Evolution and expansion of the RUNX2 QA repeat corresponds with the emergence of vertebrate complexity

Newton, Axel H; Pask, Andrew J

doi:10.1038/s42003-020-01501-3

Cited by 17 publications

(25 citation statements)

References 118 publications

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“…Mammals provide excellent examples to address these hypotheses, owing to their conserved anatomy yet remarkable craniofacial disparity or convergence, shared developmental patterns, heterochrony and lineage-specific constraints, and appropriate divergence times, e.g., within orders or across clades. Through application of these models, we can begin to tease apart how facial morphogenesis and shape diversity is regulated at the cellular and molecular level ( Newton et al, 2017 ; Usui and Tokita, 2018 ; Newton and Pask, 2020 ), informing new models of development.…”

Section: Introductionmentioning

confidence: 99%

Marsupials and Multi-Omics: Establishing New Comparative Models of Neural Crest Patterning and Craniofacial Development

Newton

2022

Front. Cell Dev. Biol.

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Studies across vertebrates have revealed significant insights into the processes that drive craniofacial morphogenesis, yet we still know little about how distinct facial morphologies are patterned during development. Studies largely point to evolution in GRNs of cranial progenitor cell types such as neural crest cells, as the major driver underlying adaptive cranial shapes. However, this hypothesis requires further validation, particularly within suitable models amenable to manipulation. By utilizing comparative models between related species, we can begin to disentangle complex developmental systems and identify the origin of species-specific patterning. Mammals present excellent evolutionary examples to scrutinize how these differences arise, as sister clades of eutherians and marsupials possess suitable divergence times, conserved cranial anatomies, modular evolutionary patterns, and distinct developmental heterochrony in their NCC behaviours and craniofacial patterning. In this review, I lend perspectives into the current state of mammalian craniofacial biology and discuss the importance of establishing a new marsupial model, the fat-tailed dunnart, for comparative research. Through detailed comparisons with the mouse, we can begin to decipher mammalian conserved, and species-specific processes and their contribution to craniofacial patterning and shape disparity. Recent advances in single-cell multi-omics allow high-resolution investigations into the cellular and molecular basis of key developmental processes. As such, I discuss how comparative evolutionary application of these tools can provide detailed insights into complex cellular behaviours and expression dynamics underlying adaptive craniofacial evolution. Though in its infancy, the field of “comparative evo-devo-omics” presents unparalleled opportunities to precisely uncover how phenotypic differences arise during development.

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Section: Introductionmentioning

confidence: 99%

Marsupials and Multi-Omics: Establishing New Comparative Models of Neural Crest Patterning and Craniofacial Development

Newton

2022

Front. Cell Dev. Biol.

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“…Repeats are highly unstable and prone to contraction or expansion by recombinational mechanisms (like gene conversion or unequal crossing-over) or replication-slippage 22 . This volatile nature of repeats contributes to functional and morphological diversity, such as the repeat length variation in the case of the RUNX2 gene 28,30 . RUNX2 is a DNA-binding transcription factor that plays a crucial role in skeletal development in vertebrates 31 .…”

Section: Introductionmentioning

confidence: 99%

“…Studies have found a positive correlation between Q/A ratio with facial shape and angle of facial bones compared to skull length between different breeds of dogs 28 . The QA repeat length variation in RUNX2 contributes to the evolution and diversity of skeletal structure across vertebrates 30 .…”

Section: Introductionmentioning

confidence: 99%

Lineage-specific protein repeat expansions and contractions reveal malleable regions of immune genes

