Physiology performance parameters

Athleticogenomics – the gene genie is out of his bottle

Over the last 40 years or so, sports science and research into genetic traits and physiology has revolutionised the way we train and fuel ourselves for sport. But as Craig Sharp explains, an even more profound revolution with far-reaching implications for sport is just around the corner. Prepare yourself for ‘athleticogenomics’

Athleticogenomics is a phrase I have coined to cover all the genetic aspects of sport, especially the physiological traits that are inherited. For a trait to be inherited, there needs to be a genetic code for it in the genetic material in the cell. At the heart of every cell is genetic material (the genome) that contains the information coding for our anatomy and physiology. This material is known as DNA (deoxyribonucleic acid), which consists of about 27,000 genes. Each gene is a long segment of DNA, containing information, or ‘instructions’, distributed among the 23 pairs of human chromosomes.

Some genes switch others on or off, and control the expression of their fellow genes. Other genes simply issue an instruction to make a protein. Just out of interest, 98% of our genes are shared with chimpanzees (13 of our chromosomes are exactly the same); indeed chimps are closer to us than they are to gorillas. Mice are 90% similar to us, fruit flies about 66%, and we even share over a third of our genes with a banana, so think of that when a fellow athlete is getting a bit too full of him or herself!

You can think of the genome as a paired set of 23 chromosome books, each containing several thousand sentences (the individual genes). Each gene-sentence is made of words (triplet codons) of three letters, chosen from combinations of the four DNA letters. Each DNA triplet word specifies an amino acid, and a sequence of hundreds of amino acids makes a protein.

Fitness genes

The first draft of the coding for the entire human genome was sequenced and published at the turn of the millennium. But there is already a ‘Human Gene Map for Performance and Health-Related Fitness Phenotypes’, which is updated every year and published in the journal Medicine and Science in Sports and Exercise.
In 1980, Canadian scientists showed that some competitors responded better than others to training, and concluded that the reasons for this were genetic (1). The first actual gene known to confer this favoured training status was the ‘ACE gene’, discovered by Hugh Montgomery and his team in London (2). Already, over 100 genes relating to physical performance have been identified by several research groups.

Like all genes, Montgomery’s ACE gene can have variants (alleles) and one, known as ACE-II, has an extra ‘inserted’ piece of DNA that increases the amount of nitric oxide in the muscle cell. This extra nitric oxide in turn improves the efficiency of organelles known as mitochondria, present especially in muscle cells. Mitochondria are responsible for actually putting to work the oxygen molecules we breathe, using them to extract aerobic energy from the food-fuels.

Normally at least 70% of the fuel energy comes away unavoidably as heat (which is why you get hot during exercise), but the ACE-II allele diverts a useful percentage of heat energy back into making extra ATP, the energy molecule that activates muscle, and this extra ATP has been shown to improve aerobic endurance (2).

Drugs, known as ACE inhibitors, which act in the same way as the ACE-II gene, are used to treat heart conditions – by similarly improving the function of heart muscle. At Sydney University, researchers found a much higher frequency than expected of the ACE-II allele among Australian competition rowers. This prompts a vision of the future; the sports physiologist/coach/team manager might enlist ACE-genotype (or other) analyses to help determine which junior aerobic endurance competitors are worth later major funding. Is this useful information for the sports bureaucrats? Or undue hassle for the competitors?

EPO and genes

Another natural ‘fitness’ gene codes for the receptor for EPO (the hormone that stimulates bone marrow to produce red blood cells). An exceedingly rare but natural mutation causes the EPO receptor to be more effective (possibly through bonding onto EPO for a longer time than normal). Eero Mantyranta, who won two cross-country skiing events at the 1964 Winter Olympics, has recently been found to have such a mutation, together with members of his family.

In the body, tissues and organs not only grow, but have to ‘know’ when to stop, and muscle is no different. Muscle in the embryo is triggered to grow by the expression of a group of ‘transcription factors’ one of which is known as myoD, produced by the MYF gene, but the normal controlling brake on muscle growth, the ‘down-regulator’, is the muscle chemical myostatin from gene GDF-8, which targets myoD. However, there is a variant gene that produces a mutant form of myostatin which acts as an ‘up-regulator’ of myoD. So far, this has only been found in a few spectacularly muscular breeds of cattle, but its natural presence is suspected in families of especially successful weightlifters, whose muscle also lacks the normal growth inhibitor.

There are a number of other examples of fitness genes, which mainly affect muscle. The gene CKMM codes for creatine kinase, which is responsible for the rapid regeneration of the energy molecule ATP during intensive muscle effort – and a rare natural human variant of CKMM is responsible for unusual increases in power. Meanwhile, the gene ATP1A2 is associated with the training response for maximum power output, while the gene VDR is associated with muscle strength. Another gene called IGF2 codes for ILG factor II, which is very influential in muscle growth (see below), and finally COL1A1 codes for type-1 collagen A-chain, important in elasticity of tendon and ligament, which helps to store movement energy.

Artificial genes

If there are specific genes that can code for proteins/hormones etc capable of enhancing sport performance, could they be produced artificially and then used to boost physical performance? The answer to the first part of the question is yes. A gene therapist can sequence the particular human gene into a retrovirus that targets the required tissue. Viruses are all made of DNA (or its sister molecule RNA) and you can think of viruses as a set of orphan genes looking for a chromosomal home.

