Conservation biology meets evo‐devo: How understanding the emergence of variation can inform its management

Parsons, Kevin J.

doi:10.1111/ede.12389

Cited by 1 publication

(1 citation statement)

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“…Hence, a plausible evo-devo view [ 77 ] of our results is that disrupting the conserved intragenic CpG structure of Trp53 –in this study, either by synonymously removing all 22 exonic CpG sites, or else by inserting 72 synonymous CpG sites–deranges the topology of site-specific MBP (e.g., MeCP2 or MBD2) interactions with Trp53 , leading to loss of pro-apoptotic gene function in the developing tooth bed [ 78 , 79 ], e.g., by splice-dependent [ 80 ] or chromatin-based trans -repression mechanisms [ 81 , 82 ]. Consistent with this, TP53 is downregulated in proliferative dental pathologies such as odontogenic keratocysts and ameloblastomas [ 83 ].…”

Section: Discussionmentioning

confidence: 99%

Synonymous alterations of cancer-associated Trp53 CpG mutational hotspots cause fatal developmental jaw malocclusions but no tumors in knock-in mice

Epstein

Lin²,

Brink³

et al. 2023

PLoS ONE

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Intragenic CpG dinucleotides are tightly conserved in evolution yet are also vulnerable to methylation-dependent mutation, raising the question as to why these functionally critical sites have not been deselected by more stable coding sequences. We previously showed in cell lines that altered exonic CpG methylation can modify promoter start sites, and hence protein isoform expression, for the human TP53 tumor suppressor gene. Here we extend this work to the in vivo setting by testing whether synonymous germline modifications of exonic CpG sites affect murine development, fertility, longevity, or cancer incidence. We substituted the DNA-binding exons 5–8 of Trp53, the mouse ortholog of human TP53, with variant-CpG (either CpG-depleted or -enriched) sequences predicted to encode the normal p53 amino acid sequence; a control construct was also created in which all non-CpG sites were synonymously substituted. Homozygous Trp53-null mice were the only genotype to develop tumors. Mice with variant-CpG Trp53 sequences remained tumor-free, but were uniquely prone to dental anomalies causing jaw malocclusion (p < .0001). Since the latter phenotype also characterises murine Rett syndrome due to dysfunction of the trans-repressive MeCP2 methyl-CpG-binding protein, we hypothesise that CpG sites may exert non-coding phenotypic effects via pre-translational cis-interactions of 5-methylcytosine with methyl-binding proteins which regulate mRNA transcript initiation, expression or splicing, although direct effects on mRNA structure or translation are also possible.

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