June 18, 2020

What’s in a face?

This is a guest post by Professor Martyn Cobourne.  We let him choose a paper to review and he has reviewed the first basic science paper  ever for this blog.  Martyn was brought up in the same Worcester country village as me, but we never met (I have illustrated this blog with the view over our village).  It is clear that Martyn is very clever and he has done a great job of bringing some proper science to our blog.

I want to thank Padhraig Fleming and Kevin O’Brien for inviting me to write a guest blog post on a paper of my choosing. I have decided to discuss a manuscript recently deposited onto BioRxiv, an open-access preprint repository for the biological sciences, which allows authors to post their work and offers the opportunity for online comment and discussion. This paper has not, therefore been formally peer-reviewed. Still, it represents a fascinating large-scale international collaborative effort investigating the genetic basis of human facial variation, and a contributing author is Stephen Richmond, Professor of Orthodontics at Cardiff University.


Insights into the genetic architecture of the human face

White JD et al



The human face is a complex structure that demonstrates almost infinite variation while conforming to the same basic organisational plan. Understanding how complex morphological structures such as the face are established during development remains a significant challenge in biology, and it will come as no surprise to orthodontists that genetics plays a vital role in this process. Over the last thirty years, many significant genes have been identified primarily through the analysis of mutant mice and linkage studies of Mendelian disorders in humans. However, the role of minor genetic variants, epigenetic influences and environmental factors has been more challenging to elucidate, mainly because it requires investigation at the population level. It is only relatively recently that the population-based genome-wide profiling techniques that are needed have become established. In this study, the authors have combined highly accurate phenotyping of facial variation with some of these sophisticated genetic analyses using several accessible international data-sets to identify regions of the genome associated with the facial variation.

What did they do?

The study utilised three-dimensional (3D) facial surface scans and genomic information derived from over 8000 individuals within three independent studies, two based in the USA and one found here in the UK – the Avon Longitudinal Study of Parents and their Children (ALSPAC) in Bristol. They began by mapping the facial scans of these individuals in great detail and using hierarchical clustering, were able to group regions of the faces into 63 correlated segments. They were then able to identify the significant phenotypic variation that existed in each facial segment and investigate patterns of association with this variation across the genomes of these individuals.

What did they find?

They found two key features associated with these global association patterns. First, the highest correlations were between segments of the same facial quadrant (lips, nose, upper face, etc.). Second, relationships between groups of segments from different quadrants also existed with some of these seeming to reflect shared embryologic origins of the segment groups (for example, the nose and upper face). A meta-analysis confirmed 203 genomic regions associated with the normal-range facial variation, and 103 of these were novel. What is interesting is that many genes in close approximation with these regions were highly enriched for processes and phenotypes associated with craniofacial development in both humans and mice. The top human phenotype was oro-facial clefting, which suggests a considerable overlap between genes involved in normal facial variation and those implicated in one of the most frequent human facial anomalies.

Moreover, many of these genes encode members of signalling pathways that are known to be involved in craniofacial development. This includes members of the WNT and TGF pathways. Some of these genes also have an essential role in limb development, which given the known associations between craniofacial and limb anomalies in many human syndromes, is perhaps not surprising.

What are the likely cell types and embryonic processes that these genomic regions influence? To answer this question, they investigated how these regions influence transcriptional activation in multiple different cell types, finding the strongest associations with cranial neural crest cells and dissected embryonic craniofacial tissues. These observations suggest that there is an embryonic origin for human facial variation that has influence at multiple time-points in development. In addition, they found particular enrichment of these genomic regions in enhancer regions – areas of the genome that regulate gene transcription, suggesting that genetic facial variation is significantly influenced by enhancer activity.

What about the known and novel genomic regions that were identified? Sixty-four of these regions harboured known craniofacial genes previously associated with human or animal craniofacial malformations, but not with normal facial variation – one of these being MSX1, a well-known cleft-causing gene in both humans and mice. However, fifty-three regions were associated with genes that had no previous association with craniofacial development, one exciting example being DACT1, which encodes an inhibitor of WNT signalling and seems to be particularly associated with variation in chin morphology.

