Genetics of Athletic Performance

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Elaine A. Ostrander,1 Heather J. Huson,1,2 and Gary K. Ostrander3

ANNUAL REVIEWS

Annu. Rev. Genom. Human Genet. 2009.10:407-429. Downloaded from arjournals.annualreviews.org by DUKE UNIVERSITY on 11/23/09. For personal use only.

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Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; email: [email protected]

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College of Natural Sciences and Mathematics, University of Alaska, Fairbanks, Alaska 99774

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Annu. Rev. Genomics Hum. Genet. 2009. 10:407–29 First published online as a Review in Advance on July 16, 2009 The Annual Review of Genomics and Human Genetics is online at genom.annualreviews.org This article’s doi: 10.1146/annurev-genom-082908-150058 c 2009 by Annual Reviews. Copyright All rights reserved 1527-8204/09/0922-0407$20.00

Pacific Biosciences Research Center, University of Hawaii, Honolulu, Hawaii 96821

Key Words SNP, behavior, endurance, polymorphism, athletics, doping

Abstract Performance enhancing polymorphisms (PEPs) are examples of natural genetic variation that affect the outcome of athletic challenges. Elite athletes, and what separates them from the average competitor, have been the subjects of discussion and debate for decades. While training, diet, and mental fitness are all clearly important contributors to achieving athletic success, the fact that individuals reaching the pinnacle of their chosen sports often share both physical and physiological attributes suggests a role for genetics. That multiple members of a family often participate in highly competitive events, such as the Olympics, further supports this argument. In this review, we discuss what is known regarding the genes and gene families, including the mitochondrial genome, that are believed to play a role in human athletic performance. Where possible, we describe the physiological impact of the critical gene variants and consider predictions about other potentially important genes. Finally, we discuss the implications of these findings on the future for competitive athletics.

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INTRODUCTION


Performance enhancing polymorphism (PEP): a variation in the DNA sequence that is associated with improved athletic performance Polymorphism: a variation in DNA sequence from the reported canonical sequence; a position in the DNA sequence where more then one allele is present in the population Phenotype: the observable characteristics of an organism that may be produced by a combination of genetic and environmental factors mtDNA: mitochondrial DNA

Performance enhancing polymorphisms (PEPs) are genetic variants that, when inherited, can lead to improved athletic performance. They are surprisingly common in the general population and were collated annually until 2005, when 165 autosomal PEPs and 5 X-linked PEPs were reported (68). It is now believed that over 200 PEPs exist (80). Not surprisingly, because they represent such a tiny percentage of the population, examination of so-called elite athletes has led to the discovery and enhancement of our understanding of genes contributing to athletic prowess. In this review we consider a subset of the variants described to date, how they were found, and what phenotypes they are believed to affect. Particular emphasis is given to how subtle variants alter normal human physiology to enhance athletic performance. We initially consider a small group of genes that affect energy production. Because mitochondrial DNA (mtDNA) has been the subject of intense discussion, we review those findings in detail. Next we consider genes that affect muscle structure. Combinations of genes or rare polygenomic profiles hypothesized to occur more commonly among elite athletes are also considered. We conclude with a discussion of the potential effect of these discoveries on organized sports.

PHENOTYPING Elite athletes are those who have represented their sport at a major competition: this includes participation at national, continental, and world championship events, as well as other

Nomenclature for performance achievement levelsa

Table 1 Label

Description of achievement level

High elite

Winners of world championships, world cups and Olympic Games

Elite

Silver or bronze medalists of the world championships, world cups, and Olympic Games or prize winners in European championships

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Qualifiers and participants at world class international competitions

Average athletes

Regional competitors with no less then 4 years experience in the relevant sport

Controls

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competitions where the participation roster rivals that of the most competitive events in the sport. Druzhevskaya and colleagues (16) have developed a helpful set of definitions for describing athletic status (Table 1). According to their definition, elite athletes are those who have won gold medals at major world competitions including, most notably, the Olympics or world championships, ending with average athletes featured in regional competitions with no less than four years of participation experience. The categorization system, however, is rapidly becoming outdated as sports physiologists and geneticists consider the biological and genetic constitutions of “ultraextreme” athletes who participate in one or more “ultraendurance” races. Popular events include the Hawaii Ironman Triathlon (3.9-km swim, 180-km bike ride, and 42-km run), Race Across America, in which cyclists race nonstop and cover more distance than the 3500-km Tour de France in about 40% of the time, and the Primal Quest Expedition Adventure Race, in which teams of four must trek, cycle, paddle, and climb a canyon covering 7000 km (see Reference 64 for a review). One commonality shared by all of these extraordinary events, together with the quadrennial Olympics, is the participation of athletes who desire more than anything to be the best at their sport. An understanding of the genes that drive people to attain ever-higher levels of physical achievement is a topic of considerable interest. However, the number of genes to consider is far too great for any single review. We have therefore selected a small number of genes that highlight how genetic variants can affect athletic performance, as well as assist readers

Taken from Druzhevskaya et al. 2008 (16).

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in understanding how such genes are found, statistically evaluated, and analyzed at a functional level. We consider, as examples, genes that affect metabolic processing, O2 transport, skeletal muscle formation, blood flow, and oxygenation.


Angiotensin-Converting Enzyme The ACE gene contains the first PEP to be identified (21). As reviewed in Thompson et al. (88), ACE (angiotensin-converting enzyme) is part of a complicated cascade of molecules known as the renin-angiotensin system. The inactive form of the angiotensin hormone, angiotensinogen, is cleaved by renin to produce angiotensin I. ACE protein catalyzes the conversion of angiotensin I to its physiologically active form, angiotensin II. Angiotensin II affects vasoconstriction and regulation of salt and water homeostasis through the release of aldosterone. ACE is also responsible for the degradation of the vasodilator bradykinin, regulation of inflammatory reactions to lung injury, respiratory drive, erythropoiesis, tissue oxygenation, and the regulation of skeletal muscle efficiency (108). The most common polymorphism associated with the human ACE gene is an intronic indel of 287 bps. Although the polymorphism itself is unlikely to alter ACE function, the I allele, which represents an insertion of 287 bp, is associated with lower serum (71) and tissue (11) ACE activity and improved performance in endurance sports. The deleted form of the variant (D allele) is associated with higher circulating and tissue ACE activity (88) and enhanced performance at sports requiring sprinting or short bursts of power. In the first study of ACE polymorphisms and athletic performance, 43 male and 21 female Australian National Rowers attending pre-Olympic trials in 1996 were evaluated for their ACE genotype (21). The study demonstrated that the frequency of the I allele was significantly increased in elite rowers compared to normal controls. The above was followed by the landmark studies of Montgomery and

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Figure 1 Distribution of ACE polymorphisms I and D. (a) Genotype distribution for 25 elite British mountaineers and 1906 healthy British male controls. (b) The mean of duration improvement stratified by ACE I/D genotype among British army recruits for repetitive elbow flexion after 10 weeks of physical training. Two-tailed paired t-test was used to compare each individual’s absolute difference preand post-training. Reprinted from Montgomery et al. (53).

colleagues in 1998 and 1999 (52, 53). The Montgomery studies demonstrated a role for the PEP in elite endurance performance among high-altitude mountaineers (53) (Figure 1). Thirty-three male British mountaineers who had a history of ascending heights >7000 m were tested for ACE genotype and compared to a set of 1906 male controls. An excess of I/I and a deficiency of D/D genotypes was noted in the climbers. Among 15 climbers who had ascended to 8000 m without oxygen, none were D/D homozygotes (53), and the very top performers were all I/I homozygotes. Similar results have been reported by Woods & Montgomergy (105) and Thompson et al. (87) (Figure 2). In a separate study aimed at addressing the potential role of ACE polymorphisms on body composition, three independent methods were used to study changes in body measurements in male army recruits over a ten-week period of intense physical training (52). Participants with the I/I genotype had a greater anabolic response than did those carrying one or more www.annualreviews.org • Performance-Enhancing Polymorphisms

ACE: angiotensinconverting enzyme Genotype: one or a combination of alleles at a particular locus Homozygote: a locus in which two identical alleles segregate; both parents have contributed the same genetic information to a specified region of the genome

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Figure 2 Mountaineering is associated with ACE I/D genotype. High-altitude mountaineers ascending over 8000 meters without supplemental oxygen show an excess in the ACE I allele frequency (53). In a set of 139 experienced mountaineers, DD homozygotes achieved a mean height of 8097 meters (±947 meters), whereas II homozygotes had a mean height achievement of 8559 meters (±565 meters) (87). Even at lower altitudes ACE genotype is apt to be relevant for success. (a) Successful ascent of Pigeon Spire Summit (3156 meters), Bugaboo Glacier, Purcell Range, British Colombia, Canada. Photo courtesy of Edward Giniger. (b) A single climber about to begin ascent in the Purcell Range, British Colombia, Canada. Photo courtesy of Adrian Ferre D’Amare. 410

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copies of the D allele (52). The same group also observed an increased frequency of the I allele in a cohort of 91 distance runners compared to 404 Olympic athletes from other sports for which endurance was not necessarily important (57). Indeed, the frequency of the I allele increased with distance run at values of 0.35, 0.53, and 0.62 for 200 m, 400–3000 m, and 5000 m, respectively (P = 0.009 for linear trend). The same investigators, using competitors from European and British championships, also reported a significant excess of the D allele in elite swimmers, compared with a control group (P = 0.004), but this association was only observed among those competing in short (nonendurance) (P = 0.005 for 400 m and below) and not long-distance events (103). Tsianos and colleagues reported support for these findings by showing a positive association of the D/I and D/D genotype with elite status swimmers competing in short-distance events (91). They also demonstrated that, as the distance of the event increases, the frequency of the I allele increases and the frequency of the D allele decreases (91). In recent years the ACE gene and its role in endurance events have been extensively reviewed (104, 105). Although there are exceptions, the I allele is generally associated with improved endurance performance, as is observed in elite distance runners, swimmers, rowers, and mountaineers, whereas the D allele is associated with training-related strength gain and elite power-oriented performances (29). The I allele is believed to alter metabolic response, thus facilitating maximization of oxidative fuel for metabolism (52). The D allele is associated with a greater increase in left ventricular mass, higher VO2 max and greater strength gain in response to training (105). Despite the numerous studies positively associating ACE gene polymorphisms with performance, other studies failed to find any association (31, 55, 62, 70, 85). This may be caused by the inclusion of mixed sporting disciplines in some studies, thereby introducing phenotypic heterogeneity. The above studies used varied criteria for defining elite athletes and combined a variety of different sports. That said, the ge-

netics of athletic performance is clearly a complex trait, and establishing the necessary statistical power to understand the role of just one gene is difficult. Positive associations are generally found when examining a single sport with a spectrum from power/strength-oriented short distances to endurance-based longer distances.

