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Deriving genetic codes for molecular phenotypes from first principles.

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Summary
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A new principle of structural correspondence links genome sequence to organism traits across all scales. This framework predicts genetic associations and guides discovery, even rediscovering the genetic code.

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Area of Science:

  • Genomics
  • Systems Biology
  • Bioinformatics

Background:

  • The relationship between genome sequence and phenotype is complex and not fully understood across biological scales.
  • Current understanding often relies on mechanistic modeling, lacking a unifying formal principle.

Purpose of the Study:

  • To identify a universal formal principle governing the genome sequence-phenotype relationship across molecular, cellular, tissue, and organ scales.
  • To establish a first-principles framework for relating genotype to phenotype and guiding mechanistic biological discovery.

Main Methods:

  • Representing phenotypes and genomes as graphs.
  • Utilizing structure preservation as the sole constraint for graph mapping.
  • Applying the principle to predict genetic associations and analyze biological data across scales.

Main Results:

  • A single principle, structural correspondence, was identified as underlying the genome sequence-phenotype relationship.
  • This principle successfully rediscovers the amino acid code without prior knowledge of translation.
  • The framework predicts established associations in cellular and tissue phenotypes and identifies regulators of spatial gene expression in cancer.

Conclusions:

  • Structural correspondence offers a unifying framework to connect genome sequence with phenotypic structure across biological scales.
  • This principle provides a powerful tool for predicting genetic associations and driving mechanistic discovery in biology and medicine.