Eri Mikami

Genomics of elite sporting performance: what little we know and necessary advances.

Numerous reports of genetic associations with performance-related phenotypes have been published over the past three decades but there has been limited progress in discovering and characterising the genetic contribution to elite/world-class performance, mainly owing to few coordinated research efforts involving major funding initiatives/consortia and the use primarily of the candidate gene analysis approach. It is timely that exercise genomics research has moved into a new era utilising well-phenotyped, large cohorts and genome-wide technologies—approaches that have begun to elucidate the genetic basis of other complex traits/diseases. This review summarises the most recent and significant findings from sports genetics and explores future trends and possibilities.

ACTN3 R577X Genotype is Associated with Sprinting in Elite Japanese Athletes

The ACTN3 R577X genotype has been found to associate with sprint/power phenotypes in all elite athlete cohorts investigated. This association has not been extensively studied in elite Asian athletes. The present study was undertaken to investigate the association between the ACTN3 R577X genotype and elite Japanese track and field athlete status. 299 elite Japanese track and field athletes (134 sprint/power athletes; 165 endurance/middle-power athletes) and 649 Japanese controls were genotyped for the ACTN3 R577X polymorphism. All athletes were of national or international level. Sprint/power athletes showed a higher frequency of RR + RX genotype than controls (111/134 [82.8%] vs. 478/649 [73.7%], P = 0.025 under the R-dominant model), while there was no significant difference between endurance/middle-power athletes and controls (126/165 [76.4%] vs. 478/649 [73.7%], P = 0.48 under the R-dominant model). Sprinters with the RR + RX genotype had significantly faster personal best times for the 100 m than those with XX genotype (10.42 ± 0.05 s vs. 10.64 ± 0.09 s, P = 0.042); no such association was found in the 400 m sprinters (47.02 ± 0.36 s vs. 47.56 ± 0.99 s, P = 0.62). ACTN3 R577X genotype is associated with sprint/power performance in elite Japanese track and field athletes, especially short sprint performance.

Mitochondrial haplogroups associated with elite Japanese athlete status

Purpose It has been hypothesised that certain mitochondrial haplogroups, which are defined by the presence of a characteristic cluster of tightly linked mitochondrial DNA polymorphisms, would be associated with elite Japanese athlete status. To examine this hypothesis, the frequencies of mitochondrial haplogroups found in elite Japanese athletes were compared with those in the general Japanese population. Methods Subjects comprised 139 Olympic athletes (79 endurance/middle-power athletes (EMA), 60 sprint/power athletes (SPA)) and 672 controls (CON). Two mitochondrial DNA fragments containing the hypervariable sequence I (m16024–m16383) of the major non-coding region and the polymorphic site at m.5178C>A within the NADH dehydrogenase subunit 2 gene were sequenced, and subjects were classified into 12 major mitochondrial haplogroups (ie, F, B, A, N9a, N9b, M7a, M7b, M*, G2, G1, D5 or D4). The mitochondrial haplogroup frequency differences among EMA, SPA and CON were then examined. Results EMA showed an excess of haplogroup G1 (OR 2.52, 95% CI 1.05 to 6.02, p=0.032), with 8.9% compared with 3.7% in CON, whereas SPA displayed a greater proportion of haplogroup F (OR 2.79, 95% CI 1.28 to 6.07, p=0.007), with 15.0% compared with 6.0% in CON. Conclusions The results suggest that mitochondrial haplogroups G1 and F are associated with elite EMA and SPA status in Japanese athletes, respectively.

Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes

BackgroundSenescence-accelerated mice (SAM) are a series of mouse strains originally derived from unexpected crosses between AKR/J and unknown mice, from which phenotypically distinct senescence-prone (SAMP) and -resistant (SAMR) inbred strains were subsequently established. Although SAMP strains have been widely used for aging research focusing on their short life spans and various age-related phenotypes, such as immune dysfunction, osteoporosis, and brain atrophy, the responsible gene mutations have not yet been fully elucidated.ResultsTo identify mutations specific to SAMP strains, we performed whole exome sequencing of 6 SAMP and 3 SAMR strains. This analysis revealed 32,019 to 38,925 single-nucleotide variants in the coding region of each SAM strain. We detected Ogg1 p.R304W and Mbd4 p.D129N deleterious mutations in all 6 of the SAMP strains but not in the SAMR or AKR/J strains. Moreover, we extracted 31 SAMP-specific novel deleterious mutations. In all SAMP strains except SAMP8, we detected a p.R473W missense mutation in the Ldb3 gene, which has been associated with myofibrillar myopathy. In 3 SAMP strains (SAMP3, SAMP10, and SAMP11), we identified a p.R167C missense mutation in the Prx gene, in which mutations causing hereditary motor and sensory neuropathy (Dejerine-Sottas syndrome) have been identified. In SAMP6 we detected a p.S540fs frame-shift mutation in the Il4ra gene, a mutation potentially causative of ulcerative colitis and osteoporosis.ConclusionsOur data indicate that different combinations of mutations in disease-causing genes may be responsible for the various phenotypes of SAMP strains.