SNP: single nucleotide polymorphism

Genes Important in Cardiac and Respiratory Function No discussion of endurance genetics is complete without consideration of genes that improve respiratory capacity and increase the rate of ATP production during exercise. This requires a large number of genes, most of which are encoded in the nuclear genome. He et al. examined the role of three SNPs (single nucleotide polymorphisms) in the nuclear respiratory factor 1 (NRF1) gene, which spans a 146kb region on human chromosome 7q32 (28). The gene has a role in mitochondrial biogenesis and oxidative phosphorylation and is critical for translating signals induced by exercise into increased capacity for energy (36). It has three SNPs located in intron 11, exon 14, and the untranslated region (UTR). In a study of 102 men of Han Chinese origin, two SNPs in NRF1, both in noncoding regions, were found to be associated with a phenotype indicative of submaximum aerobic capacity called ventilatory threshold (VT) (28). The study subjects were all nonsmokers who had not engaged in any formal supervised endurancetraining before entering the study, and who then performed three weekly sessions of strenuous endurance-building exercise including running, swimming, or cycling for 18 weeks. SNPs rs240970 and rs6949152 were shown to affect baseline and/or training response of aerobic capacity, as measured by VT (P = 0.047). This study is the first to identify polymorphisms associated with baseline response to endurance training and the authors argue their results have implications for projecting the performance of endurance athletes (28). The same study also examined the role of polymorphisms in the peroxisome www.annualreviews.org • Performance-Enhancing Polymorphisms

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PPARGC1A: peroxisome proliferators-activated receptor g coactivator 1a Linkage: the nonrandom segregation of alleles from parent to offspring due to a reduction in meiotic recombination between alleles; reduced recombination generally results from close physical proximity of loci along a chromosome Haplotype: a combination of alleles in close proximity and hence usually inherited as a unit on the same chromosome

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proliferators-activated receptor g coactivator 1a (PPARGC1A) and nuclear regulatory factor 2 (NRF2) genes in endurance training (27). PPARGC1A’s role as a human endurance gene is suggested by numerous studies of mice (see Reference 27 for a review) and humans, with the latter largely focused on Caucasians. PPARGC1A is a coactivator of the subset of oxidative phosphorylation genes that control glucose and lipid transportation and oxidation, skeletal muscle fiber-type formation, and mitochondrial biogenesis (19, 66, 93). Previous studies have shown that exercise increases PPARGC1A mRNA levels (27) and that overexpression of PPARGC1A mRNA leads to improved muscle resistance to fatigue (39). Analysis of coding variants Gly482Ser, Thr294Thr, and A2962G at the PPARGC1A locus was aimed at determining if there is an association between gene variation and human endurance capacity, as measured by running economy (RE). RE is defined as the energy demand for a given velocity of submaximal running, and is determined by measuring the steady-state consumption of oxygen (VO2 ) and the respiratory exchange ratio (77). The authors found that their data did not support results from studies of Caucasians that showed an association between a Gly482Ser variant and VO2 max (a measure of cardiorespiratory function and defined as maximal oxygen uptake) (20, 43). Rather, the data suggested that the A2962G SNP explained individual VO2 max differences in Chinese men. No causal relationship was evident between A2962G and PPARGC1A, and it may be that this SNP is in linkage disequilibrium (LD) with functionally relevant variants in this gene, or another gene entirely. In the same group of Chinese men, SNPs in NRF2 were proposed to explain some of the variance observed between individuals in endurance training. Three SNPs within an intronic region of NRF2 of unknown function were considered, with LD observed between two of them (26). When considered together, those with a particular haplotype for the three SNPs had a 57.5% higher training response (P = 0.006) than did noncarriers. Response Ostrander

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was assessed by measures of both VO2 max and RE. The authors conclude that NRF2 polymorphisms affect the baseline VO2 max and RE response, at least among the Chinese men who participated in this study.

Adrenergic Receptors Adrenergic receptors are involved in several pathways important for endurance performance and as a result are excellent candidates for PEPs. In a case-control study of elite white male endurance athletes versus controls, Wolfarth and colleagues reported a significant difference in the frequency of the Arg16Gly SNP (P = 0.03) in the β2 -adrenergic receptor (ADRB2) gene (102). An excess of the Gly allele was observed among sedentary controls versus elite athletes (P = 0.009), indicating that the Gly allele was unfavorable for elite athletic performance. It has been shown previously that Gly16 carriers have a significantly greater increase in body mass index (BMI) compared to Arg16 homozygotes (17). Body mass and composition obviously play roles in athletic performance. This would predict that athletes with two copies of the Arg allele would perform better than those with one, as suggested by Wolfarth et al. (102). In addition, ADRB2 is highly expressed in the cardiovascular system, which could set the stage for advantageous cardiovascular functions in endurance athletics, such as arterial vasodilation. Indeed, several studies have shown that ADRB2 polymorphisms located elsewhere in the gene (Ile164 versus Thr164) are associated with lower exercise capacity following heart failure (38, 96).

Mitochondrial DNA A considerable body of literature exists regarding the role of variation in mtDNA and elite endurance athletes. Mitochondria are cellular organs that perform the reactions necessary to generate energy in the readily useable form of ATP. VO2 max reaches a maximum value after optimal endurance training (14, 41). As endurance capacity improves, several physiologic


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and metabolic changes occur, such as an increase in mitochondrial density in the muscles (109). The mitochondrial genome has 37 genes. Alleles at several sites define nine common haplogroups (90). Castro et al. were among the first to study the association of each haplogroup with elite athletic performance (8). They focused on Spanish long-distance runners, rowers, and professional cyclists. Analysis of athletes versus healthy population controls revealed that haplogroup T appeared less frequently in elite endurance athletes than in controls (P = 0.012). Although the authors can only speculate as to how the SNPs might lower capacity to respond to endurance training, athletes carrying this haplotype are clearly at a genetic disadvantage for performance in endurance events. As always, not all studies agree, and small numbers are problematic. For instance, Niemi & Majamaa genotyped 52 Finnish endurance athletes as well as a modest number of sprint athletes and controls where they found that haplogroups J and K were reduced in the endurance group (59). The results were most striking for haplogroup K, which was observed in 4.5% of controls but in none of the 52 endurance athletes. However, with such small numbers it is difficult to draw definitive conclusions, especially as other investigators report conflicting results (56, 72). Also, differences in associations are likely to exist across ethnic backgrounds. In their investigation of elite Ethiopian athletes, Scott et al. reported that no mitochondrial subgroup was more associated with cases than with controls (79). However, allele frequencies often differ significantly between ethnic groups, especially when small data sets are used, highlighting the complexity of comparing results from athletes of different ethnic backgrounds.

Genes Affecting Blood Flow and Efficiency Nitric oxide synthase. Local regulation of blood flow is important for high-endurance elite performance, as the exercising muscle

requires additional oxygen and metabolic substrates (81, 101). Endothelial nitric oxide (NO) is a vasodilator. Under resting conditions, increased NO production and NO synthase (NOS) inhibition can increase and decrease, respectively, blood flow to the skeletal muscle (67, 101). NO is believed to decrease mitochondrial respiration by competing with oxygen for binding on cytochrome c oxidase, which results in inefficient electron transfer to oxygen (9). NOS inhibition blocks glucose transport during exercise, whereas NO has the opposite effect. In a comparatively large study of 615 Caucasian subjects that included 316 male endurance athletes and 299 sedentary controls termed the Genathlete study, Wolfarth et al. examined three polymorphisms: an intronic (intron 13) microsatellite, an intronic (intron 4) 27-bp repeat, and Glu298Asp SNP in coding exon 7 in NOS3 (101). Although no difference was found for the SNP or the 27-bp repeat in this study, χ 2 analysis of the microsatellite repeat revealed significant differences between the sedentary controls and elite endurance athletes, with more of the latter group carrying a particular 164-bp allele (P = 0.007). However, there was no statistically significant difference in overall allelic distribution. How can this observation be explained? In a separate study of this genetic marker and essential hypertension, an association was shown between the polymorphism and left ventricular hypertrophy (58, 84) using healthy volunteers or hypertensives without left ventricular hypertrophy as controls. In aggregate, these two studies suggest a possible role for NOS3 with regard to adaptive capacity of the heart. Alternatively, it may be that since working capacity of a muscle required for highintensity performance is limited by O2 delivery, polymorphisms affecting NOS3 ultimately affect performance (101). There is no obvious explanation for why the 164 microsatellite allele bears this association as opposed to any other allele, especially since it is intronic and not likely to affect function. More likely, this allele is in LD with other genetic variants located in exons, regulatory regions of NOS3, or even adjacent genes. As the authors www.annualreviews.org • Performance-Enhancing Polymorphisms

