All Together Now: Joint Codon Alignment, Ohmic Networks, and Error-Controlled Selection Inference in HyPhy 3

WALRUS in HyPhy 3 jointly infers codon alignment and an Ohmic reticulate network, reducing indel-driven false positives from 44.7%-58.1% to 4.4% under BUSTED.

• Why it matters: Standard selection workflows treat alignment and phylogeny as error-free, but heuristic alignment can misplace non-homologous codons and inflate gene-wide false positives above 80%.
• What they did: WALRUS maps unaligned coding sequences to a coordinate-consistent selection atlas in one run, using a single Inside-Outside likelihood table to co-estimate codon alignment, reading frames, and directional base-composition drift, then runs eight selection tests.
• The result: Across 10,020 simulated alignments, it recovers 94.6% of true columns on the 800 INDELible replicates and, under Zipfian indel saturation, cuts false positives four-fold (33.3%-83.3% to 17.0%-20.5%).

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