Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Subjects

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%.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Lewis M. Skeletal dysplasias and related conditions. In: Buikstra JE, editor. Ortner’s identification of pathological conditions in human skeletal remains. London: Academic Press; 2019. p. 615–37.

  2. McKenzie CJ, Murphy EM. Life and death in medieval Gaelic Ireland: the skeletons from Ballyhanna, Co. Donegal. Dublin: Four Courts Press; 2018. 448 p.

  3. Pacifici M. Hereditary multiple exostoses: new insights into pathogenesis, clinical complications and potential treatments. Curr Osteoporos Rep. 2017;15:142–52.

    Article  Google Scholar 

  4. Wuyts W, Schmale GA, Chansky HA, Raskind WH. Hereditary multiple osteochondromas. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2020. https://www.ncbi.nlm.nih.gov/pubmed/20301413

  5. Murphy EM, McKenzie CJ. Multiple osteochondromas in the archaeological record: a global review. J Archaeol Sci. 2010;37:2255–64.

    Article  Google Scholar 

  6. Cingolani P, Platts A, Wang LL, Coon M, Nguyen T, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly. 2012;6:80–92.

    Article  CAS  Google Scholar 

  7. Cingolani P, Patel VM, Coon M, Nguyen T, Land SJ, Ruden DM, et al. Using Drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program, SnpSift. Front Genet. 2012;3:35.

    Article  Google Scholar 

  8. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43.

    Article  CAS  Google Scholar 

  9. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–82.

    Article  CAS  Google Scholar 

  10. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013. https://doi.org/10.1002/0471142905.hg0720s76

  11. Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46:D1062–7.

    Article  CAS  Google Scholar 

  12. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  Google Scholar 

  13. McCormick C, Duncan G, Goutsos KT, Tufaro F. The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci USA 2000;97:668–73.

    Article  CAS  Google Scholar 

  14. Chahal HS, Stals K, Unterländer M, Balding DJ, Thomas MG, Kumar AV, et al. AIP mutation in pituitary adenomas in the 18th century and today. N Engl J Med. 2011;364:43–50.

    Article  CAS  Google Scholar 

  15. Boer LL, Naue J, de Rooy L, Oostra RJ. Detection of G1138A Mutation of the FGFR3 gene in tooth material from a 180-year-old museological achondroplastic skeleton. Genes. 2017. https://doi.org/10.3390/genes8090214

  16. Byrne RP, Martiniano R, Cassidy LM, Carrigan M, Hellenthal G, Hardiman O, et al. Insular Celtic population structure and genomic footprints of migration. PLoS Genet. 2018;14:e1007152.

  17. Leslie S, Winney B, Hellenthal G, Davison D, Boumertit A, Day T, et al. The fine-scale genetic structure of the British population. Nature 2015;519:309–14.

    Article  CAS  Google Scholar 

  18. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Sawcer S, Hellenthal G, Pirinen M, Spencer CCA, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–9.

  19. Moore LT, McEvoy B, Cape E, Simms K, Bradley DG. A Y-chromosome signature of hegemony in Gaelic Ireland. Am J Hum Genet. 2006;78:334–8.

    Article  CAS  Google Scholar 

  20. Marnetto D, Huerta-Sánchez E. Haplostrips: revealing population structure through haplotype visualization. Methods Ecol Evol. 2017;8:1389–92.

    Article  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Eileen Murphy or Daniel G. Bradley.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

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

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41431-022-01219-2

Search

Quick links