The best-laid plans of fruit flies and scientists sometimes go awry. Such plans include experimental designs that require fruit fly models (or other animal models) to stand in for humans. According to genetic scientists based at the University of Toronto, stretches of DNA called transcription factors (TFs), which serve as landing sites for regulatory proteins, are less conserved across species than was once thought.

The new findings, suggests the scientists from the lab of Timothy Hughes, PhD, indicate that any studies meant to draw insights about human TFs must exercise extra caution if they rely on animal models such as the fruit fly, or Drosophila melanogaster.

On a more positive note, the scientists suggest that their findings open intriguing possibilities. For example, transcription factor diversification could explain, in part, how humans evolved. And the new findings could also lead to a fuller understanding of sexual dimorphism, which refers to the differences in size or appearance between the sexes other than the differences between sexual organs.

Writing in the journal Nature Genetics (“Similarity regression predicts evolution of transcription factor sequence specificity”), the University of Toronto team describes a new computational method which allowed it to more accurately predict motif sequences each TF binds in many different species. The findings reveal that some subclasses of TFs are much more functionally diverse than previously thought.

“Even between closely related species there’s a non-negligible portion of TFs that are likely to bind new sequences,” said Sam Lambert, former graduate student in Hughes’ lab who did most of the work on the paper and has since moved to the University of Cambridge for a postdoctoral stint. “This means they are likely to have novel functions by regulating different genes, which may be important for species differences,” he added.

Even between chimps and humans, whose genomes are 99% identical, there are dozens of TFs which recognize diverse motifs between the two species in a way that would affect expression of hundreds of different genes. “We think these molecular differences could be driving some of the differences between chimps and humans,” noted Lambert.

In the Nature Genetics article, the scientists described how they used similarity regression, a significantly improved method for predicting motifs, to update and expand the Cis-BP database.

“Similarity regression inherently quantifies TF motif evolution, and shows that previous claims of near-complete conservation of motifs between human and Drosophila are inflated, with nearly half of the motifs in each species absent from the other, largely due to extensive divergence in C2H2 zinc finger proteins,” the authors wrote. “We conclude that diversification in DNA-binding motifs is pervasive, and present a new tool and updated resource to study TF diversity and gene regulation across eukaryotes.”

Image depicts motif divergence between human transcription factors and their counterparts in other species. The blue section in the pie charts represents a proportion of transcription factors, across different classes, which are dissimilar in humans. [Sam Lambert]

Lambert developed software that looks for structural similarities between the TFs’ DNA binding regions that relate to their ability to bind the same or different DNA motifs. If two TFs, from different species, have a similar composition of amino acids, building blocks of proteins, they probably bind similar motifs. But unlike older methods, which compare these regions as a whole, Lambert’s automatically assigns greater value to those amino acids—a fraction of the entire region—which directly contact the DNA. In this case, two TFs may look similar overall, but if they differ in the position of these key amino acids, they are more likely to bind different motifs. When Lambert compared all TFs across different species and matched to all available motif sequence data, he found that many human TFs recognize different sequences—and therefore regulate different genes—than versions of the same proteins in other animals.

The finding contradicts earlier research, which stated that almost all of human and fruit fly TFs bind the same motif sequences, and is a call for caution to scientists hoping to draw insights about human TFs by only studying their counterparts in simpler organisms.

“There is this idea that has persevered, which is that the TFs bind almost identical motifs between humans and fruit flies,” said Hughes, who is a professor at the University of Toronto. “And while there are many examples where these proteins are functionally conserved, this is by no means to the extent that has been accepted.”

As for TFs that have unique human roles, these belong to the rapidly evolving class of so-called C2H2 zinc finger TFs, named for zinc ion-containing finger-like protrusions, with which they bind the DNA.

Their role remains an open question, but it is known that organisms with more diverse TFs also have more cell types, which can come together in novel ways to build more complicated bodies.

Hughes is excited about a tantalizing possibility that some of these zinc finger TFs could be responsible for the unique features of human physiology and anatomy—our immune system and the brain, which are the most complex among animals. Another concerns sexual dimorphism: countless visible, and often less obvious, differences between sexes that guide mate selection—decisions that have an immediate impact on reproductive success, and can also have profound impact on physiology in the long term. The peacock’s tail or facial hair in men are classic examples of such features.

“Almost nobody in human genetics studies the molecular basis of sexual dimorphism, yet these are features that all human beings see in each other and that we are all fascinated with,” noted Hughes. “I’m tempted to spend the last half of my career working on this, if I can figure out how to do it!”

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