Collateral replacement of a conserved nuclear-receptor coactivator motif by GC-biased gene conversion in monotremes
Year: 2026
Type: article
Abstract: GC-biased gene conversion (gBGC) is a recombination-associated process that fixes G/C over A/T alleles irrespective of their effect on the protein and is a known cause of false positive-selection signals in molecular-evolution analyses. Examples of gBGC caught fixing a protein-altering change at a specific, conserved coding element, and generating a spurious selection signal in the process, remain rare. The LXXLL nuclear receptor (NR) motif is among the most conserved interaction modules in metazoan transcription, making it a stringent test case. NR1 of NCOA1, invariant as LVQLL across all non-monotreme species of a 48-species sarcopterygian sample, was fixed as PGQLP in both extant monotremes, the platypus and the short-beaked echidna. Several lines of evidence indicated that the change arose by gBGC rather than by adaptive substitution. In both monotreme genomes, the NR1 region was a local GC peak. The monotreme branch carried a weak-to-strong substitution bias across the whole gene, not only at NR1, as expected under gBGC. Branch-level tests reported positive selection on the monotreme lineage, but no site-level test detected adaptive change at NR1. When restricted to GC-conservative substitutions, which gBGC cannot drive, the monotreme-branch dN/dS remained below 1. The derived motif was identical between platypus and echidna across their ~55-million-year divergence and was fixed at the DNA level across 52 platypus genomes. FoldX modeling predicted weaker receptor binding for PGQLP than for the ancestral LVQLL (ΔΔG ≈ +6.9 kcal/mol). The same process appeared to act independently in ray-finned fishes, where NR1 was the least constrained NR box and the direction of its substitutions tracked the local GC background (Spearman r = 0.93, p = 0.008). This locus shows that a neutral process can replace a deeply conserved coding motif and produce a false signal of positive selection. The combination of tests used here can help distinguish gBGC from selection when conserved coding motifs are altered in lineages with unusual recombination or GC content.
Source: BMC Genomics
Author: Eunae Sandra Cho
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,090
OpenAlex ID: W7222478980