NO: nitric oxide Genetic marker: a locus of known DNA variation; may include microsatellites, single nucleotide polymorphisms (SNPs) or insertion/ deletions (indels)

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Mutation: a change in the nucleotide sequence that can but does not necessarily confer a phenotypic change to the organism


ACTN3: α-actinin-3

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themselves point out, KCNH2, a voltage-gated potassium channel gene for which mutations are known to cause short QT syndrome type 2, located only 12 Kb upstream of the 5 end of NOS3, is an excellent candidate (5). Trivial explanations including statistical limitations due to limited sample size must also be considered. Endothelin 1. Although most studies to date have focused on individuals with extraordinary athletic prowess, much can be learned from those who are at the other end of the continuum as well. Raniken et al. have used the Aerobic Center Longitudinal Study (HYPGENE cohort) and the HERITAGE cohort to show how physical activity and fitness levels can modify associations between a candidate gene, endothelin 1 (END1), and outcomes (69). In the first study, cases were individuals from the Aerobic Center Longitudinal Study who had been diagnosed with hypertension (n = 586), whereas controls (n = 607) were normotensive. While no allele frequency differences were noted between five EDN1 genotypes and cardiorespiratory fitness when considering hypertension alone, a significant P-value was found for the interaction with one genotype, the Lys198Asn SNP. Specifically, the minor allele (198Asn) was associated with a higher risk of hypertension among low-fit subjects (P = 0.0003), whereas the risk did not differ between genotypes among high-fit subjects. In the HERITAGE study, the conclusions were similar, as the association between minor allele genotype and blood pressure was again tempered by either physical activity or a high level of cardiorespiratory fitness. The functional mechanism by which the Lys198Asn allele works is not clear, although it is hypothesized that the change may affect message stability. The findings complement previous studies showing an association between the Lys198Asn SNP and elevated resting diastolic blood pressure in obese Japanese cases (2) and elevated resting and exercise systolic blood pressure in overweight Caucasian cases (89). The HERITAGE family study included both Caucasians and African Americans, but Ostrander

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the effect on hypertension was only observed in Caucasians. There are several possible explanations. It is possible that the EDN1 locus simply contributes less in African Americans than in Caucasians, and the greater baseline blood pressure and body mass index (BMI) levels observed in African Americans may alter the physiological pathways that contribute to exercise and subsequent changes in blood pressure. Alternatively, the tagged SNPs used in the study may not capture the same amount of information regarding overall haplotype structure in African Americans as in Caucasians. Finally, the results may be an artifact of the small sample, especially if EDN1 confers only a minor effect on blood pressure in African Americans. The very interesting and sometimes controversial topic of genetic differences in PEPs as related to race is considered later in this review.

Genes Affecting Muscle Structure α-Actinin-3 (ACTN3). In 2003, Yang and colleagues demonstrated an association between an ACTN3 genotype and human elite athletic performance (106), thus identifying the first PEP among genes known to regulate skeleto-muscle formation and function (44, 45, 47). They found that both male and female elite sprinters had a significantly higher frequency of the functional 577R genotype, which results in placement of an arginine rather than a commonly found premature stop codon in the αactinin-3 (ACTN3) gene. The frequency of the 577X null or nonfunctioning allele differs between human populations: It occurs in 16% of Africans but approaches 51% in some Eurasian populations (51). The α-actinins are members of a large family of actin-binding proteins related to dystrophin. Actin proteins are integral components of the superstructure that generates contractile force within muscle fibers. Actinins interact with a number of proteins including themselves, structural proteins of the contractile machinery, metabolic proteins, and signal transduction proteins (44, 94). Through their interaction with calcineurin, polymorphisms


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in α-actinin-3 (ACTN3) are hypothesized to contribute to the heritability of fiber-type distribution in muscle (94). In the original study by Yang et al., 436 unrelated Caucasian controls and 429 elite Caucasian athletes from 14 different sports were genotyped (106). The authors tested the hypothesis that deficiency of α-actinin-3 would reduce performance in sprint/power events and would occur much less frequently in elite sprint athletes. Sprint athletes included runners participating in events 5000 m, and skiers (Figure 3). Although there were no significant allele or genotype frequency differences between the elite athlete group as a whole and controls, there were significant differences when the sprint/power versus endurance groups were compared to male and female controls. Sprint athletes displayed a significantly lower frequency of the null genotype (6% for sprint athletes versus 18% for controls) and a higher frequency of the 577R homozygote genotype (50% for sprint athletes versus 30% for controls) (106). Allele frequencies in sprint and endurance athletes deviated in opposite directions, effectively canceling each other out and probably accounting for the lack of result when the overall dataset of athletes was compared to controls. However, one interesting finding was that none of the female elite sprint athletes was α-actinin3 deficient, compared to 8% of males. Also, every male Olympian power athlete had at least one copy of the 577R allele. In males the androgen hormone may contribute to performance in such a strong way that the role of α-actinin-3 becomes relatively minor (44, 106). The primary results have been supported by followup studies including athletes from Russia (16), Finland (59), Greece (63), Spain (75), and the United States (16, 73). The evolutionary considerations of these results are not clear. The R577X allele, caused

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Figure 3 Examples of endurance sports. (a) Swimming, (b) running, (c) biking, and (d ) mountaineering. Photos courtesy of Tyrone Spady (a), Gary Ostrander (b, Avenue of the Giants Marathon, Redwoods, CA), Christopher Heishman (c, Ironman Florida, 2002), Adrian Ferre D’Amare (d, Aiguille du Midi, French Alps, 3600 m).

by a C to T transition in exon 6 of the gene, is present in the heterozygote state in about 50% of the worldwide population, and about 18% of seemingly healthy white individuals are homozygous for this nonfunctional variant (see 45, 60). What possible evolutionary advantage could this confer to the general population? One possibility is that the power performance effects of the 577R genotype are only relevant in extreme circumstances outside the normal range of human activity, and the 577X allele was selectively neutral during human evolution. The null genotype thus became established in the human population as a result of random genetic drift. However, multiple authors have argued that this does not really make sense when www.annualreviews.org • Performance-Enhancing Polymorphisms

Heterozygote: a locus in which different alleles are segregating, reflecting differences in parental information contributing to each copy of the chromosome

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considering the high level of sequence conservation observed for ACTN3, as well as subsequent studies that demonstrate that the null (X) allele has undergone strong, recent, positive selection in Europeans and Asians (47, 51, 61). How can this be resolved? Since the 577X variant is not associated with any disease phenotype (61), and the null allele occurs at a high population frequency (61), ACTN3 is hypothesized to be functionally redundant in humans, as suggested by its high degree of sequence similarity to α-actinin-2 (51). It is proposed that the ACTN3 577X null allele represents a transitory state in the eventual loss, presumably by genetic drift, of the highly conserved but redundant ACTN3 gene (51). Based on a model proposed by Gibson & Spring (22), complete loss of the gene is unlikely to occur unless the human population is drastically reduced in size, since the mean time to fixation of a neutral mutation is about four times the effective population size. Simply put, as long as the human population remains exceedingly large, the null allele will remain in the population at its current frequency. The recent development of an Actn3 knockout mouse provided some additional insights (46). Mice lacking the gene used energy more efficiently, with the fast fibers displaying metabolic and contractile properties of slow oxidative fibers. The mice had reduced fast fiber diameters, increased activity of multiple enzymes in the aerobic metabolic pathway, altered contractile properties, and, importantly, enhanced recovery from fatigue. This suggests both a mechanistic benefit for the association between R577X and human athletic performance, as well as a practical reason for keeping the variant allele in the general population.


