Doctoral Dissertation Improvement: The Molecular Evolution of Placental Invasion in Primates

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The reproductive system has experienced profound change during primate evolution. One of the most striking reproductive changes is the evolution of invasive placentation in higher primates (tarsiers, monkeys, apes and humans). In contrast, the placentae of lower primates (lemurs and lorises) are not invasive. Invasive placentae burrow into the mother's uterus and make direct contact with her blood supply. This increases nutrient transfer from mother to fetus and provides energy for developing fetal organs. The human placenta is significantly more invasive than those of other primates. This may facilitate the development of the large human brain. Therefore, human invasive placentation may be linked to the evolution of increased brain size, a defining human adaptation. Invasive placentation requires the coordinated action of numerous genes, but the proteins encoded by Matrix Metalloproteinase 2 (MMP2) and Matrix Metalloproteinase 9 (MMP9) are most important. They are enzymes directly responsible for degrading uterine tissues. An increase in the enzymatic ability (the ability to degrade tissue) of MMP2 and MMP9 is the molecular mechanism that likely underlies invasive placentation in higher primates. Two processes can bring about an increase in MMP enzymatic ability: first, an increase in the intrinsic enzymatic activity of the proteins (protein remodeling), and second, an increase in the levels at which they are produced (gene regulatory change). (More protein produced would result in more tissue degraded.)This project uses novel methods to investigate protein remodeling and gene regulatory change in MMP2/9 among primates. The hypothesis that natural selection favored increased enzymatic MMP2/9 activity to facilitate placental invasion in higher primates (particularly humans) will be tested. MMP2/9 DNA sequences will be generated from twelve primate species to determine the effect of protein remodeling on MMP activity. Amino acid differences between primate species will be mapped onto three-dimensional protein structures to investigate the effect of DNA sequence change on enzymatic activity. A series of experiments that measure protein production in an in vitro placental cell system will test whether gene regulatory change caused increased MMP2/9 activity in higher primates.Protein mapping and in vitro gene regulatory experiments have been used successfully in other scientific fields but are new to molecular anthropology. Their use in this study will provide a critical link between evolutionary changes to DNA sequences and to the function of their encoded proteins. This will enable us to determine not only whether natural selection worked to increase the enzymatic activity of MMP2/9 in higher primates but also how the proteins changed to become more active. In this way we will be able to characterize an important aspect of primate reproductive evolution thoroughly.The methods used in this project will open significant new avenues of research in molecular anthropology. Additional broader impacts of the project are that it 1) promotes the integration of graduate training in anthropology, evolutionary biology, and molecular biology through collaboration between the Department of Anthropology and Harvard Medical School; and 2) will have educational impact by presenting research results in undergraduate courses and at professional conferences. Results will be published in peer-reviewed journals in anthropology, molecular evolution, and reproductive biology.