{
  "abstract": "Detecting Darwinian natural selection is fundamental to evolutionary biology and functional genomics, yet standard methods based on phylogenetic models that estimate the ratio of non-synonymous to synonymous substitution rates (dN/dS) fail to scale with modern genomic volumes. Fitting continuous-time Markov substitution matrices across dense trees with hundreds of species requires extensive compute, forcing comparative genomics to rely on aggressive taxon subsampling or static whole-tree summaries that dilute transient adaptive bursts. Here we present HyphAeon, a lightweight (~1.91M parameter backbone, 2.46M across the full multi-task suite) phylogeny-informed foundation transformer trained to amortize the detection of episodic diversifying selection across 742-species mammalian coding alignments (17,186 genes, 9.77 x 10^6 codons). HyphAeon approaches the discriminative accuracy of numerical maximum-likelihood selection tests (MEME) across episodic burst regimes (ROC-AUC up to 0.942, mean 0.659; empirical Precision-Recall lift up to 25.8x, mean 7.7x; rank concordance up to rho = 0.983) while executing >1,000x faster per locus (averaging <1 ms per site across genome-wide scans) and >10,000x faster at proteome scale, generalizing outside its mammalian training distribution without retraining. Beyond accelerating classical tests, embedding molecular evolution into a differentiable geometric latent space enables analytical capabilities inaccessible to static dN/dS models: (1) targeted alignment artifact correction via counterfactual attribution; (2) macromolecular contact recovery and multi-site epistatic sectors (CESI); (3) directional phenotype-to-genotype attribution in lineage space (PARS); and (4) continuous temporal surveillance regression that tracks positive sweep velocities across longitudinal cohorts (evaluated across 12,167 timestamped genomes and benchmarked against external frequencies from >9.34 million genomes), rescuing adaptive substitutions obscured by post-fixation dilution. By bridging statistical phylogenetics with geometric representation learning, HyphAeon establishes comparative genomics as an interactive, high-throughput computational framework for evolutionary discovery.",
  "abstract_shown": true,
  "affiliations": [
    "Temple University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "S. L. Kosakovsky Pond"
    },
    {
      "name": "S. Weaver"
    },
    {
      "name": "D. Callan"
    },
    {
      "name": "J. D. Zehr"
    },
    {
      "name": "A. G. Lucaci"
    },
    {
      "name": "H. Verdonk"
    },
    {
      "name": "A. Selberg"
    },
    {
      "name": "G. Brown"
    },
    {
      "name": "M. Chikina"
    },
    {
      "name": "N. L. Clark"
    },
    {
      "name": "K. D. Makova"
    },
    {
      "name": "D. P. Martin"
    },
    {
      "name": "A. Nekrutenko"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bwwhbvdchctyb.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.06.749597",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749597v1.full",
  "id": "bwwhbvdchctyb",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749597v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioinformatics"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749597v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-06",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/bwwhbvdchctyb.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:15Z",
      "native_id": "10.64898/2026.09.06.749597",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749597v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "HyphAeon: Attention on Evolution Across Deep Time Transforms Comparative Genomics",
  "title_text": "HyphAeon: Attention on Evolution Across Deep Time Transforms Comparative Genomics",
  "type": "preprint",
  "updated_at": "2026-10-30T12:21:15Z",
  "url": "https://research.draconitic.com/paper/bwwhbvdchctyb",
  "venue": "bioRxiv",
  "versions": []
}