MSTN: myostatin

Myostatin. Interest in the myostatin (MSTN ) gene moved to the forefront of public awareness in 2004 with the report of a fouryear-old German boy who was homozygous for MTSN mutations and displayed significant muscle hypertrophy (78). At birth, the child was noted to have very muscular thighs and upper arms (Figure 4). Ultrasonography 416

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Figure 4 Male child homozygous for a mutation in the MSTN gene. Note the unusually heavy musculature evident at 6 days (a) and 7 months old (b). Arrows indicate the child’s extensive muscling in both the thigh and the calf. Reprinted from Schuelke et al. (78).

demonstrated that the child’s quadriceps muscle was 7.2 SD above the mean and the thickness of the subcutaneous fat pad was 2.88 SD below the mean, of that of controls. Genetic analysis revealed that the child was homozygous for a splice site mutation in intron 1 of the MSTN gene, and the mother, a former Olympic sprint swimmer, was heterozygous for the same mutation. Other family members were unavailable for testing. At age 4.5 years the child remained unusually muscular (Figure 4), but was otherwise normal. This report was the first to identify homozygous mutations in the MSTN gene in humans (78), suggesting the gene as a possible target for gene therapy for muscular atrophy-related diseases and treatment of muscle-wasting disorders (see Reference 92 for a review). MSTN is a member of the transforming growth factor beta (TGF-β) superfamily. MSTN controls skeletal muscle mass by negatively regulating growth of skeletal muscle (Figure 5). The gene displays a high degree of sequence conservation across species from zebrafish to human, suggesting a conserved function across species (49). Studies of the first naturally occurring mutations with a homozygous loss of MSTN gene


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were published in 1997 (24, 30, 50). The phenotype of exceptional muscle development in cattle and pig was reported to be due to homozygous protein truncating deletions within the MSTN gene. Such deletions remove the bioactive carboxy-terminal domain of the protein, rending it functionally dead. Similar findings in additional breeds of cattle and pig have also been reported (48, 82). Studies in mice have illuminated genotypephenotype correlations. McPherron et al. demonstrated that Mstn null mice show a twoto threefold increase in muscle mass over wildtype mice due to an increased number of muscle fibers (49). Additional studies show that Mstn knockout mice display a larger proportion of fast type II fibers and a reduced proportion of slow type I fibers, compared to wild-type mice (23). Thus, the absence of functional Mstn protein in the knockout mouse leads to an overall faster and more glycolytic muscle phenotype (23). One additional animal model that has further illuminated the role of MSTN protein in muscle is the domestic dog (54). In 2007, Mosher et al. described the occurrence of naturally bred whippets that showed a heavily muscled phenotype, earning the nickname of “bully whippets” in the dog-breeding community. Unlike the typical whippet, whose physique is similar to that of the greyhound, the bully whippets had unusually heavy musculature in the legs, neck, and chest. Mosher and colleagues found that a frameshift mutation that removed nearly 20% of the carboxy portion of the protein was responsible for the phenotype (54). In an assessment of a large sample of whippets to determine population frequency of the mutant allele, the number of heterozygous dogs was increased among racing whippets compared to those sampled at conformation shows (P = 0.009) (54). Statistical assessment of body measurements demonstrated that heterozygotes have a physique similar to but more muscular than that of normal whippets. An analysis of 85 dogs for which racing data were available demonstrated a significant and positive correlation with racing speed and

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Figure 5 The myostatin pathway. (a) Myostatin signaling increases p21 and inhibits cyclin-E-Cdk2 activity. This in turn causes Rb inactivation and G1 arrest. (b) In the presence of nonfunctional myostatin, there is no upregulation of the p21 and the Rb stays in a hyperphosphorylated form. This results in myoblast proliferation and fiber number. Reprinted from Thomas et al. (86).

the presence of the mutation, even after correction for population substructure (54). The role of myostatin protein as a negative regulator of muscle growth and the demonstration that mutations in the MSTN gene can be positively correlated with enhanced athletic performance in dog have led to obvious questions about how the MSTN gene can be used to affect human performance, despite the fact that increased muscle cell growth comes at a cost, specifically, impaired force generation due to cellular and histological changes (1). As a result, groups such as the World Anti-Doping Agency (WADA) currently list myostatin inhibitors as a research topic of concern (18).

Race, Ancestry, and the Genetics of Performance The fact that individuals of different racial and ethnic backgrounds tend to dominate some sports is of great interest. However, inaccuracies can arise when racial classifications are used as proxies for genetic similarity, as these social categories do not represent genetically www.annualreviews.org • Performance-Enhancing Polymorphisms

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distinct population groups. Although race often correlates with geographic ancestry, the two are not interchangeable. Training practices, government interests, local and national economics, and cultural issues, in addition to genetics, affect athletic performance (12). In this short review it would not be possible to dissect all the issues related to this complex topic. But the best scientific data probably exist for runners, and a brief discussion of some of that literature provides some interesting insights. A subset of African runners has dominated both middle (8000–10000 m) and long-distance (half- to full marathons) international running competitions for years. The reasons are not clear. Some research suggests that African runners from certain geographic backgrounds have greater economy of movement, superior fatigue resistance, lower lactate accumulation, or can maintain a comparatively higher proportion of maximal oxygen consumption throughout an event (see Reference 32 for a review). Others argue in favor of more optimal metabolic profiles (97). However, many studies have been confounded by significant differences in body size between black African and Caucasian runners and poor controls for training distance. Indeed, some studies suggest that it is anthropometric measures themselves that account for the differences (42). While no germline variants have been identified that explain the different success rates of African Americans and Caucasians in different sports, several studies have begun to address the differences in underlying physiology between African American and Caucasian elite athletes. In 2000 Weston et al. recruited eight African and eight Caucasian well-trained distance runners who were matched for 10-km running performance times and measured their RE (77), fractional utilization of maximal oxygen consumption, as well as metabolite concentrations under a set of controlled conditions (98). The latter is important since several studies suggest that African runners accumulate less plasma lactate and less plasma ammonia than do their Caucasian counterparts


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(see Reference 98 for a review). No significant differences were observed between the groups in terms of anthropometric results. However, African runners were able to utilize a considerably higher percentage of their maximal oxygen uptake and to exercise at a higher heart rate. Thus, the African runners were able to achieve the same performance as the Caucasian group over a 10-km distance, despite having a considerably lower maximal oxygen uptake (13% lower, P = 0.01). Factors that allow this phenomenon include greater RE or the ability to sustain a higher percentage of their VO2 max. In this study, an 8% greater RE was observed in the African runners when compared to the Caucasian (P < 0.05), which is in agreement with reports of black Kenyan runners (74). African runners could also sustain a higher relative running intensity than Caucasian runners, utilizing 92.2% of their maximal oxygen uptake, compared to the 86% for Caucasians (P < 0.01), as reported by others (6, 10). Running at this higher intensity did result in a higher concentration of plasma ammonia, but the levels of lactic acid were the same between groups. Since ammonia and lactate have been shown to rise in parallel (7), one interpretation of these data is that lactate removal is improved in African versus Caucasian runners. The same researchers had predicted this phenomenon earlier (97). This interpretation presents a host of genes in which to search for new PEPs. Addressing the same issue but with a different focus, Kohn et al. (32) asked if skeletal muscle phenotypes differ between black Central African Xhosa versus Caucasian endurance runners matched for training and racing distance. This study demonstrated clear differences in muscle phenotype and physiological characteristics between the two groups, with lower plasma lactate concentrations reported at submaximal exercise intensity among the Xhosa athletes. Xhosa athletes also had high lactate dehydrogenase (LDH) activity and a distinct LDH profile (32). Again no distinguishing germline variants have been reported thus far in


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any obvious genes, but such differences are sure to exist. The overall issue is, of course, somewhat politically charged. It is not possible to disentangle the contribution of cultural differences and opportunities from underlying genetics (12). All athletes presenting themselves at competition compete with an entwined genetic and environmental history. Understanding each is important for reaching full potential. Allele frequencies obviously differ between ancestral groups for many genes, but they differ between geographic ethnic groups within social races as much or, in some instances, more. Thus, for the scientist the most useful way to think about the question of genetics and performance is not to think about it in terms of race, but rather to take a global and evolutionary perspective in trying to understand when certain alleles appeared evolutionarily, what advantages they might confer, and how they have come to be as globally dispersed as they are. For the athletes themselves, the more useful perspective is to consider individual genetic endowment and develop a training program that will allow it to be optimized (40).

Combinations of Polymorphisms It is clear from the presence of extremely high performers in nearly all competitive sports that individuals exist who have combinations of alleles at multiple distinct loci that generate superior performance. The ACE pathway provides a simple example. Williams et al. have shown that a common +9 versus −9 variant in the bradykinin receptor gene BDKRB2 is associated with higher receptor mRNA expression (99). When tested to determine if the variant was associated with efficient muscular contraction among 115 controls and 81 Olympic track athletes, the authors found that the ACE I/BDKRB2-9 haplotype was significantly associated with endurance among elite athletes (P = 0.003) (99). In addition, the BDKRB2 gene also appears to interact with NOS3 to affect endurance performance as evidenced

by assays of those competing in the Ironman Triathlon (76). One whole class of genes not considered by any studies are those involved in recovery time. Accumulating evidence suggests that elite athletes quickly recover from injury and high intensity workouts (3). Intuitively, this makes sense as the same genes that will drive optimal muscle performance will also enhance muscle recovery. However, enhanced expression of other genes, such as those involved in the breakdown of lactic acid, could also play a role, and these genes are a potential area for further study. To find more genes involved in athletic performance, De Moor et al. conducted a genome-wide linkage scan on 700 British female dizygotic twin pairs in an effort to identify combinations of critical polymorphisms (13). The study revealed that athletic status in women is a heritable trait and showed suggestive linkage on chromosomes 3q22-q24 and 4q31-q34. The peak on chromosome 3 had not been previously associated with performance. The region identified on chromosome 4, however, supports two previous linkage studies that associated the fatty acid binding protein 2 gene (FABP2) and the uncoupling protein 1 gene (UCP1) gene with physical fitness (13). Studies such as these have led other researchers to test the statistical probability of an individual having the “perfect” genetic profile for elite human physical performance. One can easily imagine athletes such as swimmer Michael Phelps, track and field star Carl Lewis, mountaineer Reinhold Messner, and cyclist Lance Armstrong falling into such a category, although to be clear no genetic evidence exists to suggest as much (Figure 6). To address how many “ultraelite” athletes might exist, Williams & Folland identified 23 PEPs and ascertained their respective genotype frequencies in the general population using the scientific literature (100). They then ran computer simulations to determine the probability that any single individual in the world would carry the “perfect” 23-allele endurance profile. They found that the chance of any single

