Evolution of the Cytochrome c Oxidase Subunit 4 Paralogs
Bibliographic record
Abstract
The largest subunit of cytochrome c oxidase exists as two paralogs in most vertebrates: a constitutive COX4‐1 and hypoxia‐inducible COX4‐2. In primates and rodents, COX4‐2 is a hypoxia‐responsive gene encoding a protein with its ATP‐binding site disrupted by a disulfide bridge, precluding COX from the allosteric regulation that is exerted through the this site in COX4‐1. In an effort to understand the evolution of the gene, we examined role of the paralogs in fish. COX4‐2 of fish differs from mammals in three respects. First, the fish COX4‐2 gene does not appear to be hypoxia responsive at either the mRNA or protein level. This was shown in mammalian cells transfected with fish promoter constructs, and hypoxia treatments of cultured fish cells and whole animals. We used fish species from multiple lineages and differing in hypoxia tolerance, exposed to different degrees and durations of low oxygen. Second, the fish COX4‐2 protein lacks the structural features (paired CYS residues) that distinguish COX4‐2 from COX4‐1 in mammals. This pair of CYS residues in COX4‐2 protein appears only in the lineage of vertebrates that encompasses rodents and primates. Third, COX4‐2 expression patterns are quite different in fish. They show higher constitutive expression of COX4‐2 in all tissues, and demonstrate changes in COX4‐2 expression with development. Immunohistochemistry of tissues expressing both COX4 paralogs revealed that some tissues displayed both proteins in most cells, whereas other tissues showed cell‐specific patterns. In heart, individual myocytes expressed both COX4 paralogs, although select non‐myocytes expressed only COX4‐1. The paralog patterns also changed with size/age. Heart was dominated by COX4‐1 mRNA and protein in small fish but transitioned to predominately mRNA and COX4‐2 in large fish. The distinctions in COX4‐2 between mammalian models (rodents, humans) and other vertebrates (other mammalian lineages, reptiles, fish) bring into question the genetic origins of the paralog pair and its functional evolution during vertebrate diversification. Support or Funding Information Supported by NSERC Canada
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".