When Eric Mueller, who had been adopted, first saw a photograph of his birth mother, he was overwhelmed by how similar their faces were.
“It was the first time I saw someone who looked like me,” he wrote.
The experience led Mueller, a Minneapolis photographer, to begin a three-year project in which he photographed hundreds of groups of related people, culminating in the book Family
Resemblance
.
Of course, such similarities are common and point to a strong underlying genetic influence on the face.
But the more scientists dig into the genetics of facial features, the more complex the picture becomes.
Hundreds, if not thousands, of genes affect facial shape, often in subtle ways that make it nearly impossible to predict what a person's face will look like just by examining the impact of each gene.
As scientists learn more, some are beginning to conclude that they need to look elsewhere to develop an understanding of faces.
“Maybe we're chasing the wrong thing when we try to create explanations at the genetic level,” says Benedikt Hallgrimsson, a developmental geneticist and evolutionary anthropologist at the University of Calgary in Canada.
Instead, Hallgrimsson and other colleagues believe they can group genes into teams, which work together as the face forms.
Understanding how these teams work and the developmental processes they affect should be much more manageable than trying to sort out the effects of hundreds of individual genes.
If they are right, faces may be less complicated than we think.
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When geneticists first set out to understand faces, they started with the easiest task: identifying the genes responsible for facial abnormalities.
In the 1990s, for example, they learned that a mutation in one gene causes Crouzon syndrome—characterized by widely spaced, often bulging eyes and an underdeveloped upper jaw—while a mutation in a different gene leads to small, bulging eyes. downward slanting, lower jaw and cleft palate, which is Treacher Collins syndrome.
It was a start, but these extreme cases say little about why normal faces vary so much.
Then, about a decade ago, geneticists began taking a different approach.
First, they quantified thousands of normal faces by identifying landmarks on each person's face—the tip of the chin, the corners of the mouth, the tip of the nose, the outer corner of each eye, among others—and measuring the distances. among them.
They then examined the genomes of those individuals to see if any genetic variants matched particular facial measurements, using an analysis known as a genome-wide association study (or GWAS).
About 25 GWAS on facial shape have been published so far, with more than 300 genes identified in total.
“Each region is explained by multiple genes,” says Seth Weinberg, a craniofacial geneticist at the University of Pittsburgh.
“There are some genes that push outwards and others that push inwards.
It is the total balance that ends up becoming you and your appearance.”
Scientists have identified more than 300 genes associated with specific facial features, although their overall effect is small.
Here are some characteristics in which genes make a difference.
Not only are multiple genes involved in each particular facial region, but the variants discovered so far do not explain well the specific characteristics of each face.
In a study on the genetics of faces, published in the 2022
Annual Review of Genomics and Human Genetics
, Weinberg and his colleagues collected GWAS results on the faces of 4,680 people of European ancestry.
Known genetic variants explain only about 14% of the differences in faces.
The age of an individual represented 7%;
sex, 12%;
and body mass index, approximately 19% of the variation, leaving an incredible 48% unexplained.
It is clear that GWAS failed to capture something important in determining face shape.
Of course, some of that unknown variation must be explained by the environment;
In fact, scientists have noted that certain parts of the face, including the cheeks, lower jaw, and mouth, appear more susceptible to environmental influences such as diet, aging, and climate.
However, some agree that another clue to this missing factor lies in the families' unique genetics.
Large and small variants
If faces were simply the sum of hundreds of tiny genetic effects, as the GWAS results imply, then each child's face would be a perfect mix of its two parents, says Hallgrimsson, arguing for the same reason that if we toss a coin at air 300 times, 150 times it will come up heads.
However, you only need to look at certain families to see that that is not the case.
“My son has his grandmother's nose,” Hallgrimsson details.
“That must mean that there are genetic variants that have a great effect within families.”
But if some of the facial genes have important effects, which are visible within the relatives who carry them, why are they not observed in the GWAS?
Perhaps the variants are very rare in the general population.
“Face shape is really a combination of common and rare variations,” says Peter Claes, a geneticist who studies medical imaging at KU Leuven in Belgium.
As a possible example he points to the characteristic nose of the French actor Gérard Depardieu.
“You don't know the genetics, but you perceive that it is a rare variant,” he explains.
Some other distinctive facial features that are heritable, such as dimples, cleft chins and unibrows, could also be candidates for identification as rare, high-impact variants, says Stephen Richmond, a researcher in the field of orthodontics at Cardiff University. (Wales, United Kingdom) who studies facial genetics.
However, to search for such rare variants, scientists will have to go beyond GWAS and explore large data sets of whole-genome sequences.
This task will have to wait until such sequences, linked to facial measurements, become much more abundant, says Claes.
Another possibility is that the same genetic variants with small effects could have larger effects in certain families.
Hallgrimsson has observed this in mice: together with a group of colleagues, in particular Christopher Percival, now at Stony Brook University (USA), they introduced mutations that affect craniofacial shape in three inbred lineages of mice.
They found that the three lineages ended up having very different facial shapes.
“The same mutation in a different strain of mice can have a different, sometimes even opposite, effect,” highlights Hallgrimsson.
Very familiar faces
If something similar occurs in people, it is possible that within a particular family (such as with a specific strain of mice) that family's unique genetic background makes certain face shape variants more potent.
But proving that this happens in people, without the help of inbred strains, will probably be difficult, Hallgrimsson says.
