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Interpreting mammalian synonymous site conservation in light of the unwanted transcript hypothesis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology, Genetics and Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-6355-7581
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology, Genetics and Genomics.ORCID iD: 0000-0003-4084-3099
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology, Genetics and Genomics.ORCID iD: 0000-0002-0850-230x
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology, Genetics and Genomics.ORCID iD: 0000-0001-6209-4100
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2025 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 16, article id 2007Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer Nature, 2025. Vol. 16, article id 2007
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Evolutionary Biology
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URN: urn:nbn:se:uu:diva-552348DOI: 10.1038/s41467-025-57179-wISI: 001435264300001PubMedID: 40011430OAI: oai:DiVA.org:uu-552348DiVA, id: diva2:1944633
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Swedish Research Council, 2022-06725Available from: 2025-03-14 Created: 2025-03-14 Last updated: 2025-03-14Bibliographically approved

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Christmas, MatthewDong, Michael X.Meadows, Jennifer R. S.Kozyrev, Sergey V.Lindblad-Toh, Kerstin
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