New genes are those that originated relatively recently and are only present in a subset of species in a phylogeny. Evidence from humans and other species has demonstrated that, despite their young age, new genes can exhibit novel functions that are essential for the survival of an organism. One potential mechanism by which new genes gain essential functions is through the acquisition of many new interactions with pre-existing genes. This hypothesis is consistent with well-established observations that genes with many interaction partners are more likely to have essential functions. However, the accumulation of gene-gene interactions is, on average, a slow evolutionary process. This raises the question of how, in a short evolutionary time, new genes can acquire multiple novel interactions and how this might lead to their essential roles in the survival of an organism.
The aim of this proposal is to formally test the hypothesis that new genes become essential through the acquisition of novel gene-gene interactions, and to elucidate the underlying evolutionary process. This proposed research will use Drosophila as a model system and focus on characterizing the functional importance and evolutionary history of a young gene (CG7804) that is less than four million years old and is essential for the survival of Drosophila melanogaster. CG7804 duplicated from TBPH, which is known to regulate the alternative splicing of a large set of genes in Drosophila. Unlike the evolutionarily highly conserved TBPH, CG7804 has been under strong positive selection since its origination, especially in protein domains mediating protein-nucleic acid interactions. This suggests that CG7804 likely has evolved novel essential functions through the acquisition of new interaction partners by regulating the alternative splicing of a distinct set of genes from that of TBPH. In order to test test whether CG7804 has evolved novel functions that are divergent from TBPH, this project will use tissue-specific RNA interference to compare the functional impacts of CG7804 and TBPH on D. melanogaster fitness, transcriptome regulation and alternative splicing. Nucleic acid binding profiling will identify direct functional targets of CG7804 and TBPH, enabling a formal test of the hypothesis that the acquisition of new interaction partners of new genes has led to their essentiality. Finally, ancestral CG7804 sequences will be reconstructed and functionally tested in order to identify the sequential formation of new gene-gene interactions and elucidate the dynamic process by which CG7804 became essential. This proposed research will provide a detailed functional analysis of a young gene essential for survival and, more importantly, be the first to directly characterize the underlying evolutionary processes leading to new genes'novel essential functions.
Despite their young age and presence in only one species, many human-specific genes have essential functions and are associated with complex human diseases. I will investigate how newly arisen genes quickly become essential through the acquisition of novel gene-gene interactions that rewire the gene-gene interaction network. This research will advance our understanding of the evolutionary process that leads to disease-causing human-specific new genes.