We present a DNA library preparation method that has allowed us to reconstruct a high-coverage (30×) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome allows a direct estimation of Denisovan heterozygosity indicating that genetic diversity in these archaic hominins was extremely low. It also allows tentative dating of the specimen on the basis of “missing evolution” in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans.

https://science.sciencemag.org/content/sci/338/6104/222.full.pdf

A high-coverage genome sequence from an archaic Denisovan individual

This paper presents the 12th update of the human obesity gene map, which incorporates published results up to the end of October 2005. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTL) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2005, 176 human obesity cases due to single-gene mutations in 11 different genes have been reported, 50 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 244 genes that, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 408. The number of human obesity QTLs derived from genome scans continues to grow, and we now have 253 QTLs for obesity-related phenotypes from 61 genome-wide scans. A total of 52 genomic regions harbor QTLs supported by two or more studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably, with 426 findings of positive associations with 127 candidate genes. A promising observation is that 22 genes are each supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. The electronic version of the map with links to useful publications and relevant sites can be found at http://obesitygene.pbrc.edu.

/pdf/the-human-obesity-gene-map-the-2005-update-3zvtci1u6f.pdf

The human obesity gene map: the 2005 update.

This paper presents the eleventh update of the human obesity gene map, which incorporates published results up to the end of October 2004. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTLs) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2004, 173 human obesity cases due to single-gene mutations in 10 different genes have been reported, and 49 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 166 genes which, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 221. The number of human obesity QTLs derived from genome scans continues to grow, and we have now 204 QTLs for obesity-related phenotypes from 50 genome-wide scans. A total of 38 genomic regions harbor QTLs replicated among two to four studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably with 358 findings of positive associations with 113 candidate genes. Among them, 18 genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, >600 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful publications and genomic and other relevant sites can be found at http://obesitygene.pbrc.edu.

https://onlinelibrary.wiley.com/doi/pdf/10.1038/oby.2005.50

The human obesity gene map: the 2004 update.

Sarcopenia is a loss of muscle protein mass and loss of muscle function. It occurs with increasing age, being a major component in the development of frailty. Current knowledge on its assessment, etiology, pathogenesis, consequences and future perspectives are reported in the present review. On-going and future clinical trials on sarcopenia may radically change our preventive and therapeutic approaches of mobility disability in older people.

/pdf/sarcopenia-its-assessment-etiology-pathogenesis-consequences-44lsxabedh.pdf

Sarcopenia: Its assessment, etiology, pathogenesis, consequences and future perspectives

Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, has been shown to be a negative regulator of myogenesis. Here we show that myostatin functions by controlling the proliferation of muscle precursor cells. When C2C12 myoblasts were incubated with myostatin, proliferation of myoblasts decreased with increasing levels of myostatin. Fluorescence-activated cell sorting analysis revealed that myostatin prevented the progression of myoblasts from the G1- to S-phase of the cell cycle. Western analysis indicated that myostatin specifically up-regulated p21Waf1, Cip1, a cyclin-dependent kinase inhibitor, and decreased the levels and activity of Cdk2 protein in myoblasts. Furthermore, we also observed that in myoblasts treated with myostatin protein, Rb was predominately present in the hypophosphorylated form. These results suggests that, in response to myostatin signaling, there is an increase in p21 expression and a decrease in Cdk2 protein and activity thus resulting in an accumulation of hypophosphorylated Rb protein. This, in turn, leads to the arrest of myoblasts in G1-phase of cell cycle. Thus, we propose that the generalized muscular hyperplasia phenotype observed in animals that lack functional myostatin could be as a result of deregulated myoblast proliferation.

Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation.

