This proposal is focused on integrating comparative genetics and molecular evolution with functional neurobiology as a means of generating a better understanding of human neuropsychiatric and addiction disorders and developing better animal disease models. This will concentrate initially on monoamine oxidase A (MAOA). MAOA has been associated with neuropsychiatric and addiction disorders including alcoholism, depression, and autism among others and is a target for widely prescribed anti-depression and anti-anxiety medications. MAOA is also hypothesized to have undergone positive selection in humans since the divergence from chimpanzees but harbors a regulatory polymorphism that is functionally homologous between humans, apes, and certain old-world monkey species. Understanding differences in MAOA function in humans may lead to better understandings of the causes of its associated neuropsychiatric disorders and allow for the development of more appropriate genetic models of these diseases in non-human primates. Here we propose to catalog the complete MAOA locus across primate species, including polymorphic variation in the more commonly used biomedical model species. We then propose to functionally investigate the consequences of these differences, as well as the functionality of ancestral sequences, in vitro. We will also assess the effects of polymorphic variation from non-human primates ex vivo and in vivo through measurement of mRNA levels and neurochemical concentrations in cerebrospinal fluid and neuroendocrine effects in blood plasma. Finally, we will integrate MAOA genotypes into existing alcohol self-administration studies in rhesus macaques to elucidate this genotype/phenotype relationship and develop better genetic models of alcohol use disorders. Through this work, a better understanding will be gained of the relevance of molecular evolution and comparative genetics to functional neuroscience and the study of human neuropsychiatric disease. Specifically, this work will elucidate if specific psychiatric disorders or symptoms are unique to humans resulting from human-specific genetic changes and the extent to which and ways that these psychiatric disorders and their treatment can be modeled in other organisms, particularly non-human primates. This will allow a better integration of the two fields and allow researchers to leverage the power of molecular evolution and comparative genetics to greater effect in studies of human disease going forward. It will also allow scientists to refine candidate gene analyses and better place into context animal models of neuropsychiatric disease.

Public Health Relevance

The goal of this grant is to understand the functional genetic differences between humans and other primates at the monoamine oxidase a gene and to use this information to understand human neurobiology and behavior. We will identify the differences among primate species and test these differences for functional effects of gene expression and protein function before considering how they affect behaviors and neurochemical levels in the body. This work will allow us to better understand how the human brain works, what goes wrong in neuropsychiatric disorders and ways in which we might develop better animal models for studying human disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AA019688-05
Application #
8702035
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Parsian, Abbas
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
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Ward, Joshua M; Buslov, Alexander M; Vallender, Eric J (2014) Twinning and survivorship of captive common marmosets (Callithrix jacchus) and cotton-top tamarins (Saguinus oedipus). J Am Assoc Lab Anim Sci 53:7-11
Ogawa, Lisa M; Vallender, Eric J (2014) Genetic substructure in cynomolgus macaques (Macaca fascicularis) on the island of Mauritius. BMC Genomics 15:748
Goswami, Dharmendra B; Ogawa, Lisa M; Ward, Joshua M et al. (2013) Large-scale polymorphism discovery in macaque G-protein coupled receptors. BMC Genomics 14:703
Vallender, Eric J (2013) How brains are built: genetics and evolution. Brain Behav Evol 81:71-3
Sweeney, Carolyn G; Curran, Elizabeth; Westmoreland, Susan V et al. (2012) Quantitative molecular assessment of chimerism across tissues in marmosets and tamarins. BMC Genomics 13:98
Vallender, Eric J (2012) Genetic correlates of the evolving primate brain. Prog Brain Res 195:27-44
Vallender, Eric J (2011) Comparative genetic approaches to the evolution of human brain and behavior. Am J Hum Biol 23:53-64