Periodic Reporting for period 4 - EvoConBiO (Uncovering and engineering the principles governing evolution and cellular control of bioenergetic organelles)
Reporting period: 2024-01-01 to 2025-05-31
Mitochondria and chloroplasts obtain and process energy in eukaryotes (plants, animals, fungi, and more). Originally independent organisms, these organelles retain their own genomes, which have evolved over history and continue to evolve in organisms' cells. This organelle DNA, or oDNA, encodes parts of cellular machinery that are essential for bioenergetics and metabolism – and mutations in oDNA can have devastating consequences.
But despite this central importance, there are outstanding questions about the evolution and maintenance of oDNA. Much of its content has been lost or transferred to the cell’s nucleus over evolutionary history – so why are any genes retained in oDNA, given its propensity to become damaged? Why are different profiles of oDNA genes retained in different species? And how do species maintain and protect the oDNA that they retain? These are both outstanding basic science question at the heart of eukaryotic evolution and cell biology, and important for the understanding of human diseases and crop breeding strategies connected to oDNA. EvoConBiO combines mathematical, computational, and experimental approaches to address these complicated, coupled questions, and to discover: What universal principles underlie organelle genome evolution?
But despite this central importance, there are outstanding questions about the evolution and maintenance of oDNA. Much of its content has been lost or transferred to the cell’s nucleus over evolutionary history – so why are any genes retained in oDNA, given its propensity to become damaged? Why are different profiles of oDNA genes retained in different species? And how do species maintain and protect the oDNA that they retain? These are both outstanding basic science question at the heart of eukaryotic evolution and cell biology, and important for the understanding of human diseases and crop breeding strategies connected to oDNA. EvoConBiO combines mathematical, computational, and experimental approaches to address these complicated, coupled questions, and to discover: What universal principles underlie organelle genome evolution?
Our peer-reviewed findings so far have included exciting answers to the three above long-standing questions: why different genes are differentially retained in organelles across species, why different species retain different profiles of organelle genes, and how oDNA maintenance takes places across eukaryotic kingdoms. This final point has opened up an exciting new avenue of research: why mitochondria behave so differently in different organisms, and why they move with such complex collective dynamics in plants. We have created a “social network” picture of genetic exchange to explain these phenomena and have published a collection of peer-reviewed articles in this new paradigm. We have published a wide variety of experimental data, mathematical models and simulation code, and bioinformatics pipelines via public repositories to allow further research.
Specifically, we have found that:
- Strategies for avoiding organelle "mutational meltdown" depend on an organism's ability to set aside protected cells for inheritance between generations. Several animals can do this, allowing the relatively well-known mtDNA bottleneck. Plants, fungi, and single cells cannot, and we have shown a role for a process called gene conversion that can compensate for this inability. This theory has been experimentally verified in plants in collaboration with colleagues. In so doing we have created the most general explanation of which we are aware for how organelles spread mutational damage.
- Plant mitochondria move to resolve a tension between staying spread through the cell and meeting to exchange contents. We used video microscopy, computational analysis, and network science to define the "social networks" of mitochondria -- the meetings of mitochondria in the cell. These social networks are surprisingly good at supporting beneficial exchange of contents between mitochondria, and we have shown with experiments on mutant lines and followup theory that this "trade network" is controlled in such a way as to optimise exchange.
- The retention of genes in organelles is shaped by a combination of factors, including hydrophobicity, protein product centrality, and nucleic acid biochemistry. This relationship is so universal that statistical models trained on retention patterns in chloroplasts can predict those in mitochondria, and vice versa. The same features also describe gene retention in independent endosymbionts.
- The extent of oDNA gene loss is connected in part to features of an organism’s environment. Theoretical models and bioinformatic surveys agree that strongly varying environmental demands on metabolism (like those found in intertidal zones, and through pronounced diurnal variation) favour the retention of more genes in oDNA, aligned with the theory of colocation for redox regulation (CoRR). The extent of gene retention in mitochondria and plastids is coupled, supporting this picture.