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Figure 6 Superior elite athletes. Athletes who have reached the pinnacle of their sports are likely to have benefited from superior training, nutrition, as well as genetics. (a) Swimmer Michael Phelps, (b) all-around gymnast Nadia Comaneci, (c) cyclist Lance Armstrong, (d ) tennis great Andre Agassi, and (e) track star Carl Lewis. Each has achieved the highest honors of their sport including world records (Lewis, Phelps, Armstrong), multiple Olympic and world competition gold medals (Phelps, Lewis, and Comaneci), Tour de France wins (Armstrong), and multiple Grand Slam winner (Agassi).

super athletes. Although many such athletes may go unrecognized, a more likely explanation is that the estimate of 23 relevant SNPs is a gross underestimation. As the number of identified PEPs grows, the true probability of any single person carrying all preferred variants is likely to emerge as dramatically lower. However, in considering this statistic note that the population is not static, but rather is constantly replenishing, offering new opportunities for ultraelite athletes to enter the population. In addition, mating is not necessarily random, further increasing the probability of athletic superstars. Consider the progeny of marriages between extraordinary talents like tennis stars Andre Agassi and Steffi Graf or gymnasts Nadia Comaneci and Bart Conner, or the father-daughter Olympic gymnastic gold medalists Valeri and Nastia Liukin. Further evidence is obvious when considering the tennis champions sisters Serena and Venus Williams. But perhaps the more interesting question is how often ultraelite athletes are born into the population by chance. To assess the polygenic endurance potential of a theoretical human population of one million, a total genotype score for the 23 abovementioned polymorphisms was calculated for each person in the theoretical population of Williams & Folland (100). The results demonstrated considerable genetic homogeneity, with 99% of people differing by no more than seven genotypes from a so-called typical profile. As expected, highly advantageous polygenic profiles emerged only very rarely, fitting with our observations of world-class sporting events. Each occurrence of the Olympics Games seems to feature no more than one Michael Phelps or Carl Lewis, each of whom has likely drawn an unbelievably lucky genetic hand.

Gene Therapy Versus Gene Doping individual having the preferred form of all 23 polymorphisms was 0.0005%. This number is surprisingly high, arguing than that there must be millions of people in the world with the preferred genotype. Yet we see few examples of true 420

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As long as there has been athletic competition there has been significant effort directed toward gaining technological, psychological, and physiological advantages over competitors. Unfortunately, these efforts sometimes cross


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the boundaries of fair play. Concomitantly, the ever-increasing number of studies related to identification and function of PEPs may be ushering in what may be ultimately viewed as the darkest period of competitive athletics: the genetic engineering of superior athletes. Gene doping, the nontherapeutic use of cells, genes, or genetic elements to enhance athletic performance, originates from gene therapy or the transfer of genetic material for the treatment or prevention of disease (25, 95). Thus, there exists an obvious blurring of the line between gene therapy and gene doping. While therapeutic gene transfer can strengthen individuals with degenerative muscle conditions (insulin-like growth factor-1), increase angiogenesis among heart patients (vascular endothelial growth factor), and reduce chronic pain (e.g., endorphins and enkephalins), these same vectors will also enhance athletic performance. Therefore, as gene therapies become regularized in treatment they will need to be judged in light of doping criteria, as is currently the norm for prescription medicines (25). For the foreseeable future, detection of gene doping may be impossible. Gene transfer will likely involve human DNA and will be delivered by injection. As such the doping will not be revealed by blood or urine, but will require invasive tests (e.g., biopsies). The only conceivable exceptions will be the cases where SNPs exist in the gene that encode the recombinant form of the protein versus the wild type that can be detected by forensic PCR-based methods. However, carefully engineered vectors self-destruct rapidly and encoded RNA is short-lived, making detection a near impossibility unless the engineered protein is somehow distinct from the wild type, as is the case with erythropoietin (EPO). As described below, however, sophisticated techniques are required to detect such subtle differences. EPO is a glycoprotein hormone that is produced in the adult kidney and liver and is critical in the modulation of erythropoiesis. Therapeutic uses include the treatment of severe anemia in AIDS and cancer patients. As a doping agent, EPO leads to an increase in the number of red

blood cells. This in turn translates to an increase in oxygen transfer from lungs to tissues and a resultant increase in endurance. EPO has been a doping agent of choice among endurance athletes for years. Recombinant human erythropoietin is produced in cell culture and can be easily injected. With a relatively short half-life of about 8.5 h when intravenously administered, and only a subtle difference from endogenous EPO, it has required the development of advanced testing of blood (five hematological parameters) and urine together with a sophisticated statistical modeling to detect doping (15, 33). Unfortunately, indirect methods of testing for EPO abuse do not allow for differentiation of naturally occurring genetic polymorphisms. Eero Mäntyranta, a Finnish cross-country skier, won seven Olympic medals over three winter Olympic Games in the 1960s and was later found to have a mutation in his own naturally occurring EPO receptor that led to overactivation and a 25%–50% increase in oxygencarrying capacity. In the future, experts predict that administration of exogenous EPO protein, mimics, and/or analogs will be replaced by the introduction of an appropriate EPO-related gene that directly targets the relevant system (34). Specifically, one could utilize in vivo gene transfer, the efficacy of which was demonstrated by Svensson and colleagues (83) following intramuscular injection of adenoviruses encoding EPO in mice and monkeys for the treatment of EPO-responsive anemias. They demonstrated that a single intramuscular injection of replication-effective adenovirus/g body weight produced physiological levels of erythropoietin in the systemic circulation of both species. Elevated EPO persisted in mice for at least one year and in monkeys for at least 84 days following injection. Of course, if noninvasive techniques for viral particle detection were developed, other methods of gene delivery could include plasmid DNA, liposomes, protein-DNA conjugates (15), or even intraarterial delivery of EPO gene to the muscles, as has been demonstrated for nonhuman primates (107). www.annualreviews.org • Performance-Enhancing Polymorphisms

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Of potential benefit to those looking for a method to detect gene doping is the report of Perou and colleagues (65) revealing that 54 genes are upregulated and 36 downregulated as a result of EPO exposure. The good news, then, is that one can look for quantitative changes in expression profiles of other genes to test for recent gene-doping events. The unfortunate news, however, is that such results present dozens or even hundreds of new untested targets for gene doping. Sadly, it also raises the danger of maligning athletes with superior natural physiology. The challenge for effective gene doping, as is the case for gene therapy, is controlling expression of the transgene and resulting gene product. Overexpression of an EPO gene will likely lead to toxicity symptoms including thrombosis, hypertension, hyperviscosity, and even heart failure. Even though modulation of transgene expression is currently an active area of research, it is not likely that a safe and reliable method for self-regulation of EPO levels is imminent. The development of Repoxygen in 2002, a viral delivery vector carrying the human EPO gene under the control of a hypoxia response element, suggests that this is theoretically possible. In fact, in 2006 a German track coach accused of giving performanceenhancing drugs to high school athletes was also implicated in an attempt to obtain Repoxygen (4). “Direct” gene doping targets genes that have already been associated with enhanced athletic performance such as many of those described in this review. However, a more subtle approach may be to consider genes upstream of target molecules or those involved in drug metabolism. Legge et al. (35) recently observed that natural variations exist in the ability of individuals to metabolize therapeutic substances (e.g., scores of cytochrome P450 enzymes). The authors concluded that as we increase our understanding of the genetic basis of drug metabolism, we could improve athletic performance by building on the knowledge that banned substances and their metabolites could be cleared from athletes’ systems within


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days or even hours of an event. This effectively increases by manyfold the number of potential genes/gene products that must be considered when testing. Application of the rapidly expanding field of genomics will undoubtedly lead to new approaches for gene doping. For example, one could imagine utilization of RNA interference technology to silence key genes, such as myostatin, possibly even through dietary administration, with minimal detection ability. A vicious cycle has emerged in which those focused on cheating tend to be ahead of those focused on testing for the sake of fairness. What is inescapable is that even when serious health risks, public ridicule, and alienation are the risks, the potential for wealth, government pressure, escape from poverty, accolades, or simple personal achievement makes gene doping seem worthwhile.

CONCLUSIONS In this review we have considered several classes of performance enhancing genetic variants that lead to improved athletic performance. It is worth stating, as has Helen Pearson, that we may have missed the most important class of all, those that control the brain and nervous system (64). All of the body’s critical organs including lungs, muscles, and heart will, when taxed beyond comfort, send signals to the brain ordering the body to cease (64). Yet in elite athletes we find an extraordinary ability to disobey those signals. One can only imagine the numbers of genes controlling neurotransmitters, their receptors and factors specifying neuronal cell type, which could expand by thousands the number of PEPs. When watching the extraordinary performances of some of the athletes mentioned in this article, we perceive an intangible quality that, for lack of a better term, is often called “heart.” In every elite athlete there seems to be the ability to “dig down deep” and find the extra energy that is needed to train the extra lap, finish first, break the record, or capture the

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medal. Are there hormones or receptors with PEPs that control production of the underlying endorphins? It may be that tolerance to chronic pain reflects differences in the endogenous synthesis of morphine by CYP2D6 in the human brain, and perhaps polymorphisms at that locus may also be important to athletic performance. Some have argued that humans have adapted well to many sports, such as long-distance running, so that we could compete effectively with

other carnivores for food (37). We might argue, then, that most of us have not achieved our full genetic potential. With the right early coaching, training, and nutritional guidance, together with the innate desire to excel, most of us could have achieved far more as athletes than we ever dreamed. As we muse every four years how we would look with an Olympic gold medal dangling from our necks, it is truly an intriguing thought.

