The GFI1 Gene Family: Evolution, Structure, and Its Role in Immune Responses

The immune system's evolution is crucial for its role in fighting pathogens and involvement in autoimmune and neurodegenerative diseases. The GFI1 gene family plays a role in the regulation of the function of immune cells, including neutrophils and CD4 + T cells. GFI1 consists of two members, GFI1A and GFI1B. GFI1A is vital for myeloid and lymphoid differentiation, while GFI1B is crucial for generating red blood cells and platelets. Both genes share a repressor SNAG domain and C2H2 zinc finger domains. However, the full relationship between their structure and function remains unclear. We aimed to decipher the relationship between structural evolution and novel functionalization in the GFI1 gene family. We employed a comprehensive phylogenetic approach that integrated tree construction, ancestral state reconstruction, positive selection analysis, motif mining, and non-homology-based functional prediction to trace GFI1 family evolutionary history over 700 million years. Our analysis revealed that the GFI1 gene family originated from a single ancestral gene in early metazoans and underwent multiple lineage-specific duplication events in invertebrates, jawless vertebrates, and jawed vertebrates, indicating adaptive diversification across evolutionary lineages, albeit without evidence of significant positive selection. We identified new motifs in the less-characterized middle regions, such as the SPOP-binding motif in GFI1A, potentially regulating cytokine production in CD4 + T cells, and the FEDFW motif, possibly involved in neutrophil recruitment. These motifs are unique to GFI1A in higher vertebrates. In GFI1B, we discovered a unique EPLRP motif, a separase cleavage site linked to sister chromatid separation. Our results indicate that GFI1 has evolved new functions to adapt to the complexity of the vertebrate immune system.