Evolution and expansion of the RUNX2 QA repeat corresponds with the emergence of vertebrate complexity.
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ABSTRACT:
SUBMITTER: Newton AH
PROVIDER: S-EPMC7738678 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundShort tandem repeat (STR) expansion disorders are an important cause of human neurological disease. They have an established role in more than 40 different phenotypes including the myotonic dystrophies, Fragile X syndrome, Huntington's disease, the hereditary cerebellar ataxias, amyotrophic lateral sclerosis and frontotemporal dementia.Main bodySTR expansions are difficult to detect and may explain unsolved diseases, as highlighted by recent findings including: the discovery of a biallelic intronic 'AAGGG' repeat in RFC1 as the cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS); and the finding of 'CGG' repeat expansions in NOTCH2NLC as the cause of neuronal intranuclear inclusion disease and a range of clinical phenotypes. However, established laboratory techniques for diagnosis of repeat expansions (repeat-primed PCR and Southern blot) are cumbersome, low-throughput and poorly suited to parallel analysis of multiple gene regions. While next generation sequencing (NGS) has been increasingly used, established short-read NGS platforms (e.g., Illumina) are unable to genotype large and/or complex repeat expansions. Long-read sequencing platforms recently developed by Oxford Nanopore Technology and Pacific Biosciences promise to overcome these limitations to deliver enhanced diagnosis of repeat expansion disorders in a rapid and cost-effective fashion.ConclusionWe anticipate that long-read sequencing will rapidly transform the detection of short tandem repeat expansion disorders for both clinical diagnosis and gene discovery.
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Project description:BackgroundRunt-related transcription factor 2 (RUNX2) is a transcription factor essential for skeletal development. Variation within the RUNX2 polyglutamine / polyalanine (QA) repeat is correlated with facial length within orders of placental mammals and is suggested to be a major driver of craniofacial diversity. However, it is not known if this correlation exists outside of the placental mammals.ResultsHere we examined the correlation between the RUNX2 QA repeat ratio and facial length in the naturally evolving sister group to the placental mammals, the marsupials. Marsupials have a diverse range of facial lengths similar to that seen in placental mammals. Despite their diversity there was almost no variation seen in the RUNX2 QA repeat across individuals spanning the entire marsupial infraclass. The extreme conservation of the marsupial RUNX2 QA repeat indicates it is under strong purifying selection. Despite this, we observed an unexpectedly high level of repeat purity.ConclusionsUnlike within orders of placental mammals, RUNX2 repeat variation cannot drive craniofacial diversity in marsupials. We propose conservation of the marsupial RUNX2 QA repeat is driven by the constraint of accelerated ossification of the anterior skeleton to facilitate life in the pouch. Thus, marsupials must utilize alternate pathways to placental mammals to drive craniofacial evolution.
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