Once the virus’s genes for virulence are deleted, an instruction is added along the lines of ‘Make a copy of me and insert it into one of your chromosomes’. This was first tried on a very rare and often-fatal inherited disease – severe combined immune deficiency (SCID), which is due to a single altered base on chromosome 20 in the ‘ADA gene’(3). The treatment produced 14 successes and three failures and established that human gene therapy was a reality.

Lee Sweeney and his colleagues in the USA in 2004 dramatically spliced a synthetic gene coding for insulin-like growth factor one (ILGF-1) into the adeno-associated virus (AAV), which is known to infect muscle harmlessly (5). ILGF is a doping agent used by bodybuilders, which triggers the replication of muscle satellite cells and stimulates muscle hypertrophy.

Sweeney’s group injected their AAV-IGLF-1 into the muscle of one hind leg in rats then strength-trained both hind legs. After eight weeks, the experimental leg muscle showed nearly twice the strength gains of the control legs; even sedentary control rats treated with AAV-IGLF-1, but not strength-trained, increased 15% over those controls that were neither treated nor strength-trained. Note also that it was the gene that was introduced into the muscle – not the drug. In other words, it would be virtually undetectable by current doping control technology.

Gene doping in sport

Every time a cell divides, all of its DNA has to divide, but in replicating, mistakes may be made. A single base-letter may be missed, or it may be wrong, or whole lengths of DNA may be duplicated, omitted or reversed. In the embryo this produces mutations. It also creates the possibility for gene replacement therapy, where new lengths of DNA, artificially sequenced in the laboratory, may be introduced to replace or modify existing genes.

Although it’s one way forward to treat a whole variety of genetic diseases, it could also be a way forward for ‘gene doping’ in sport, by replacing normal ‘fitness’ genes with better ones! Many more ‘fitness’ genes will be discovered, and ‘loaded’ retroviruses and genes artificially sequenced in the lab may well be used to target them. Likely target tissues include bone marrow and blood formation, heart and skeletal muscle (affecting fibre types), mitochondria and their aerobic enzymes, oxygen-storing myoglobin, anaerobic enzymes, acid-neutralising buffers, creatine, muscle capillary blood vessels and possibly connective tissues such as collagen and elastin.

However, such gene manipulations are far more complicated than those described here, requiring other gene sequences called ‘promoters’, ‘enhancers’, ‘silencers’ and ‘insulators’. Although there is as yet a notable lack of information about the sequences required for most human genes, this will inevitably come in time.

Gene typing realised?

Gene typing is the process of screening DNA to determine the presence or otherwise of specific genes. But how useful is it/will it be? Genetic Technologies, a biotech company based in Australia, has developed a DNA test, which it claims can identify whether a child has the genetic make-up to excel in either sprint and power sports or endurance sports. Professor Deon Venter, a director of the company, is reported to have researched the ACTN3 gene in the Australian Institute of Sport. ACTN3 codes for a so-called ‘actinin’ protein, which has an important function both in the structure and in regulation of the speed of muscle contraction, especially in the muscle’s ‘fast’ fibres. A corresponding gene or allele, known as R577X, has an important function in ‘slow’ fibres. The muscle of top-class sprinters contains upwards of 80% fast (or ‘power’) fibres, and that of distance runners about the same proportion of slow (or ‘endurance’) fibres, so in theory a test screening for such genes might be able to indicate potential for power or for endurance events.

However, in one sense, this appears to be like using a sledgehammer to crack a nut – any good PE teacher or coach can easily categorise youngsters into one or other (or neither) of the two disciplines. But the test, costing some AUS$45, is almost certainly a portent of things to come. A finely detailed knowledge of the individual ‘genetic expression’ of a sportsperson would be extremely useful, regarding their trainability and thus the specificity of training regimens.

In summary

The integration of genome datasets with physiological performance parameters is in its infancy, but will accelerate. It is not only the encoded proteins themselves, but their rate of transcription and the encoded gene control logic, that are also important, so relevant gene-expression profiling or typing may also quite legitimately be used by sports scientists, coaches and competitors. Just as pharmacogenomics can highlight differences in response to medicinal drugs in patients, so an equivalent aspect of athleticogenomics could help to optimise training very specifically. However, athleticogenomics is a Pandora’s box with profound implications for sport – some beneficial to sports medicine (gene therapy), some helping the sports scientist and coach (gene profiling), some opening a door to cheating (gene doping). Do the 15-second 200m sprint or the three-minute mile beckon? Will they be legitimate? Will we be able to tell?

Craig Sharp is an emeritus professor of sports science at Brunel University, holds honorary professorships at the Universities of Stirling and Exeter and has coached at the ‘72, ‘76, ‘80 and ‘88 Olympic games


  1. Bouchard C, Malina RM, Perusse L (1999) The Genetics of Fitness and Physical Performance, Champaign IL: Human Kinetics
  2. Nature (2000) 403, 614
  3. Ridley M (2000) The Genome, London: Fourth EstateHamer C, Copeland J (1998), Living with our Genes, New York: Doubleday
  4. 4. Hamer C, Copeland J (1998), Living with our Genes, New York: Doubleday
  5. Scientific American (2004) 291(1), 36-43
  6. Parisotto, R (2006) Blood Sports: The inside dope on drugs in sport, Victoria, Australia: Hardie Grant Books

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