Previous reports have shown a lower proportion of the ACTN3 X/X genotype (R577X nonsense polymorphism) in sprint-related athletes compared to the general population, possibly attributed to impairment of muscle function related to α-actinin-3 deficiency. In the present study, we examined the frequency of the X/X genotype in both Black and White elite-level bodybuilders and strength athletes in comparison to the general population. A reference population of 668 Whites (363 men and 305 women) and 208 Blacks (98 men and 110 women) was genotyped for the ACTN3 R577X polymorphism. Strength athletes (52 white and 23 black; 4 women) consisting predominantly of world class and locally competitive bodybuilders, and elite powerlifters were recruited and similarly genotyped. Significantly lower X/X genotype frequencies were observed in the athletes (6.7%) vs controls (16.3%; P = 0.005). The X/X genotype was significantly lower in White athletes (9.7%) vs controls (19.9%; P = 0.018). No black athletes (0%) were observed with the X/X genotype, though this finding only approached statistical significance vs controls (4.8%; P = 0.10). The results indicate that the ACTN3 R577X nonsense allele (X) is under-represented in elite strength athletes, consistent with previous reports indicating that α-actinin-3 deficiency appears to impair muscle performance.

/pdf/the-actn3-r577x-nonsense-allele-is-under-represented-in-wv7dvk83vl.pdf

The ACTN3 R577X nonsense allele is under-represented in elite-level strength athletes.

Background. The alpha-actinin-3 (ACTN3) R577X polymorphism has been associated with muscle power performance in cross-sectional studies. Methods. We examined baseline knee extensor concentric peak power (PP) and PP change with ;10 weeks of unilateral knee extensor strength training (ST) using air-powered resistance machines in 71 older men (65 [standard deviation ¼ 8] years) and 86 older women (64 [standard deviation ¼ 9] years). Results. At baseline in women, the XX genotype group had an absolute (same resistance) PP that was higher than the RR (p ¼ .005) and RX genotype groups (p ¼ .02). The women XX group also had a relative (70% of one-repetition maximum [1-RM]) PP that was higher than that in the RR (p ¼.002) and RX groups (p ¼.008). No differences in baseline absolute or relative PP were observed between ACTN3 genotype groups in men. In men, absolute PP change with ST in the RR (n ¼16) group approached a significantly higher value than in the XX group (n ¼9; p ¼.07). In women, relative PP change with ST in the RR group (n ¼ 16) was higher than in the XX group (n ¼ 17; p ¼ .02). Conclusions. The results indicate that the ACTN3 R577X polymorphism influences the response of quadriceps muscle power to ST in older adults.

/pdf/alpha-actinin-3-actn3-r577x-polymorphism-influences-knee-3fxqrrh489.pdf

Alpha-Actinin-3 (ACTN3) R577X Polymorphism Influences Knee Extensor Peak Power Response to Strength Training in Older Men and Women

The R577X polymorphism in the α-actinin-3 encoding gene (ACTN3) has been associated with elite athletic performance, and recently with differences in isometric and dynamic muscle strength and power...

ACTN3 genotype is associated with muscle phenotypes in women across the adult age span

The human androgen receptor (AR) gene contains a CAG (glutamine) repeat polymorphism in exon 1 that is inversely associated with transcriptional activity of the AR. We studied the association of AR...

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.00537.2004

Androgen receptor CAG repeat polymorphism is associated with fat-free mass in men

Purpose of reviewThis review discusses recent developments in myostatin research, focusing on the basic actions of myostatin on skeletal muscle, the identification of key regulatory elements of the myostatin pathway, and the promise of myostatin as a therapeutic target in muscle-related disorders.Re

Sean Walsh

Papers

The ACTN3 R577X nonsense allele is under-represented in elite-level strength athletes.

Alpha-Actinin-3 (ACTN3) R577X Polymorphism Influences Knee Extensor Peak Power Response to Strength Training in Older Men and Women

ACTN3 genotype is associated with muscle phenotypes in women across the adult age span

Androgen receptor CAG repeat polymorphism is associated with fat-free mass in men

Myostatin: a therapeutic target for skeletal muscle wasting.