October 26, 2013
BehindTheMedspeak: Face-Shape Secrets May Lie in "Junk" DNA
Caption for the graphic above: "Craniofacial developmental enhancers contribute to craniofacial morphology. We identified distant-acting transcriptional enhancers active in the developing craniofacial complex and studied their activity patterns in detail in transgenic mice. Selected enhancers were deleted from the genome in mice in order to examine their role in modulating craniofacial morphology."
Face shape is largely determined by genetics, yet no two faces are entirely alike.
How do genes bring about faces with subtle differences while avoiding dramatic disruptions and facial malformations such as cleft lip and palate?
The answer may lie in "junk DNA," a new study has found.
Noncoding DNA — sometimes called junk DNA — refers to sequences in a genome that do not produce proteins.
Studying mice, researchers identified more than 4,000 small regions in the genome that are likely a type of noncoding DNA called enhancers, which amplify the expression of a gene.
These regions were active while the face of a mouse embryo developed, according to a paper in the October 25 issue of the journal Science.
Most of these enhancer sequences are found in humans as well, so it is likely that they have similar face-shaping functions in humans, the researchers said.
"Our results suggest it is likely there are thousands of enhancers in the human genome that are somehow involved in craniofacial development," said study author Axel Visel, a geneticist at Lawrence Berkeley National Laboratory's genomics division.
To test whether these enhancers are indeed important in shaping the face, the researchers deleted three of the enhancers in mice and compared them with normal mice at 8 weeks of age.
The results showed that each enhancer deletion caused a distinct set of differences in the shape of the face — for instance, causing an increase or decrease in facial length and an increase or decrease in the width of various parts of the face, such as the base of the skull or the palate.
In the study, to avoid the challenge of recognizing individual mouse faces, the researchers created 3D images using a process called microcomputed tomography to link changes in face shape with alterations in the function of each of the enhancers.
Identifying enhancers that regulate a gene's activity is challenging, because such enhancers aren't necessarily located next to their target gene; rather, they could be acting from "long-distance" locations in the genome.
Studying genes that drive normal facial variations would offer an opportunity for human geneticists to look for mutations specifically in enhancers that may play a role in birth defects, Visel said.
Below, the abstract of the Science paper.
Fine Tuning of Craniofacial Morphology by Distant-Acting Enhancers
Introduction: The shape of the face is one of the most distinctive features among humans, and differences in facial morphology have substantial implications in areas such as social interaction, psychology, forensics, and clinical genetics. Craniofacial shape is highly heritable, including the normal spectrum of morphological variation as well as susceptibility to major craniofacial birth defects. In this study, we explored the role of transcriptional enhancers in the development of the craniofacial complex. Our study is based on the rationale that such enhancers, which can be hundreds of kilobases away from their target genes, regulate the spatial patterns, levels, and timing of gene expression in normal development.
Methods: To identify distant-acting enhancers active during craniofacial development, we used chromatin immunoprecipitation on embryonic mouse face tissue followed by sequencing to identify noncoding genome regions bound by the enhancer-associated p300 protein. We used LacZ reporter assays in transgenic mice and optical projection tomography (OPT) to determine three-dimensional expression patterns of a subset of these candidate enhancers. Last, we deleted three of the craniofacial enhancers from the mouse genome to assess their effect on gene expression and craniofacial morphology during development.
Results: We identified more than 4000 candidate enhancer sequences predicted to be active in the developing craniofacial complex. The majority of these sequences are at least partially conserved between humans and mice, and many are located in chromosomal regions associated with normal facial morphology or craniofacial birth defects. Characterization of more than 200 candidate enhancer sequences in transgenic mice revealed a remarkable spatial complexity of in vivo expression patterns. Targeted deletions of three craniofacial enhancers near genes with known roles in craniofacial development resulted in changes of expression of those genes as well as quantitatively subtle but definable alterations of craniofacial shape.
Discussion: Our analysis identifies enhancers that fine tune expression of genes during craniofacial development in mice. These results support that variation in the sequence or copy number of craniofacial enhancers may contribute to the spectrum of facial variation we find in human populations. Because many craniofacial enhancers are located in genome regions associated with craniofacial birth defects, such as clefts of the lip and palate, our results also offer a starting point for exploring the contribution of noncoding sequences to these disorders.
October 26, 2013 at 12:01 PM | Permalink
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