports

Introduction to the APOE gene (Apolipoprotein E) The ApoE gene has a well-established link to Alzheimer’s disease. There are three common forms of the APOE gene (E2, E3, and E4). People with one copy of the E4 version of the gene are at increased risk for developing Alzheimer’s disease, and the risk is even greater for people with two copies of E4 *. However, as discussed above, APOE is only one piece of the puzzle: While people with two copies of E4 have a significantly increased chance of developing Alzheimer’s disease, some never do. Some people who do not carry the E4 variant still develop Alzheimer’s disease. Genetic testing cannot guarantee who will develop the disease, at what age symptoms will start or how rapidly the disease will progress.

Nature of APOE variants The E3 variant is the most common. The E2 and E4 variants each differ from E3 by a single amino acid substitution. Some variants are protective Genetic variants do not always increase our risk for disease; some are protective. It is thought that the E2 variant actually decreases one’s risk for developing Alzheimer’s disease. E3 is considered to be neutral (not associated with increased or decreased risk). APOE influences multiple traits The APOE gene is pleiotropic, meaning that it influences multiple traits: Alzheimer’s disease and possibly recovery from concussions as well as cardiovascular disease.

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The gene, ACTN3, produces a protein that helps fast-twitch muscle fibers to contract. There is a version of ACTN3 that has been linked to sprinting ability. ~95% of elite sprinters have at least one copy of this version of the gene. ~80% of people in the general population also have at least one copy of this version. The ACTN3 gene and its link to speed

Introduction to the ACTN3 gene (alpha-actinin-3) The ACTN3 gene plays a role in fast twitch muscle fibers, responsible for generating powerful muscle contractions. There are two versions of the ACTN3 gene that are commonly found in people, R and X. The R variant can produce the actinin-3 protein, while the X variant does not. The R variant of ACTN3 has been linked to sprinting ability in studies showing that elite sprinters rarely carry the X variant. ACTN3 cannot predict which individuals will become elite sprinters; it is unusual for an elite sprinter not to have the R version, but there are exceptions.

Mutations are not always bad People carrying two copies of the X variant (X/X) do not make actinin-3 protein. It is estimated that over a billion people worldwide lack the actinin-3 protein, and most probably don’t even know it. While X/X individuals are less likely to be elite sprinters, the X variant has been weakly associated with endurance in some studies of elite athletes.

Gene regulation The ACTN3 gene encodes a protein that is expressed specifically in fast twitch muscle fibers. The actinin-3 protein binds to a component of the cytoskeleton, known as actin, involved in muscle contractions. Nature of ACTN3 variants The R and X variants of actinin-3 differ at a single nucleotide (known as a single nucleotide polymorphism or SNP). The R variant encodes the amino acid, arginine (R), at position 577 in the protein. The X variant encodes a stop codon that prematurely signals the ribosome to stop translation (also referred to as a nonsense SNP). As a result, individuals homozygous for the X variant (X/X) do not produce a functional actinin-3 protein.

Discussion questions: How effective might genetic analysis be in predicting athletic performance? Should genetic analysis be used to screen athletes for health conditions? Why or why not? From a scientific perspective, what are the most important facts when examining the link between athletic performance and genetics? What should a family consider when a child is thinking about playing a contact sport? How can genetic information both illuminate and complicate how parents decide what is right for their children?