The expert believes that it would be better to study the developmental processes underlying the formation of faces.
These processes involve groups of genes working together (often to regulate the activity of other genes) to control how certain organs and tissues are formed during embryonic development.
To identify processes related to face shape, Hallgrimsson and his team first used sophisticated statistics to find genes that affect craniofacial variation in more than 1,100 mice.
They then turned to genetic databases to identify the developmental processes in which each gene participated.
The analysis pointed to three especially important processes: cartilage development, brain growth and bone formation.
It is possible, Hallgrimsson speculates, that individual differences in the rate and occurrence of these three processes (and probably others) largely explain why one person's face is different from another's.
Interestingly, it appears that some of these gene clusters may have captains who direct the activity of other team members.
Thus, researchers seeking to understand facial variation could focus on the action of those master genes, rather than hundreds of individual genetic players.
Support for this idea comes from an intriguing new study by Sahin Naqvi, a geneticist at Stanford University, and his colleagues.
Naqvi began with a paradox.
He knew that most developmental processes are so finely tuned that even subtle changes in the activity of the genes that regulate them can cause serious developmental problems.
But he also knew that small differences in those same genes are probably the reason his own face looks different than his neighbor's.
How could both ideas be true? Naqvi wondered.
Strong family resemblances are common, as shown here by former British Prime Minister Boris Johnson (second from right), his father, sister and brother.
Some researchers suggest that these similarities could be the result of rare genetic variants that have large effects within a family.David M. Benett (Getty Images)
To try to reconcile these two contradictory notions, Naqvi and his colleagues decided to focus on a regulatory gene,
SOX9
, which controls the activity of many other genes involved in the development of cartilage and other tissues.
If a person has only one functional copy of
SOX9
, the result is a craniofacial disorder called Pierre Robin syndrome, characterized by an underdeveloped lower jaw and many other problems.
Naqvi's team set out to gradually reduce the activity of
SOX9
and measure what effect this had on the genes it regulates.
To do this, they genetically engineered human embryonic cells to be able to reduce the regulatory activity of
SOX9
at will.
The researchers then measured the effect of six different levels of
SOX9
on the activity of the other genes.
Would genes under the control of
SOX9
maintain their activity despite small changes in that gene, thus sustaining stable development, or would their activity decrease in proportion to changes in
SOX9
?
The team discovered that the genes fell into two classes.
Most of them did not change their activity unless
SOX9
levels fell to 20% or less of normal.
That is, they seemed to be protected even against relatively large changes in
SOX9
.
This buffering, possibly the result of other regulatory genes compensating for reductions in
SOX9,
would help keep development in tune.
But a small subset of genes turned out to be sensitive to even small changes in
SOX9
, increasing or decreasing their own activity in a coordinated manner.
And those genes, the scientists found, tended to affect jaw size and other altered facial features in Pierre Robin syndrome.
In fact, these unbuffered genes appear to determine to what extent (a lot or a little) a normal face resembles a feature of Pierre Robin syndrome.
At one end of the range are the underdeveloped jaw and other structural changes of the syndrome.
And at the other end?
“You can think of the anti-Pierre Robin as an overdeveloped, elongated jaw, with a prominent chin;
actually, kind of like mine,” says Naqvi.
Pierre Robin syndrome (PRS) is a craniofacial disorder characterized in part by a small lower jaw, caused by a mutation in the regulatory gene SOX9.Knowable
In essence,
SOX9
leads a group of genes that define a direction, or axis, in which faces can vary: from most to least similar to Pierre-Robin syndrome.
Naqvi now wants to see if other groups of genes, each led by a different regulatory gene, define additional axes of variation.
He suspects, for example, that genes sensitive to small changes in a gene called
PAX3
might define an axis related to the shape of the nose and forehead, while those sensitive to another called
TWIST1
—which when mutated, leads to premature fusion of the skull bones—could define an axis related to the length of the skull and forehead.
Variation lines on faces
Other evidence suggests that Naqvi might be on the right track in thinking that faces vary along predefined axes.
For example, geneticist Hanne Hoskens, a former student of Claes and doing her postdoc in Hallgrimsson's laboratory, classified people's faces according to their resemblance to traditional characteristics of achondroplasia (the most common form of dwarfism), such as a prominent forehead. and the flattened nose, among other features.
The expert found that those people at the end of the range with features more similar to dwarfism tended to have different variants of genes related to cartilage development than those with faces less similar to traditional ones.
If similar patterns occur in other developmental pathways, they can set up barriers that restrict how faces develop.
That could help geneticists cut through the complexities to extract broader principles underlying facial shape.
“There is a limited set of directions in which faces can vary,” says Hallgrimsson.
“There are enough directions that there is a huge amount of variation, but we only see a small subset of the geometric possibilities.
And it is because these axes are determined by development processes, and these processes are relatively few.”
Until there are more results, it's too early to say whether this new approach actually holds an important clue to why one person's face looks different from another's;
and to understand the
shock
of recognition that Eric Mueller experienced when he saw the photo of his mother for the first time.
But if Hallgrimsson, Naqvi and their colleagues are on the right track, focusing on developmental pathways may be a way to cut through the thicket of hundreds of genes that have, for so long, obscured our understanding of faces.
Article translated by
Daniela Hirschfeld
.
This article originally appeared on
Knowable en español
, a nonprofit publication dedicated to making scientific knowledge available to everyone.
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