Constantina, during her PhD and Post Doc, focused her research on further developing genomic methods that could be used to establish a universal vertebrate gene nomenclature. Her project’s overall aim was to revise the traditional gene nomenclature, which is based on outdated tools from the pre-genomic era. Back then, biochemists were naming genes based solely on their DNA sequence, in a way that small amino-acid changes between orthologous genes (meaning, the “same” genes) in different species led them to give them different names. As a result, scientists nowadays are still using different names for orthologous genes in different species or lineages, something that leads to great difficulties in translating findings across species. A great example is the oxytocin gene (and gene family), where for the same gene, oxytocin is used in mammals, mesotocin in birds, reptiles and frogs, isotocin, glumitocin and neurophysin-1 in different fish species, and aspargtocin in sharks, among others.
Theofanopoulou et al. 2021 (Nature) decisively established that gene nomenclature should be based on synteny (the surrounding territory of a gene; “what is outside of a gene”), and not on gene identity solely (its nucleotide sequence; “what is inside a gene”). They set the genomic and phylogenetic criteria that a universal gene nomenclature should fulfill, introducing a set of novel genomic analyses. They applied these criteria on the oxytocin and vasotocin ligand and receptor family, paving the way for a revolutionary change in how scientists will understand and speak about genes across species. In these analyses, they made use of platinum quality assemblies generated by the Vertebrate Genomes Project in a study (2021 Nature) that Constantina co-authored. In a follow-up study, Theofanopoulou and Jarvis 2023 (Nature) further showed and proposed how this method could be applied in the rest of the gene families with problematic nomenclature, a practice that could help scientists establish a common language (nomenclature) for all genes.
By identifying the right gene orthologous and paralogous relationships, Constantina also sought to resolve the conundrum of vertebrate genome evolution, and particularly the question of how many rounds of whole genome duplication vertebrate genomes have gone through. In her Theofanopoulou 2021 (Developmental Biology) she used the oxytocin-vasotocin receptor family as a case study to show that these genes' evolution can be explained by either one or two rounds of whole genome duplication.