Recent presentations of our research at the American
Society for Human Genetics 60th Annual Meeting,
Washington, D.C. November 2010:

Humans and other primates show varying selection pressures on Matrix Metalloproteinase 9 (MMP9), a gene responsible for placental invasion.

A. Lobell, M. Ruvolo. Department of Human Evolutionary Biology, Harvard University, Cambridge, MA.

The ability to produce healthy offspring is critical to evolutionary fitness and is a phenotypic trait controlled largely by reproductive genes. Among humans, polymorphisms in the placentally-expressed Matrix Metalloproteinase 9 (MMP9) gene are associated with pathologies of pregnancy caused by insufficient transfer of nutrients across the placenta. While the negative health effects of these pathologies are well known, the evolutionary genetics of human placental invasion has not been characterized. Understanding the molecular evolution of human placental invasion is important because extremely deep placental invasion is a uniquely human trait that likely underlies key adaptations including increased brain size. Humans’ deep placental invasion arose in the context of more ancient evolutionary changes that increased placental invasion in haplorhine primates (tarsiers, monkeys, apes, and humans). Our study investigates the forces that shaped MMP9 evolution in humans and other haplorhines in order to link adaptive change in placental invasion to its underlying genetic mechanisms. Using maximum likelihood analysis and a new full Bayesian test for positive selection on complete MMP9 coding sequences from 18 mammalian species, we demonstrate statistically significant signals of adaptive evolution (ω > 1) in MMP9 only at the phylogenetic points in haplorhine evolution where increases in placental invasion arise. An intensification of positive selection is detected in regions critical to MMP9’s enzymatic ability within the human/chimpanzee/gorilla clade and along the human lineage. These results suggest that increased placental invasion was the primary selection pressure acting on MMP9 in non-human primates and along the human lineage. However, an analysis of 10.5 Kb of resequencing data from 50 diverse human chromosomes does not find signals of recent adaptation for increased placental invasion in MMP9. Instead, patterns of variation in human MMP9 suggest the action of competing selection pressures that may be related to MMP9’s role as a human oncogene.

Epistatic Interactions Among Genes for Athleticism.

E. McRae1, J. R. Ruiz2, F. Gómez-Gallego3, C. Santiago3, A. Buxens4, A. Lucia3, M. Ruvolo1,5

1) Dept. of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA
2) Dept. of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
3) Universidad Europea de Madrid, Madrid, Spain
4) Progenika Biopharma, Zamudio, Spain
5) Dept. of Human Evolutionary Biology, Harvard University, Cambridge, MA

Human athleticism is a complex trait, influenced by many genes as well as the environment. Hundreds of alleles have been identified as being associated with athletic performance and fitness, and the number continues to grow. For the majority of the history of this field, such work has focused on the influence of individual genes. While such studies inform us about what genes could be involved in athleticism, they do not help us understand the complex nature of the trait. The goal of this study was to look for genes that interact epistatically in determining elite athlete status. We examined 37 health-related genes, 13 of which had prevniously been associated with athleticism, in 253 males of Spanish ancestry - 100 elite endurance athletes, 53 elite power athletes, and 100 sedentary controls. We used several methods to look for these interactions, including multifactor dimensionality reduction (MDR), generalized MDR (GMDR), and entropy-based methods. We found a significant interaction between the Met235Thr SNP of angiotensinogen (AGT) and the C-786T SNP of the endothelial nitric oxide synthase 3 (NOS3) gene that strongly distinguishes endurance athletes from power athletes. We found that an interaction between these same SNPs also distinguishes elite athletes as a group from sedentary controls, along with a second interaction between myostatin (GDF8) and the Ile105Val polymorphism of glutathione S-transferase π1 (GSTP1). We also found a suggestive four-way interaction between AGT, GSTP1 (105), NOS3 (-786), and superoxide dismutase 2 (SOD2). We found no significant interactions distinguishing endurance athletes and controls, only main effects from α-actinin 3 (ACTN3) and the β3 adrenergic receptor (ADRB3) gene. Finally, in examining power athletes and controls, we found a significant two-way interaction between the Cys112Arg SNP of apolipoprotein E (APOE) and the Glu298Asp polymorphism of NOS3. This comparison also yielded a suggestive four-way interaction among angiotensin I-converting enzyme (ACE), the Arg268Lys SNP of N-acetyltransferase 2 (NAT2), interleukin-6, and NOS3 (-786). This study allows us, for the first time, to look at specific gene interactions that are associated with elite athletic performance. Most of the polymorphisms identified have previously been associated with athleticism, but others had not, and should therefore be studied more closely.