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bioRxiv · 10.64898/2026.04.13.718263

Punctuated Evolution of Endomembrane Compartments in Proto-Eukaryotes

Shridhar, S.·Kumari, K.·Thattai, M.
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Abstract

Eukaryotic cells are defined by their endomembranes: compartments such as the endoplasmic reticulum (ER), Golgi and endosomes, exchanging cargo via vesicles. The evolutionary origins of endomembrane compartments remain unclear. Here we construct molecular-evolutionary trajectories for the stepwise addition of compartments after the emergence of the proto-ER in an ancestral eukaryote. We represent compartments and vesicles as nodes and edges of a directed graph. Vesicle budding and fusion regulators such as coats and SNAREs control cargo flows and determine compartment compositions. We computationally sample billions of possible graphs, and enumerate how duplication, deletion and mutation of regulators drive graph transitions. We find that evolutionary trajectories display punctuated shifts in compartment composition and number, interspersed with thousands of neutral mutations. The first added compartment inherits functions from the proto-ER or plasma membrane, or gains novel functions. Our results show how, given a billion years, simple molecular steps can generate complex endomembrane systems. SO_SCPLOWIGNIFICANCEC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWEukaryotic cells contain a system of endomembrane compartments that sort, process and deliver molecules to precise cellular destinations. This endomembrane system is a defining feature of all complex life, yet its evolutionary origins remain obscure. How did a proto-eukaryote with a single ancestral endomembrane compartment evolve into a cell with a Golgi, endosomes, lysosomes and other compartments characteristic of modern eukaryotes? We model this process from first principles, connecting the duplication, deletion and mutation of molecular regulators to compartment gain or loss. We find a punctuated pattern of endomembrane elaboration: a long phase of neutral exploration, driven by the mutation of duplicate gene copies, precedes the emergence of new compartments and functions.

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Shridhar, S., Kumari, K., Thattai, M.. 2026-04-14. Punctuated Evolution of Endomembrane Compartments in Proto-Eukaryotes. https://doi.org/10.64898/2026.04.13.718263

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