SUMMARY POINTS 1. The criteri for “elite” athletic status generally encompass an individual’s rankings in national and world championship-level events including the Olympic Games. In addition, they may include measures of health-related fitness and body composition measures. 2. The gene encoding angiotensin-converting enzyme (ACE) has two alleles commonly associated with human performance. An intronic insertion of 287 bp (I allele) is associated with improved endurance performance. An intronic deletion (D allele) of 287 bp in the same position (D allele) is associated with training-related strength gain and poweroriented performance. 3. Myostatin (MSTN) is a negative regulator of muscle cell growth that, when deleted, causes an increase in glycolytic or fast-twitch muscles. Naturally occurring homozygous deletions, documented in humans and other mammals, result in heavy musculature. 4. The α-actinin-3 protein (ACTN3) is a component of the contractile apparatus in fast skeletal muscle fibers and is important for generating force at high velocity. Elite sprinters have a higher frequency of the 577R genotype compared to the 577X (null) genotype. 5. Genetic variants associated with over 200 genes are documented to effect athletic performance. They affect a variety of functions including blood flow to muscles, muscle structure, oxygen transport, lactate turnover, and energy production. 6. Few, if any, polymorphisms have been reported to explain the dominance of athletes from some geographic regions or ethnic backgrounds in specific sports. However, clear physiologic differences between populations have been reported, providing testable hypotheses regarding where to look for germline variants. 7. Combinations of PEPs such as ACE I/BDKRB2 and NOS3/BDKRB2 work together to produce an enhanced or synergistic effect on performance. Genome-wide scans and whole-genome association studies suggest a multitude of PEPs, although the number of individuals who have inherited a profile of largely optimal genotypes is apt to be tiny in the population. 8. Gene doping is, unfortunately, a major consideration in competitive athletics. With several excellent mechanisms of delivery existing, the number of potential targets is virtually unscreenable using current technologies.


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FUTURE ISSUES 1. How will the ability to undertake large genome-wide association studies and new sequencing technologies affect the rate at which new PEPs are identified? 2. Identification of athletes with highly desirable genetic profiles is an intriguing area of research. Does the development of training programs suited to such athletes argue that a host of world records remain to be broken?


3. Gene doping is a growing concern as delivery technologies and targets grow. Can effective means be developed for controlling this difficult problem?

DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS We thank Drs. Tyrone Spady, Edward Giniger and Adrian Ferre D’Amare for photography, the athletes pictured for permission to print their pictures and Drs. Vence Bonham, Heidi Parker, Cheryl Maslen, Jeff Schoenebeck, Pascale Quignon and Danielle Karyadi for careful reading of this manuscript and thoughtful comments. Finally, we acknowledge Pascale Quignon and Jeff Schoenebeck for assistance with figures. We apologize to the many authors whose work we were unable to cite in the interest of space. We gratefully acknowledge the Intramural Program of the National Human Genome Research Institute for continued support.

LITERATURE CITED 1. Amthor H, Macharia R, Navarrete R, Schuelke M, Brown SC, et al. 2007. Lack of myostatin results in excessive muscle growth but impaired force generation. Proc. Natl. Acad. Sci. USA 104:1835–40 2. Asai T, Ohkubo T, Katsuya T, Higaki J, Fu Y, et al. 2001. Endothelin-1 gene variant associates with blood pressure in obese Japanese subjects: the Ohasama Study. Hypertension 38:1321–24 3. Barnett A. 2006. Using recovery modalities between training sessions in elite athletes: Does it help? Sports Med. 36:781–96 4. Barry P. 2008. Finding the golden genes. Sci. News 174:16 5. Borggrefe M, Wolpert C, Antzelevitch C, Veltmann C, Giustetto C, et al. 2005. Short QT syndrome. Genotype-phenotype correlations. J. Electrocardiol. 38:75–80 6. Bosch AN, Goslin BR, Noakes TD, Dennis SC. 1990. Physiological differences between black and white runners during a treadmill marathon. Eur. J. Appl. Physiol. Occup. Physiol. 61:68–72 7. Buono MJ, Clancy TR, Cook JR. 1984. Blood lactate and ammonium ion accumulation during graded exercise in humans. J. Appl. Physiol. 57:135–39 8. Castro MG, Terrados N, Reguero JR, Alvarez V, Coto E. 2007. Mitochondrial haplogroup T is negatively associated with the status of elite endurance athlete. Mitochondrion 7:354–57 9. Cleeter MW, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AH. 1994. Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases. FEBS Lett. 345:50–54 10. Coetzer P, Noakes TD, Sanders B, Lambert MI, Bosch AN, et al. 1993. Superior fatigue resistance of elite black South African distance runners. J. Appl. Physiol. 75:1822–27 424

Ostrander

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11. Danser AH, Schalekamp MA, Bax WA, Van Den Brink AM, Saxena PR, et al. 1995. Angiotensinconverting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation 92:1387–88 12. Davids K, Baker J. 2007. Genes, environment and sport performance: why the nature-nurture dualism is no longer relevant. Sports Med. 37:961–80 13. De Moor MH, Spector TD, Cherkas LF, Falchi M, Hottenga JJ, et al. 2007. Genome-wide linkage scan for athlete status in 700 British female DZ twin pairs. Twin Res. Hum. Genet. 10:812–20 14. di Prampero PE. 2003. Factors limiting maximal performance in humans. Eur. J. Appl. Physiol. 90:420–29 15. Diamanti-Kandarakis E, Konstantinopoulos PA, Papailiou J, Kandarakis SA, Andreopoulos A, Sykiotis GP. 2005. Erythropoietin abuse and erythropoietin gene doping: detection strategies in the genomic era. Sports Med. 35:831–40 16. Druzhevskaya AM, Ahmetov II, Astratenkova IV, Rogozkin VA. 2008. Association of the ACTN3 R577X polymorphism with power athlete status in Russians. Eur. J. Appl. Physiol. 103:631–34 17. Ellsworth DL, Coady SA, Chen W, Srinivasan SR, Elkasabany A, et al. 2002. Influence of the beta2adrenergic receptor Arg16Gly polymorphism on longitudinal changes in obesity from childhood through young adulthood in a biracial cohort: the Bogalusa Heart Study. Int. J. Obes. Relat. Metab. Disord. 26:928– 37 18. Fedoruk MN, Rupert JL. 2008. Myostatin inhibition: a potential performance enhancement strategy? Scand. J. Med. Sci. Sports 18:123–31 19. Finck BN, Kelly DP. 2006. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J. Clin. Investig. 116:615–22 20. Franks P, Barroso I, Luan J, Ekelund U, Crowley VE, et al. 2003. PGC-1alpha genotype modifies the association of volitional energy expenditure with VO2 max. Med. Sci. Sports Exerc. 35:1998–2004 21. Gayagay G, Yu B, Hambly B, Boston T, Hahn A, et al. 1998. Elite endurance athletes and the ACE I allele—the role of genes in athletic performance. Hum. Genet. 103:48–50 22. Gibson TJ, Spring J. 1998. Genetic redundancy in vertebrates: polyploidy and persistence of genes encoding multidomain proteins. Trends Genet. 14:46–49 23. Girgenrath S, Song K, Whittemore LA. 2005. Loss of myostatin expression alters fiber-type distribution and expression of myosin heavy chain isoforms in slow- and fast-type skeletal muscle. Muscle Nerve 31:34–40 24. Grobet L, Martin LJ, Poncelet D, Pirottin D, Brouwers B, et al. 1997. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat. Genet. 17:71–74 25. Haisma HJ, de Hon O. 2006. Gene doping. Int. J. Sports Med. 27:257–66 26. He Z, Hu Y, Feng L, Lu Y, Liu G, et al. 2007. NRF2 genotype improves endurance capacity in response to training. Int. J. Sports Med. 28:717–21 27. He Z, Hu Y, Feng L, Bao D, Wang L, et al. 2008. Is there an association between PPARGC1A genotypes and endurance capacity in Chinese men? Scand. J. Med. Sci. Sports 18:195–204 28. He Z, Hu Y, Feng L, Li Y, Liu G, et al. 2008. NRF-1 genotypes and endurance exercise capacity in young Chinese men. Br. J. Sports Med. 42:361–66 29. Jones A, Montgomery HE, Woods DR. 2002. Human performance: a role for the ACE genotype? Exerc. Sport Sci. Rev. 30:184–90 30. Kambadur R, Sharma M, Smith TP, Bass JJ. 1997. Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res. 7:910–16 31. Karjalainen J, Kujala UM, Stolt A, Mäntysaari M, Viitasalo M, et al. 1999. Angiotensinogen gene M235T polymorphism predicts left ventricular hypertrophy in endurance athletes. J. Am. Coll. Cardiol. 34:494–99 32. Kohn TA, Essén-Gustavsson B, Myburgh KH. 2007. Do skeletal muscle phenotypic characteristics of Xhosa and Caucasian endurance runners differ when matched for training and racing distances? J. Appl. Physiol. 103:932–40 33. Lasne F, de Ceaurriz J. 2000. Recombinant erythropoietin in urine. Nature 405:635 34. Lasne F, Martin L, de Ceaurriz J, Larcher T, Moullier P, Chenuaud P. 2004. “Genetic doping” with erythropoietin cDNA in primate muscle is detectable. Mol. Ther. 10:409–10 35. Legge M, Fitzgerald R, Jones L. 2008. An alternative consideration in drug testing in elite athletes. NZ Med. J. 121:73–77 www.annualreviews.org • Performance-Enhancing Polymorphisms

