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Quantitative shape comparison (morphometrics) traditionally uses manually located landmarks and is limited by landmark number and operator accuracy. Here, we apply a landmark-free method to characterise the craniofacial skeletal phenotype of the Dp1Tyb mouse model of Down syndrome and a population of the Diversity Outbred (DO) mouse model, comparing it with a landmark-based approach. We identified cranial dysmorphologies in Dp1Tyb mice, especially smaller size and brachycephaly (front-back shortening), homologous to the human phenotype. Shape variation in the DO mice was partly attributable to allometry (size-dependent shape variation) and sexual dimorphism. The landmark-free method performed as well as, or better than, the landmark-based method but was less labour-intensive, required less user training and, uniquely, enabled fine mapping of local differences as planar expansion or shrinkage. Its higher resolution pinpointed reductions in interior mid-snout structures and occipital bones in both the models that were not otherwise apparent. We propose that this landmark-free pipeline could make morphometrics widely accessible beyond its traditional niches in zoology and palaeontology, especially in characterising developmental mutant phenotypes.<\/jats:p>","DOI":"10.1242\/dev.188631","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T09:25:14Z","timestamp":1615541114000},"source":"Crossref","is-referenced-by-count":50,"title":["A landmark-free morphometrics pipeline for high-resolution phenotyping: application to a mouse model of Down syndrome"],"prefix":"10.1242","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4696-465X","authenticated-orcid":false,"given":"Nicolas","family":"Toussaint","sequence":"first","affiliation":[{"name":"School of Biomedical Engineering and Imaging Sciences, King's College London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushi","family":"Redhead","sequence":"additional","affiliation":[{"name":"Centre for Craniofacial Biology & Regeneration, King's College London, UK"},{"name":"The Francis Crick Institute, London NW1 1AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7617-7329","authenticated-orcid":false,"given":"Marta","family":"Vidal-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Cell Biology & Anatomy, University of Calgary, Calgary AB T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5465-6801","authenticated-orcid":false,"given":"Lucas","family":"Lo Vercio","sequence":"additional","affiliation":[{"name":"Department of Cell Biology & Anatomy, University of Calgary, Calgary AB T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cell Biology & Anatomy, University of Calgary, Calgary AB T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2850-9936","authenticated-orcid":false,"given":"Elizabeth M. C.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7192-9103","authenticated-orcid":false,"given":"Benedikt","family":"Hallgr\u00edmsson","sequence":"additional","affiliation":[{"name":"Department of Cell Biology & Anatomy, University of Calgary, Calgary AB T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2439-0798","authenticated-orcid":false,"given":"Victor L. 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