Beyond HIF: Deciphering Alternative Hypoxia Response Mechanisms in HIF-Deficient Crustaceans

Building on Graham & Barreto (2020), which uncovered crustacean lineages that have independently lost key HIF pathway genes, this project proposes a comparative, multi-omics approach to identify what compensatory or alternative mechanisms allow these animals to survive low oxygen. While most research focuses on the highly conserved HIF pathway, these 'natural knockouts' are a goldmine for uncovering new oxygen sensors or effectors. By integrating single-cell RNA-seq (as highlighted in recent advances, e.g., Campello et al., 2025) and proteomics under normoxic and hypoxic conditions in both HIF-deficient and HIF-expressing species, we could pinpoint candidate genes and pathways unique to these adaptations. The discovery of a parallel or backup hypoxia response system would revolutionize our understanding of oxygen sensing and could have applications in medicine (e.g., hypoxia tolerance), biotechnology, and evolutionary biology.

References:

1. Independent losses of the Hypoxia-Inducible Factor (HIF) Pathway within Crustacea.. A. Graham, Felipe S. Barreto (2020). Molecular biology and evolution.
2. Transcriptional Heterogeneity and Differential Response of Rod Photoreceptor Pathway Uncovered by Single‐Cell RNA Sequencing of the Aging Mouse Retina. Laura Campello, Matthew J Brooks, Benjamin R. Fadl, Hyo Sub Choi, Soumitra Pal, Anand Swaroop (2025). Aging Cell.