This research team is elucidating the genetic changes that orchestrated the expansion of the brain's neocortex during humankind's ancestry. This interdisciplinary team of scientists has compiled a list of genes that are important for the brain's anatomical development or its biochemical functioning. By utilizing the comparative genomic sequence data that are publicly available, the investigators are identifying in their list of brain-important genes those showing evidence of adaptive change in humankind's ancestry. The investigators intend to find out if such adaptive change is indeed associated with encephalization, the process that brought about brains with marked neocortical enlargements and increased cognitive capacities. To do so, the comparative gene sequence data will be enlarged to include a selection of other primates and other mammals. The species selected will allow testing of the hypothesis that those brain-important genes showing adaptive change in the lineage to humans will also show a higher frequency of adaptive change in non-human lineages where encephalization increased than in lineages where encephalization did not increase. For example, the investigators will compare the encephalized bottle-nosed dolphin (Tursiops truncatus) to the less encephalized odontocete sperm whale (Physeter macrocephalus) and mysticete blue whale (Balaenoptera musculus). In addition to the gene data, other types of molecular data on encephalization will also be gathered. To this end, the investigators will use immunohistochemical techniques to determine whether particular neuroanatomical structures show increasing levels of activity for genes involved in aerobic energy production in the series of macaques, chimpanzees and humans, a result that would correlate with the marked expansion of the neocortex in the human lineage. A database of neocortical phenotypic features will be constructed for a diverse range of primates and other mammals in order to search for cortical histological features that characterize the emergence of brains with increased cognitive capacities. Broader impacts include the establishment of a web site to disseminate these genotypic and phenotypic data that distinguish encephalized from non-encephalized lineages. Taken together, this work will further our goal of identifying the genetic underpinnings of humankind and determining which of the underpinnings are truly unique for humans. The interdisciplinary team of primatologists, biochemical geneticists, neuroscientists and anthropologists bridges diverse disciplines in order to elucidate the linked genotypic-phenotypic changes that shaped the human brain. By yielding a more objective view of the biological place of humans in nature, this research should have broad societal impact. Identifying the genetic changes that shaped the human brain could prove to be of great value in the search for new therapeutic agents in the field of mental health.
A primary goal of the proposed project has been to elucidate the genetic changes that orchestrated the expansion of the brain’s neocortex during humankind’s evolutionary history. In pursuit of this goal, we have been studying genes judged by their developmental brain expression profiles and by gene ontology information to be important either for the brain’s anatomical development or its biochemical functioning. By utilizing the comparative genomic sequence data that are publicly available, we identified in their list of brain-important genes those showing evidence of adaptive change in humankind’s ancestry. A major goal has been to find out if such adaptive change is indeed associated with encephalization, the process that brought about brains with marked neocortical enlargements and increased cognitive capacities. In aid of this goal, we sought to illuminate the relationship between body mass and brain mass among adult mammalian species by performing an extensive literature search to collect body and brain mass data on mammals from across as many taxa as possible, including both male and female data whenever available. We were able to trace the evolution of encephalization among mammals by first reconstructing the ancestral state for absolute brain mass, body mass and relative brain mass for all mammalian species and use this comprehensive data collection to see the different degrees of encephalization across a representation of all mammals. Furthermore, we were able to determine encephalization vs. non-encephalization lineages and can use this data to test for adaptive evolution of brain-important genes. At the anatomical level, we discovered, based on examining a series of primate brains, that the ratio of glia to neurons increases as absolute brain size increases. Glia are helper cells for neurons whose functions include providing metabolic support, and the finding suggests that human neocortical neurons require greater metabolic support in the context of an enlarged brain. To dissect the genetic pathways underlying these observations, much of our effort has gone into identifying and analyzing genes that are highly expressed in brain tissue and have undergone adaptive evolution in human ancestry. First we looked at genes that can be grouped based on their expression in time or space. Different functional groups of genes turned out to be targets of evolution in fetal compared to adult tissues. For example, genes related to energy production were major targets in adult but not fetal brain, where gene groups related to membranes and cell adhesion were the major targets. To study brain evolution at a deeper level, we focused on specific genes and organisms of interest. Among genes we investigated lactate dehydrogenase, a key metabolic enzyme; placental-specific galectins, involved in immune tolerance at the maternal-fetal interface, of interest because humans have the most invasive placentation; cytochrome oxidase subunit 5A, which contains human-specific amino acid changes and is most abundant in the mitochondria of large projection neurons; and protocadherin gene 8, a cell adhesion protein highly expressed in both fetal and adult brain that has undergone significant protein evolution in primates. Among organisms, we studied the highly encephalized elephant brain's expressed genes and showed that similar energy metabolism genes as in human have undergone adaptive evolution. We also studied the dolphin genome to reveal molecular correlates of the remarkable phenotypic features of these aquatic mammals. Finally, we sequenced a capuchin monkey's transcriptome for comparison to the less encephalized and shorter lived marmoset. By yielding a more objective view of the biological place of humans in nature, this research should have broad societal impact. Identifying the genetic changes that shaped the human brain could prove to be of great value in the search for new therapeutic agents in the field of mental health.