2022

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Functional diversi cation, a higher evolutionary rate, and intense positive selection help a limited number of immune genes interact with many continuously evolving pathogens. Repeats in protein-coding regions are a well-known source of rapid functional diversi cation, adaptive variation, and evolutionary novelty.Repeats play a crucial role in biochemical functions like functional diversi cation of transcription regulation, protein kinases, cell adhesion, signaling pathways, morphogenesis, DNA repair, recombination, and RNA processing. Repeat length variation can change the associated protein's interaction, e cacy, and overall protein network. Repeats have an intrinsic unstable nature and can potentially evolve rapidly and expedite the acquisition of complex phenotypic traits and functions. Because of their ability to generate rapid, adaptive variations over short evolutionary distances, repeats are considered "tuning knobs." Repeat length variation in speci c genes, like RUNX2 and ALX4, is associated with morphological and physiological changes across vertebrates. Here we study repeat length variation as a potent source of species-speci c immune diversi cation across several clades of tetrapods. Moreover, we provide a clade-wise comprehensive list of immune genes with repeat types for future studies of morphological/evolutionary changes within species groups. We observe signi cant repeat length variation of FASLG in Rodentia and C1QC in Primates' contrasting species groups.

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“…The RUNX2 gene encodes the RunT-related master bone transcription factor, which plays a key role in the osteogenic differentiation process, being essential during the development of the vertebrate skeleton 7 . RunT-related protein (RUNX) coding genes are considered “evolutionary tuning knobs”, whose sequence variations led to key changes in protein functions 8 . Three RUNX gene paralogs are found in vertebrates ( RUNX1 , RUNX2 and RUNX3 ), with structural homology and conserved protein domains, despite their tissue-specific expression patterns indicating different functions 9 , 10 .…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, RUNX2 underwent a significant evolutionary pressure that modelled its structure and expression across different vertebrate species. This includes the presence of a unique additional poly-glutamine, poly-alanine tandem repeat domain (QA), which plays a role in protein transactivation 8 and is thought to be involved in the regulation of membranous ossification and craniofacial growth 11 . RUNX2 haploinsufficiency causes cleidocranial dysplasia (CCD), a developmental disorder characterized by an altered growth of membranous bones, including hypoplasia or aplasia of the clavicles, delayed closure of cranial sutures and dental anomalies 12 – 15 .…”

Section: Introductionmentioning

confidence: 99%

Shaping modern human skull through epigenetic, transcriptional and post-transcriptional regulation of the RUNX2 master bone gene

Pietro

Barba

Palacios

et al. 2021

Sci Rep

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RUNX2 encodes the master bone transcription factor driving skeletal development in vertebrates, and playing a specific role in craniofacial and skull morphogenesis. The anatomically modern human (AMH) features sequence changes in the RUNX2 locus compared with archaic hominins’ species. We aimed to understand how these changes may have contributed to human skull globularization occurred in recent evolution. We compared in silico AMH and archaic hominins’ genomes, and used mesenchymal stromal cells isolated from skull sutures of craniosynostosis patients for in vitro functional assays. We detected 459 and 470 nucleotide changes in noncoding regions of the AMH RUNX2 locus, compared with the Neandertal and Denisovan genomes, respectively. Three nucleotide changes in the proximal promoter were predicted to alter the binding of the zinc finger protein Znf263 and long-distance interactions with other cis-regulatory regions. By surface plasmon resonance, we selected nucleotide substitutions in the 3’UTRs able to affect miRNA binding affinity. Specifically, miR-3150a-3p and miR-6785-5p expression inversely correlated with RUNX2 expression during in vitro osteogenic differentiation. The expression of two long non-coding RNAs, AL096865.1 and RUNX2-AS1, within the same locus, was modulated during in vitro osteogenic differentiation and correlated with the expression of specific RUNX2 isoforms. Our data suggest that RUNX2 may have undergone adaptive phenotypic evolution caused by epigenetic and post-transcriptional regulatory mechanisms, which may explain the delayed suture fusion leading to the present-day globular skull shape.

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Evolution and expansion of the RUNX2 QA repeat corresponds with the emergence of vertebrate complexity

Cited by 17 publications

References 118 publications

Marsupials and Multi-Omics: Establishing New Comparative Models of Neural Crest Patterning and Craniofacial Development

Marsupials and Multi-Omics: Establishing New Comparative Models of Neural Crest Patterning and Craniofacial Development

Lineage-specific protein repeat expansions and contractions reveal malleable regions of immune genes

Shaping modern human skull through epigenetic, transcriptional and post-transcriptional regulation of the RUNX2 master bone gene

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