During this progress, we have also developed and published several highly generalisable tools for bioinformatic, evolutionary, and cell biological modelling, including powerful machinery for “accumulation modelling” (the parallel acquisition or loss of traits across lineages), phylogenetic comparative methods for non-standard data structures, and simulation models for agents in cell biology.
Progress beyond the state of the art and expected results until the end of the project
Specifically, we have found that:
- Strategies for avoiding organelle "mutational meltdown" depend on an organism's ability to set aside protected cells for inheritance between generations. Several animals can do this, allowing the relatively well-known mtDNA bottleneck. Plants, fungi, and single cells cannot, and we have shown a role for a process called gene conversion that can compensate for this inability. This theory has been experimentally verified in plants in collaboration with colleagues. In so doing we have created the most general explanation of which we are aware for how organelles spread mutational damage.
- Plant mitochondria move to resolve a tension between staying spread through the cell and meeting to exchange contents. We used video microscopy, computational analysis, and network science to define the "social networks" of mitochondria -- the meetings of mitochondria in the cell. These social networks are surprisingly good at supporting beneficial exchange of contents between mitochondria, and we have shown with experiments on mutant lines and followup theory that this "trade network" is controlled in such a way as to optimise exchange.
- The retention of genes in organelles is shaped by a combination of factors, including hydrophobicity, protein product centrality, and nucleic acid biochemistry. This relationship is so universal that statistical models trained on retention patterns in chloroplasts can predict those in mitochondria, and vice versa. The same features also describe gene retention in independent endosymbionts.
- The extent of oDNA gene loss is connected in part to features of an organism’s environment. Theoretical models and bioinformatic surveys agree that strongly varying environmental demands on metabolism (like those found in intertidal zones, and through pronounced diurnal variation) favour the retention of more genes in oDNA, aligned with the theory of colocation for redox regulation (CoRR). The extent of gene retention in mitochondria and plastids is coupled, supporting this picture.
During this progress, we have also developed and published several highly generalisable tools for bioinformatic, evolutionary, and cell biological modelling, including powerful machinery for “accumulation modelling” (the parallel acquisition or loss of traits across lineages), phylogenetic comparative methods for non-standard data structures, and simulation models for agents in cell biology.
Progress beyond the state of the art and expected results until the end of the project
By providing answers to several outstanding questions with novel and powerful interdisciplinary approaches, EvoConBiO has gone well beyond the state of the art in the study of oDNA evolution and maintenance, generating insights that would have been impossible without the combination of disciplines involved. Now at the end of the project, EvoConBiO has delivered a self-consistent “umbrella: theory, supported by bioinformatic and experimental evidence, on the universal principles underlying organelle genome evolution. The full story can only be told by the various articles involved, but to condense (thereby losing some important nuance):
- Why are genes retained in organelles at all? In part, a tradeoff between availability/control (ability to import product, and the benefits of that product for local organelle control) and genetic robustness
- Why do different species retain different sets of genes? In part, environmental demands on organelle control (more dynamic environmental demands favour more local control of organelle gene expression and therefore more oDNA retention, following CoRR)
- How do species avoid mutations building up in organelles? In addition to selection, segregation of damage via either an animal-like bottleneck, or recombination – the latter of which can necessitate “social dynamics” for exchange and complementation
It is, however, not the end of the research programme: ongoing work will pursue the new research avenues that EvoConBiO has opened up, particularly looking at oDNA maintenance in non-bilaterian eukaryotes.
- Why are genes retained in organelles at all? In part, a tradeoff between availability/control (ability to import product, and the benefits of that product for local organelle control) and genetic robustness
- Why do different species retain different sets of genes? In part, environmental demands on organelle control (more dynamic environmental demands favour more local control of organelle gene expression and therefore more oDNA retention, following CoRR)
- How do species avoid mutations building up in organelles? In addition to selection, segregation of damage via either an animal-like bottleneck, or recombination – the latter of which can necessitate “social dynamics” for exchange and complementation
It is, however, not the end of the research programme: ongoing work will pursue the new research avenues that EvoConBiO has opened up, particularly looking at oDNA maintenance in non-bilaterian eukaryotes.