A mathematical framework for the quantitative analysis of genetic buffering.
Genetic buffering plays a pivotal role in orchestrating the relationship between genotype and phenotype in outbred populations. While high-throughput screens have identified many instances of genetic buffering - through the detection of "synthetic lethality" or "synthetic sickness&quo...
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Public Library of Science (PLoS)
2025-06-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1011730 |
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| author | Jim Karagiannis |
| author_facet | Jim Karagiannis |
| author_sort | Jim Karagiannis |
| collection | DOAJ |
| description | Genetic buffering plays a pivotal role in orchestrating the relationship between genotype and phenotype in outbred populations. While high-throughput screens have identified many instances of genetic buffering - through the detection of "synthetic lethality" or "synthetic sickness" - a formal and general method for its quantitative analysis across systems is lacking. In this report, an axiomatic mathematical framework that can be used to classify, quantify, and compare buffering relationships between genes is described. Importantly, this methodology employs a ratio scale as its basis, thereby permitting the definition of a novel neutrality model for gene interaction - the "parallel" model - which complements the commonly used "product" model. Evidence supporting the parallel model is provided through the statistical analysis of previously published yeast gene interaction data. This analysis reveals the consistent underestimation of double mutant fitness in strains carrying non-interacting query-array pairings (as predicted by the existence of "parallel" relationships between genes). Moreover, a model incorporating parallel neutrality in the determination of expected double mutant fitness largely corrects the underestimation. Finally, it is shown that simple extensions of this newly developed framework permit the unambiguous definition and classification of gene interactions in a formal, general, and mathematical way. Consequently, the concept of genetic buffering as first conceived by Leland Hartwell becomes a specific case within a comprehensive model of gene interaction. |
| format | Article |
| id | doaj-art-3dc72d69a4574251a5f9bc6b28d41180 |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-3dc72d69a4574251a5f9bc6b28d411802025-08-20T02:22:06ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042025-06-01216e101173010.1371/journal.pgen.1011730A mathematical framework for the quantitative analysis of genetic buffering.Jim KaragiannisGenetic buffering plays a pivotal role in orchestrating the relationship between genotype and phenotype in outbred populations. While high-throughput screens have identified many instances of genetic buffering - through the detection of "synthetic lethality" or "synthetic sickness" - a formal and general method for its quantitative analysis across systems is lacking. In this report, an axiomatic mathematical framework that can be used to classify, quantify, and compare buffering relationships between genes is described. Importantly, this methodology employs a ratio scale as its basis, thereby permitting the definition of a novel neutrality model for gene interaction - the "parallel" model - which complements the commonly used "product" model. Evidence supporting the parallel model is provided through the statistical analysis of previously published yeast gene interaction data. This analysis reveals the consistent underestimation of double mutant fitness in strains carrying non-interacting query-array pairings (as predicted by the existence of "parallel" relationships between genes). Moreover, a model incorporating parallel neutrality in the determination of expected double mutant fitness largely corrects the underestimation. Finally, it is shown that simple extensions of this newly developed framework permit the unambiguous definition and classification of gene interactions in a formal, general, and mathematical way. Consequently, the concept of genetic buffering as first conceived by Leland Hartwell becomes a specific case within a comprehensive model of gene interaction.https://doi.org/10.1371/journal.pgen.1011730 |
| spellingShingle | Jim Karagiannis A mathematical framework for the quantitative analysis of genetic buffering. PLoS Genetics |
| title | A mathematical framework for the quantitative analysis of genetic buffering. |
| title_full | A mathematical framework for the quantitative analysis of genetic buffering. |
| title_fullStr | A mathematical framework for the quantitative analysis of genetic buffering. |
| title_full_unstemmed | A mathematical framework for the quantitative analysis of genetic buffering. |
| title_short | A mathematical framework for the quantitative analysis of genetic buffering. |
| title_sort | mathematical framework for the quantitative analysis of genetic buffering |
| url | https://doi.org/10.1371/journal.pgen.1011730 |
| work_keys_str_mv | AT jimkaragiannis amathematicalframeworkforthequantitativeanalysisofgeneticbuffering AT jimkaragiannis mathematicalframeworkforthequantitativeanalysisofgeneticbuffering |