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Key paper for understanding the role of the alpha-actinin-3 gene in athletic performance

One of the first papers to describe the role for polymorphisms in the ACE gene and performance athletics

Excellent description of a canine animal model for myostatin deletion and its relation to racing speed

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36. Li B, Holloszy JO, Semenkovich CF. 1999. Respiratory uncoupling induces delta-aminolevulinate synthase expression through a nuclear respiratory factor-1-dependent mechanism in HeLa cells. J. Biol. Chem. 274:17534–40 37. Lieberman DE, Bramble DM. 2007. The evolution of marathon running: capabilities in humans. Sports Med. 37:288–90 38. Liggett SB, Wagoner LE, Craft LL, Hornung RW, Hoit BD, et al. 1998. The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J. Clin. Investig. 102:1534– 39 39. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, et al. 2002. Transcriptional coactivator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418:797–801 40. Lippi G. 2008. Genomics and sports, building a bridge towards a rational and personalized training framework. Int. J. Sports Med. 29:264–65 41. Lortie G, Simoneau JA, Hamel P, Boulay MR, Landry F, Bouchard C. 1984. Responses of maximal aerobic power and capacity to aerobic training. Int. J. Sports Med. 5:232–36 ´ 42. Lucia A, Esteve-Lanao J, Oliván J, Gomez-Gallego F, San Juan AF, et al. 2006. Physiological characteristics of the best Eritrean runners—exceptional running economy. Appl. Physiol. Nutr. Metab. 31:530–40 43. Lucia A, Gomez-Gallego F, Barroso I, Rabadan M, Bandres F, et al. 2005. PPARGC1A genotype (Gly482Ser) predicts exceptional endurance capacity in European men. J. Appl. Physiol. 99:344–48 44. MacArthur DG, North KN. 2004. A gene for speed? The evolution and function of alpha-actinin3. BioEssays 26:786–95 45. MacArthur DG, North KN. 2007. ACTN3: a genetic influence on muscle function and athletic performance. Exerc. Sport Sci. Rev. 35:30–34 46. MacArthur DG, Seto JT, Chan S, Quinlan KG, Raftery JM, et al. 2008. An Actn3 knockout mouse provides mechanistic insights into the association between alpha-actinin-3 deficiency and human athletic performance. Hum. Mol. Genet. 17:1076–86 47. MacArthur DG, Seto JT, Raftery JM, Quinlan KG, Huttley GA, et al. 2007. Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nat. Genet. 39:1261–65 48. Marchitelli C, Savarese MC, Crisa A, Nardone A, Marsan PA, Valentini A. 2003. Double muscling in Marchigiana beef breed is caused by a stop codon in the third exon of myostatin gene. Mamm. Genome 14:392–95 49. McPherron AC, Lawler AM, Lee SJ. 1997. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387:83–90 50. McPherron AC, Lee SJ. 1997. Double muscling in cattle due to mutations in the myostatin gene. Proc. Natl. Acad. Sci. USA 94:12457–61 51. Mills M, Yang N, Weinberger R, Vander Woude DL, Beggs AH, et al. 2001. Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy. Hum. Mol. Genet. 10:1335–46 52. Montgomery H, Clarkson P, Barnard M, Bell J, Brynes A, et al. 1999. Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training. Lancet 353:541–45 53. Montgomery HE, Marshall R, Hemingway H, Myerson S, Clarkson P, et al. 1998. Human gene for physical performance. Nature 393:221–22 54. Mosher DS, Quignon P, Bustamante CD, Sutter NB, Parker HG, et al. 2007. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet. 3:e79 55. Muniesa CA, González-Freire M, Santiago C, Lao JI, Buxens A, et al. 2008. World-class performance in lightweight rowing: Is it genetically influenced? A comparison with cyclists, runners and nonathletes. Br. J. Sports Med.: bjsm.2008.051680 56. Murakami H, Ota A, Simojo H, Okada M, Ajisaka R, Kuno S. 2002. Polymorphisms in control region of mtDNA relates to individual differences in endurance cpacity or trainability. Jpn. J. Physiol. 52:247–56 57. Myerson S, Hemingway H, Budget R, Martin J, Humphries S, Montgomery H. 1999. Human angiotensin I-converting enzyme gene and endurance performance. J. Appl. Physiol. 87:1313–16 Ostrander

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·

Ostrander


ANRV386-GG10-19

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29 July 2009

15:39

58. Nakayama T, Soma M, Takahashi Y, Izumi Y, Kanmatsuse K, Esumi M. 1997. Association analysis of CA repeat polymorphism of the endothelial nitric oxide synthase gene with essential hypertension in Japanese. Clin. Genet. 51:26–30 59. Niemi AK, Majamaa K. 2005. Mitochondrial DNA and ACTN3 genotypes in Finnish elite endurance and sprint athletes. Eur. J. Hum. Genet. 13:965–69 60. North K. 2008. Why is alpha-actinin-3 deficiency so common in the general population? The evolution of athletic performance. Twin Res. Hum. Genet. 11:384–94 61. North KN, Yang N, Wattanasirichaigoon D, Mills M, Easteal S, Beggs AH. 1999. A common nonsense mutation results in alpha-actinin-3 deficiency in the general population. Nat. Genet. 21:353–54 62. Oh SD. 2007. The distribution of I/D polymorphism in the ACE gene among Korean male elite athletes. J. Sports Med. Phys. Fitness 47:250–54 63. Papadimitriou ID, Papadopoulos C, Kouvatsi A, Triantaphyllidis C. 2008. The ACTN3 gene in elite Greek track and field athletes. Int. J. Sports Med. 29:352–55 64. Pearson H. 2006. Physiology: freaks of nature? Nature 444:1000–1 65. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, et al. 2000. Molecular portraits of human breast tumours. Nature 406:747–52 66. Puigserver P, Spiegelman BM. 2003. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr. Rev. 24:78–90 67. R˚adegran G, Saltin B. 1999. Nitric oxide in the regulation of vasomotor tone in human skeletal muscle. Am. J. Physiol. 276:H1951–60 68. Rankinen T, Bray MS, Hagberg JM, Pérusse L, Roth SM, et al. 2006. The human gene map for performance and health-related fitness phenotypes: the 2005 update. Med. Sci. Sports Exerc. 38:1863–88 69. Rankinen T, Church T, Rice T, Markward N, Leon AS, et al. 2007. Effect of endothelin 1 genotype on blood pressure is dependent on physical activity or fitness levels. Hypertension 50:1120–25 70. Rankinen T, Wolfarth B, Simoneau JA, Maier-Lenz D, Rauramaa R, et al. 2000. No association between the angiotensin-converting enzyme ID polymorphism and elite endurance athlete status. J. Appl. Physiol. 88:1571–75 71. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. 1990. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J. Clin. Investig. 86:1343–46 72. Rivera MA, Wolfarth B, Dionne FT, Chagnon M, Simoneau JA, et al. 1998. Three mitochondrial DNA restriction polymorphisms in elite endurance athletes and sedentary controls. Med. Sci. Sports Exerc. 30:687–90 73. Roth SM, Walsh S, Liu D, Metter EJ, Ferrucci L, Hurley BF. 2007. The ACTN3 R577X nonsense allele is under-represented in elite-level strength athletes. Eur. J. Hum. Genet. 16:391–94 74. Saltin B, Larsen H, Terrados N, Bangsbo J, Bak T, et al. 1995. Aerobic exercise capacity at sea level and at altitude in Kenyan boys, junior and senior runners compared with Scandinavian runners. Scand. J. Med. Sci. Sports 5:209–21 75. Santiago C, González-Freire M, Serratosa L, Morate FJ, Meyer T, et al. 2008. ACTN3 genotype in professional soccer players. Br. J. Sports Med. 42:71–73 76. Saunders CJ, Xenophontos SL, Cariolou MA, Anastassiades LC, Noakes TD, Collins M. 2006. The bradykinin beta 2 receptor (BDKRB2) and endothelial nitric oxide synthase 3 (NOS3) genes and endurance performance during Ironman Triathlons. Hum. Mol. Genet. 15:979–87 77. Saunders PU, Pyne DB, Telford RD, Hawley JA. 2004. Factors affecting running economy in trained distance runners. Sports Med. 34:465–85 78. Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T, et al. 2004. Myostatin mutation associated with gross muscle hypertrophy in a child. N. Engl. J. Med. 350:2682–88 79. Scott RA, Wilson RH, Goodwin WH, Moran CN, Georgiades E, et al. 2005. Mitochondrial DNA lineages of elite Ethiopian athletes. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 140:497–503 80. Sharp NC. 2008. The human genome and sport, including epigenetics and athleticogenomics: a brief look at a rapidly changing field. J. Sports Sci. 10:1–7 www.annualreviews.org • Performance-Enhancing Polymorphisms

Describes the role for a common nonsense mutation in the ACTN3 gene and its role in both the general population and athletes

Presents the first description of a human homozygous for protein truncating mutations in the myostatin gene

