424: LECA's Ancient Interactome and Modern Disease

Cox RM et al., Cell Genomics 6, 101254 - Cox et al. reconstruct a conserved protein interaction network for the last eukaryotic common ancestor using >26,000 mass spectrometry experiments across 31 species and demonstrate how the ancient interactome predicts and explains modern human disease mechanisms. Key terms: LECA, protein interactome, co-fractionation mass spectrometry, ciliopathy, V-ATPase.

Study Highlights:
The authors inferred a core LECA gene set and integrated ∼26,000 mass spectrometry experiments from 31 eukaryotes to reconstruct a conserved interactome of 109,466 pairwise interactions among 3,193 orthogroups. The map recovers known complexes (e.g., ARP2/3, TRAPP, V-ATPase, HOPS/CORVET) and reveals unexpected ancient interactions and lineage-specific losses. Network propagation on this interactome predicted novel gene-disease links validated experimentally: EFHC2 mislocalization linked to ciliopathic renal failure, ATP6V1A implicated in osteopetrosis with corresponding increased bone density in mouse knockouts, and GLG1 disruption impairing IFT and ciliation relevant to SRTD. The dataset supports a complex LECA capable of cell projection machinery and provides a framework for linking deep conservation to medical phenotypes.

Conclusion:
An experimentally reconstructed LECA interactome defines deeply conserved macromolecular assemblies that have persisted for nearly two billion years and can predict modern disease mechanisms, as shown by validated links to ciliopathies, osteopetrosis, and short-rib thoracic dysplasia.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
A protein interactome for the last eukaryotic common ancestor illuminates the biochemical basis of modern genetic diseases

First author:
Cox RM

Journal:
Cell Genomics 6, 101254

DOI:
10.1016/j.xgen.2026.101254

Reference:
Cox RM, Papoulas O, Shril S, et al. A protein interactome for the last eukaryotic common ancestor illuminates the biochemical basis of modern genetic diseases. Cell Genomics. 2026;6:101254. https://doi.org/10.1016/j.xgen.2026.101254

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
More at basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/leca-interactome-modern-disease

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-23.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited transcript sections: LECA concept and health relevance; CFMS data integration across 31 species; conserved vesicle tethering complexes and actin cytoskeleton in LECA; primordial origins of cell projection/phagocytosis; EFHC2 ciliopathy mechanism; ATP6V1A osteopetrosis; GLG1 in ciliogenesis and SRT
- transcript topics: LECA concept and health relevance; CFMS data integration across 31 species; Conserved vesicle tethering complexes (TRAPP, GARP/COG, HOPS); Actin cytoskeleton and ARP2/3 in LECA; Primordial origins of cell projection and phagocytosis; EFHC2 ciliary mechanism in renal disease

QC Summary:
- factual score: 10/10
- metadata score:...

Chapters

• (00:00:20) - Papercast: Dating the genetics of humans
• (00:01:29) - Machine-learning maps the interactions of a billion year old cell
• (00:04:44) - Could the LECA Intersectome Identify Human Diseases?