Yun Ding, Ph.D. - US grants

PROJECT SUMMARY Deciphering how natural genetic variations influence complex phenotypic traits is a central goal in human genetics and evolutionary biology. Over the past decades, empirical studies in model systems have conceptually advanced the genetic understanding of natural variations in physiological and morphological traits. In contrast, how natural behavioral variations arise from genetic changes altering neural functions remains a fundamental mystery. Although numerous correlations between genetic variations and behavioral variations have been identified across a wide range of species including human, the identity and functional nature of casual genetic changes are largely out of reach. The evolution of courtship song in closely related Drosophila species provides a rare opportunity to establish such causal links, by offering extraordinary behavioral diversity and unparalleled genetic, neuronal and behavioral tractability. The overarching goal of this proposal is to leverage this powerful system and employ our innovative platforms to identify causal genetic and molecular changes that mediate the evolution of the nervous system and behaviors. Our research will proceed in two independent but complementary directions. First, by combining a targeted genetic mapping approach and automated behavioral quantification with unprecedented throughput, we will perform a gene-resolution dissection of defined trait-associated genomic regions to delineate the causal genes and mutations underlying a species-specific courtship song trait. Second, building on our knowledge of relevant neurons in courtship song evolution and our expertise in genetically labeling these neurons across species, we will exploit possible neural sites of adaptive changes as an entry and use single-cell transcriptomes to probe gene expression changes, especially cis-regulatory changes, that are responsible for species-specific neural functions and behaviors. Importantly, for each direction, we will examine the phenotypic effects of candidate genetic and molecular changes using integrative approaches such as definitive genetic tests and neuron-specific gene silencing. The two directions are synergistic in connecting the dots between evolutionary changes at different levels of biological organization. This study will lead to a rich understanding of how evolution operates on the genes and the nervous system to yield adaptive behavioral traits, which will allow us to derive principal mechanisms generalizable across species, and in turn, inform the etiological conditions of behavioral disorders and mental disease in human.