Down syndrome (trisomy 21): Developmental implications from morphometric investigations of the effects of gene-dosage imbalance upon craniofacial phenotypes in humans and the Ts1Yey Down syndrome mouse model.

摘要

This project investigates different aspects of craniofacial phenotypes exhibited in individuals with Down syndrome (DS), siblings of individuals with DS, and typically developing sibling pairs. A human sample (4-12 yrs.) consisting of 3D facial surface images (n = 55 for four separate samples: i.e. n = 220 overall) was used to explore developmental instability of the face and patterns of facial covariation between individuals with DS, their siblings, and typically developing sibling pairs. Morphometric analyses were used to infer how gene-dosage imbalance, caused by trisomy 21, is affecting DS craniofacial development. Overall we found increased fluctuating asymmetry in the faces of individuals with DS, which provides evidence for the "amplified developmental instability" model put forth by Shapiro (1975, 1983). However, the patterns of differences that we found suggest specific disruptions to regions of the face during craniofacial development rather than the generalized disruptions described by Shapiro under the amplified developmental instability model. Additionally, the results of our investigation found that covariation of facial metrics is different in DS individuals and in DS siblings relative to typically developing siblings. Based on differences in the pattern and strength of integration within and between facial regions in the DS and DS sibling samples, we put forth an "aneuploid conception model" to explain why facial integration is lowest in DS siblings and strengthened in DS relative to DS siblings.;In addition to the human-based analyses, micro-computed tomography (µCT) scans and morphometric analysis were employed to evaluate a complete genetic mouse model for DS - the Ts1Yey mouse. Morphometric comparison of craniofacial measures for Ts1Yey mice and euploid littermates (n = 12 for each sample) was done to determine if this model exhibits craniofacial differences similar to differences seen in humans with DS and in previously established DS mouse models. Overall, our results validate this mouse model for use in craniofacial DS investigations.