Supervisor(s): Hannah Long, Veronique Vitart & Colin Semple Image Image Variant from normal-range facial GWAS. SNP rs9915190 is associated with variation in nose shape (Indencleef et al) and falls in the proximity of three putative chondrocyte regulatory elements (boxed). Genetic changes in non-protein-coding regions of the genome are associated with human disease, driving both classical Mendelian inherited disorders and can contribute to susceptibility for more complex diseases. Genetic diversity within a population is also responsible in large part for why we look different from one another. In many cases, these genetic changes will impact gene regulatory elements called enhancers, leading to alteration of developmental gene expression and impacting the form and function of tissues. Here, we will focus on the formation of the human face which is highly divergent amongst individuals and is highly sensitised to genetic and environmental perturbation, with around one third of human developmental disorders exhibiting craniofacial changes. Therefore, human facial development is a powerful model to study how changes in the genome impact human phenotypes (Long et al). In this project, we aim to elucidate mechanisms of gene regulation during human craniofacial development to uncover how non-coding variation contributes to human facial diversity within the population, and in extreme cases drives human disease. Firstly, we will leverage whole genome sequencing datasets and de novo variants identified from from patients with craniofacial malformations to investigate the distribution and impact of DNA sequence variants in the vicinity of Mendelian craniofacial genes (an estimated 1,103 genes). Using enhancer-profiling data from in vitro differentiation of human facial progenitors (cranial neural crest cells, CNCCs) that form the majority of the face during development, and skeletal derivatives including chondrocytes and bone, we will identify patient mutations overlapping putative enhancers. A second focus of the project will explore genome-wide association studies performed for both normal-range facial morphology and disease. For example, two lead SNPs have been identified at the SOX9 locus that are associated with morphological normal-range nasal variation and fall near putative regulatory elements from neural crest-derived chondrocytes. To functionally explore the regulatory impact of both rare and common non-coding variants implicated in facial variation and disease, we will characterise associated enhancer elements using our human in vitro models and determine spaciotemporal activity explored using zebrafish development. Together, we will explore the impact of regulatory variation in human development, and the consequence for normal facial appearance and disease. Indencleef et al, Front Genet, 2021 Long et al, Cell Stem Cell, 2020 This article was published on 2024-06-21