Finally, these investigators hypothesised that because the human face demonstrates such complexity, it is likely that groups of genomic regions may also contribute to the same trait. Using structural equation modelling, a technique that uses multivariate analysis, they identified four genomic region combinations with significant pairwise interaction in specific facial regions. One of these was between PRDM16 and GLI3 – and associated with morphology of the premaxillary region. Interestingly, both these genes encode proteins involved in the Hedgehog signalling, a pathway that has strong associations with craniofacial development. Indeed, GLI3 mutations in humans and mice cause Greig cephalopolysyndactyly syndrome, a condition associated with abnormal facial morphology, including broadening of the nasal bridge.

What did I think?

This is a significant international study that has used complex phenotypic and genetic analysis to identify genomic regions of individuals with European ancestry that are associated with the normal facial variation. It has used data from several longitudinal studies, including one from the UK and will form a useful springboard for further investigations into this fascinating area of biology. It goes beyond the analysis of major loci that cause significant defects and begins to unravel the contribution of minor traits in normal variation. It is a slightly different study to those normally discussed on this blog site. Still, I thought it might be of interest to the orthodontic community, and it is great to see the involvement of an orthodontist!


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Have your say!

  1. Precious contribution to craniofacial development understanding

  2. Many thanks to Prof Cobourne for a very interesting paper.
    Would a translation be possible for some of the lesser genetically erudite amongst the orthodontic specialty, myself included?

  3. Very interesting and exciting research! We have come a long way on facial development from my research I read the first year of orthodontic residency written by Dr Enlow and Dr Moffit!

  4. Kevin:
    Not sure I agree that “this is a significant international study” since the paper has not been thru the formal peer-review process. It doesn’t really help the clinical orthodontist much since the discussion on specific homeobox genes expressed during embryonic development are far removed from the children/adults that most orthodontists see on a daily basis. However, the role of SHH (sonic hedgehog) in producing craniofacial anomalies such as holoprosencephaly (cyclopia) are known to those orthodontists working craniofacial-cleft palate teams who see these rare craniofacial disorders on a more regular basis. The more interesting point is complexity, of which there are two types. The first is structural, which is alluded to briefly, but the second one is mathematical in the sense that, given alternative splicing, there are a finite number of clinical outcomes and behaviors but it is impossible to predict which ones might actually occur in a particular case. I explored this theme in my previous book (written 10 years ago, with a new edition in the offing some time this year), exploring how an orthodontist might deploy the genetic potential of an individual patient clinically altho’ further work on predictive modeling is past due.

  5. Many thanks Kevin and Prof Cobourne. If we clinical orthodontists claim to diagnose and treat dentoFACIAL deformities and believe that our interventions may camouflage, alleviate or even eradicate (depending where you went to school) certain dentofacial traits contributing to malocclusion and associated dentofacial deviations (or are they?), then we need to keep up with the front line of research in the aetiology, classification and possibly, subsequently, intervention of dentofacial formation. If today we learn that our intervention is minimal, misdirected, or far removed from the genetic and environmental principles that cause variation in facial structures; that may not be the case in years to come. If we continue to delegate the study, ignore it as being difficult, unethical, or irrelevant to our day to day treatment; if we dont keep learning the principles as they are elucidated, we wont ever be able to define what we are actually treating, or claim to treat! So many ortho programs have minimized these basic science areas in favour of lighter, sexier (can I say that?), easier to teach topics. Are we specialists of treating dentofacial deformity, or not? Reading the comments of respected colleagues above, it is pretty clear that those of my gen especially, crave a serious update in this area! I also am thrilled that Stephen Richmond is lending his talent to this area of study. Objectifying malocclusion severity has become possible thanks to Stephen (and Shaw), and it is high time that our specialty contribute to the knowledge surrounding the aetiology of the conditions that we claim to treat daily – dentofacial architecture.

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