Polymorphisms in the control region of mitochondrial DNA associated with elite Japanese athlete status

The control region of mitochondrial DNA (mtDNA) contains the main regulatory elements for mtDNA replication and transcription. Certain polymorphisms in this region would, therefore, contribute to elite athletic performance, because mitochondrial function is one of determinants of physical performance. The present study was undertaken to examine the effect of polymorphisms in this region on elite athlete status by sequencing the mtDNA control region. Subjects comprised 185 elite Japanese athletes who had represented Japan at international competitions (i.e., 100 endurance/middle‐power athletes: EMA; 85 sprint/power athletes: SPA), and 672 Japanese controls (CON). The mtDNA control region was analyzed by direct sequencing. Frequency differences of polymorphisms (minor allele frequency ≥ 0.05) in the mtDNA control region between EMA, SPA, and CON were examined. EMA displayed excess of three polymorphisms [m.152T>C, m.514(CA)n repeat (n ≥ 5), and poly‐C stretch at m.568–573 (C ≥ 7)] compared with CON. On the other hand, SPA showed greater frequency of the m.204T>C polymorphism compared with CON. In addition, none of the SPA had m.16278C>T polymorphism, whereas the frequencies of this polymorphism in CON and EMA were 8.3% and 10.0%, respectively. These findings imply that several polymorphisms detected in the control region of mtDNA may influence physical performance probably in a functional manner.

Comprehensive analysis of common and rare mitochondrial DNA variants in elite Japanese athletes: a case–control study

The purpose of the present study was to identify mitochondrial DNA (mtDNA) polymorphisms and rare variants that associate with elite Japanese athletic status. Subjects comprised 185 elite Japanese athletes who had represented Japan at international competitions (that is, 100 endurance/middle-power athletes: EMA; 85 sprint/power athletes: SPA) and 672 Japanese controls (CON). The entire mtDNA sequences (16 569 bp) were analyzed by direct sequencing. Nucleotide variants were detected at 1488 sites in the 857 entire mtDNA sequences. A total of 311 variants were polymorphisms (minor allele frequency⩾1% in CON), and the frequencies of these polymorphisms were compared among the three groups. The EMA displayed excess of seven polymorphisms, including subhaplogroup D4e2- and D4g-specific polymorphisms, compared with CON (P<0.05), whereas SPA displayed excess of three polymorphisms and dearth of nine polymorphisms, including haplogroup G- and subhaplogroup G2a-specific polymorphisms, compared with CON (P<0.05). The frequencies of 10 polymorphisms, including haplogroup G- and subhaplogroup G2a-specific polymorphisms, were different between EMA and SPA (P<0.05): although none of these polymorphisms differed significantly between groups after correcting for multiple comparison (false discovery rate q-value⩾0.05). The number of rare variants in the 12S ribosomal RNA and NADH dehydrogenase subunit I genes were also higher in SPA than in CON (P<0.05). Analysis of the entire mtDNA of elite Japanese athletes revealed several haplogroup- and subhaplogroup-specific polymorphisms to be potentially associated with elite Japanese athletic status.

Extended screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss.

Hearing loss (HL) is the most common sensory disorder in humans. Many patients with mitochondrial diseases have sensorineural HL (SNHL). The HL of these patients manifests as a consequence of either syndromic or nonsyndromic mitochondrial diseases. Furthermore, the phenotypes vary among patients even if they are carrying the same mutation. Therefore, these features make it necessary to analyze every presumed mutation in patients with hereditary HL, but the extensive analysis of various mutations is laborious. We analyzed 373 patients with suspected hereditary HL by using an extended suspension-array screening system for major mitochondrial DNA (mtDNA) mutations, which can detect 32 other mtDNA mutations in addition to the previously analyzed 29 mutations. In the present study, we detected 2 different mtDNA mutations among these 373 patients; m.7444G>A in the MT-CO1 gene and m.7472insC in the MT-TS1 gene in 1 patient (0.3%) for each. As these two patients had no clinical features other than HL, they had not been suspected of having mtDNA mutations. This extended screening system together with the previous one is useful for the genetic diagnosis and epidemiological study of both syndromic and nonsyndromic HL.