Interpreting mammalian synonymous site conservation in light of the unwanted transcript hypothesis

Matthew J. Christmas (), Michael X. Dong, Jennifer R. S. Meadows, Sergey V. Kozyrev and Kerstin Lindblad-Toh
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Matthew J. Christmas: Uppsala University
Michael X. Dong: Uppsala University
Jennifer R. S. Meadows: Uppsala University
Sergey V. Kozyrev: Uppsala University
Kerstin Lindblad-Toh: Uppsala University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Mammalian genomes are biased towards GC bases at third codon positions, likely due to a GC-biased ancestral genome and the selectively neutral recombination-related process of GC-biased gene conversion. The unwanted transcript hypothesis posits that this high GC content at synonymous sites may be beneficial for protecting against spurious transcripts, particularly in species with low effective population sizes. Utilising a 240 placental mammal genome alignment and single-base resolution conservation scores, we interpret sequence conservation at mammalian four-fold degenerate sites in this context and find evidence in support of the unwanted transcript hypothesis, including a strong GC bias, high conservation at sites relating to exon splicing, less human genetic variation at conserved four-fold degenerate sites, and conservation of sites important for epigenetic regulation of developmental genes. Additionally, we show that high conservation of four-fold degenerate sites in essential developmental genes, including homeobox genes, likely relates to the low mutation rates experienced by these genes.

Date: 2025
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DOI: 10.1038/s41467-025-57179-w

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