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81. Stamler JS, Meissner G. 2001. Physiology of nitric oxide in skeletal muscle. Physiol. Rev. 81:209–37 82. Stinckens A, Luyten T, Bijttebier J, Van Den Maagdenberg K, Dieltiens D, et al. 2008. Characterization of the complete porcine MSTN gene and expression levels in pig breeds differing in muscularity. Anim. Genet. 39:586–96 83. Svensson EC, Black HB, Dugger DL, Tripathy SK, Goldwasser E, et al. 1997. Long-term erythropoietin expression in rodents and nonhuman primates following intramuscular injection of a replication-defective adenoviral vector. Hum. Gene Ther. 8:1797–806 84. Takahashi Y, Nakayama T, Soma M, Uwabo J, Izumi Y, Kanmatsuse K. 1997. Association analysis of TG repeat polymorphism of the neuronal nitric oxide synthase gene with essential hypertension. Clin. Genet. 52:83–85 85. Taylor RR, Mamotte CD, Fallon K, van Bockxmeer FM. 1999. Elite athletes and the gene for angiotensinconverting enzyme. J. Appl. Physiol. 87:1035–37 86. Thomas M, Langley B, Berry C, Sharma M, Kirk S, et al. 2000. Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J. Biol. Chem. 275:40235–43 87. Thompson J, Raitt J, Hutchings L, Drenos F, Bjargo E, et al. and the Caudwell Xtreme Everest Research Group. 2007. Angiotensin-converting enzyme genotype and successful ascent to extreme high altitude. High Alt. Med. Biol. 8:278–85 88. Thompson WR, Binder-Macleod Stuart A. 2006. Association of genetic factors with selected measures of physical performance. Phys. Ther. 86:585–91 89. Tiret L, Poirier O, Hallet V, McDonagh TA, Morrison C, et al. 1999. The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension 33:1169–74 90. Torroni A, Huoponen K, Francalacci P, Petrozzi M, Morelli L, et al. 1996. Classification of European mtDNAs from an analysis of three European populations. Genetics 144:1835–50 91. Tsianos G, Sanders J, Dhamrait S, Humphries S, Grant S, Montgomery H. 2004. The ACE gene insertion/deletion polymorphism and elite endurance swimming. Eur. J. Appl. Physiol. 92:360–62 92. Tsuchida K. 2008. Targeting myostatin for therapies against muscle-wasting disorders. Curr. Opin. Drug Discov. Dev. 11:487–94 93. Tunstall RJ, Mehan KA, Wadley GD, Collier GR, Bonen A, et al. 2002. Exercise training increases lipid metabolism gene expression in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 283:E66–72 94. Vincent B, De Bock K, Ramaekers M, Van Den Eede E, Van Leemputte M, et al. 2007. ACTN3 (R577X) genotype is associated with fiber type distribution. Physiol. Genomics 32:58–63 95. World Anti-Doping Agency. 2005. The world anti-doping code. The 2006 prohibited list. International standard. Keynote address, WADA health medical and research committee. In 1-1-2006. http://www.wada-ama.org/en/dynamic.ch2?pageCategory.id=250 96. Wagoner LE, Craft LL, Singh B, Suresh DP, Zengel PW. 2000. Polymorphisms of the beta2 -adrenergic receptor determine exercise capacity in patients with heart failure. Circ. Res. 86:834–40 97. Weston AR, Karamizrak O, Smith A, Noakes TD, Myburgh KH. 1999. African runners exhibit greater fatigue resistance, lower lactate accumulation, and higher oxidative enzyme activity. J. App. Physiol. 86:915–23 98. Weston AR, Mbambo Z, Myburgh KH. 2000. Running economy of African and Caucasian distance runners. Med. Sci. Sports Exerc. 32:1140–44 99. Williams AG, Dhamrait SS, Wootton PT, Day SH, Hawe E, et al. 2004. Bradykinin receptor gene variant and human physical performance. J. Appl. Physiol. 96:938–42 100. Williams AG, Folland JP. 2008. Similarity of polygenic profiles limits the potential for elite human physical performance. J. Physiol. 586:113–21 ¨ 101. Wolfarth B, Rankinen T, Muhlbauer S, Ducke M, Rauramaa R, et al. 2008. Endothelial nitric oxide synthase gene polymorphism and elite endurance athlete status: the Genathlete study. Scand. J. Med. Sci. Sports 18:485–90 ¨ 102. Wolfarth B, Rankinen T, Muhlbauer S, Scherr J, Boulay MR. 2007. Association between a beta2adrenergic receptor polymorphism and elite endurance performance. Metabolism 56:1649–51 103. Woods D, Hickman M, Jamshidi Y, Brull D, Vassiliou V, et al. 2001. Elite swimmers and the D allele of the ACE I/D polymorphism. Hum. Genet. 108:230–32 Ostrander

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Huson

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Ostrander


ANRV386-GG10-19

ARI

29 July 2009

15:39

104. Woods DR, Brull D, Montgomery HE. 2000. Endurance and the ACE I/D polymorphism. Sci. Prog. 84:317–36 105. Woods DR, Montgomergy HE. 2001. Angiotensin-converting enzyme and genetics at high altitude. High Alt. Med. Biol. 2:201–10 106. Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, et al. 2003. ACTN3 genotype is associated with human elite athletic performance. Am. J. Hum. Genet. 73:627–31 107. Zhang G, Budker V, Williams P, Subbotin V, Wolff JA. 2001. Efficient expression of naked DNA delivered intraarterially to limb muscles of nonhuman primates. Hum. Gene Ther. 12:427–38 108. Zhang X, Wang C, Dai H, Lin Y, Zhang J. 2008. Association between angiotensin-converting enzyme gene polymorphisms and exercise performance in patients with COPD. Respirology 13:683–88 109. Zoll J, Sanchez H, N’Guessan B, Ribera F, Lampert E, et al. 2002. Physical activity changes the regulation of mitochondrial respiration in human skeletal muscle. J. Physiol. 543:191–200


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Contents Chromosomes in Leukemia and Beyond: From Irrelevant to Central Players Janet D. Rowley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1

Annual Review of Genomics and Human Genetics Volume 10, 2009

Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration Anand Swaroop, Emily Y. Chew, Catherine Bowes Rickman, and Gon¸calo R. Abecasis p p p19 Syndromes of Telomere Shortening Mary Armanios p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p45 Chronic Pancreatitis: Genetics and Pathogenesis Jian-Min Chen and Claude Férec p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p63 The Genetics of Crohn’s Disease Johan Van Limbergen, David C. Wilson, and Jack Satsangi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p89 Genotyping Technologies for Genetic Research Jiannis Ragoussis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 117 Applications of New Sequencing Technologies for Transcriptome Analysis Olena Morozova, Martin Hirst, and Marco A. Marra p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 135 The Posttranslational Processing of Prelamin A and Disease Brandon S.J. Davies, Loren G. Fong, Shao H. Yang, Catherine Coffinier, and Stephen G. Young p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 153 Genetic Testing in Israel: An Overview Guy Rosner, Serena Rosner, and Avi Orr-Urtreger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 175 Stewardship of Human Biospecimens, DNA, Genotype, and Clinical Data in the GWAS Era Stephen J. O’Brien p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 193 Schistosoma Genetics: New Perspectives on Schistosome Biology and Host-Parasite Interaction Ze-Guang Han, Paul J. Brindley, Sheng-Yue Wang, and Zhu Chen p p p p p p p p p p p p p p p p p p p p 211 Evolution of Genomic Imprinting: Insights from Marsupials and Monotremes Marilyn B. Renfree, Timothy A. Hore, Geoffrey Shaw, Jennifer A. Marshall Graves, and Andrew J. Pask p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 241 v

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Methods for Genomic Partitioning Emily H. Turner, Sarah B. Ng, Deborah A. Nickerson, and Jay Shendure p p p p p p p p p p p p p 263 Biased Gene Conversion and the Evolution of Mammalian Genomic Landscapes Laurent Duret and Nicolas Galtier p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 285 Inherited Variation in Gene Expression Daniel A. Skelly, James Ronald, and Joshua M. Akey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 313 Annu. Rev. Genom. Human Genet. 2009.10:407-429. Downloaded from arjournals.annualreviews.org by DUKE UNIVERSITY on 11/23/09. For personal use only.

Genomic Analyses of Sex Chromosome Evolution Melissa A. Wilson and Kateryna D. Makova p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 333 Sequencing Primate Genomes: What Have We Learned? Tomas Marques-Bonet, Oliver A. Ryder, and Evan E. Eichler p p p p p p p p p p p p p p p p p p p p p p p p p p p 355 Genotype Imputation Yun Li, Cristen Willer, Serena Sanna, and Gon¸calo Abecasis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 387 Genetics of Athletic Performance Elaine A. Ostrander, Heather J. Huson, and Gary K. Ostrander p p p p p p p p p p p p p p p p p p p p p p p p 407 Genetic Screening for Low-Penetrance Variants in Protein-Coding Diseases Jill Waalen and Ernest Beutler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 431 Copy Number Variation in Human Health, Disease, and Evolution Feng Zhang, Wenli Gu, Matthew E. Hurles, and James R. Lupski p p p p p p p p p p p p p p p p p p p p p 451 The Toxicogenomic Multiverse: Convergent Recruitment of Proteins Into Animal Venoms Bryan G. Fry, Kim Roelants, Donald E. Champagne, Holger Scheib, Joel D.A. Tyndall, Glenn F. King, Timo J. Nevalainen, Janette A. Norman, Richard J. Lewis, Raymond S. Norton, Camila Renjifo, and Ricardo C. Rodríguez de la Vega p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 483 Genetics, Medicine, and the Plain People Kevin A. Strauss and Erik G. Puffenberger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 513 Indexes Cumulative Index of Contributing Authors, Volumes 1–10 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 537 Cumulative Index of Chapter Titles, Volumes 1–10 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 541 Errata An online log of corrections to Annual Review of Genomics and Human Genetics articles may be found at http://genom.annualreviews.org/ vi

Contents