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Millennium-old pathogenic Mendelian mutation discovery for multiple osteochondromas from a Gaelic Medieval graveyard

European Journal of Human Genetics volume 31, pages 248–251 (2023)Cite this article

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Abstract

Only a limited number of genetic diseases are diagnosable in archaeological individuals and none have had causal mutations identified in genome-wide screens. Two individuals from the Gaelic Irish Medieval burial ground of Ballyhanna, Co. Donegal, showed evidence of bone tumours consistent with the autosomal dominant condition multiple osteochondromas. Genome sequencing of the earlier individual uncovered a missense mutation in the second exon of EXT1, a specific lesion that has been identified in several modern patients. The later individual lacked this but displayed a novel frameshift mutation leading to a premature stop codon and loss of function in the same gene. These molecular confirmations of a paleopathological diagnosis within a single rural ancient context are surprisingly disjunct, given the observation of clusters of this disease in modern isolated populations and a de novo mutation rate of only 10%.

Cases of Mendelian genetic disease have been uncovered in the archaeological record, but diagnosis is restricted to osteologically visible conditions, with more commonly encountered conditions including achondroplasia, multiple epiphyseal dysplasia and Léri-Weill dyschondrosteosis [1].

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Fig. 1: Examples of lesions and alignment of NGS data at putative disease variants.
Fig. 2: Principal component analysis of Northwest European populations.

Data availability

Raw FASTQ and aligned BAM files are available from the European Nucleotide Archive (ENA) under accession number PRJEB50653.

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Acknowledgements

We acknowledge Trinseq for sequencing support and the DJEI/DES/SFI/HEA Irish Centre for High-End Computing (ICHEC) for the provision of computational facilities. We wish to thank the National Museum of Ireland for granting the necessary licences for the study (licence to alter: 6861). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Funding

We wish to thank Transport Infrastructure Ireland and Donegal County Council who funded the Ballyhanna Research Project. This work was funded by the Science Foundation Ireland/Health Research Board/Wellcome Trust Biomedical Research Partnership Investigator Award No. 205072 to DGB, “Ancient Genomics and the Atlantic Burden” and IJ was supported by the Science Foundation Ireland Centre for Research Training in Genomics Data Science (18/CRT/6214).

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Authors and Affiliations

  1. Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland

    Iseult Jackson, Valeria Mattiangeli, Lara M. Cassidy & Daniel G. Bradley

  2. The SFI Centre for Research Training in Genomics Data Science, NUI Galway, Galway, Ireland

    Iseult Jackson

  3. Archaeology and Palaeoecology, School of Natural and Built Environment, Queen’s University Belfast, Belfast, Northern Ireland

    Eileen Murphy

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  1. Iseult Jackson
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Contributions

DGB and EM supervised the study. EM curated samples. IJ, VM and LMC generated data through laboratory work. IJ processed and analysed the data with input from LMC. IJ, EM and DGB wrote the paper with input from all authors.

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Correspondence to Eileen Murphy or Daniel G. Bradley.

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The authors declare no competing interests.

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This research was carried out under the approval of the Trinity College Dublin School of Natural Sciences Research Ethics Committee, reference number 2019–03.

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Jackson, I., Mattiangeli, V., Cassidy, L.M. et al. Millennium-old pathogenic Mendelian mutation discovery for multiple osteochondromas from a Gaelic Medieval graveyard. Eur J Hum Genet 31, 248–251 (2023). https://doi.org/10.1038/s41431-022-01219-2

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