Researchers at the Donnelly Centre in Toronto have found that dozens
of genes, previously thought to have similar roles across different
organisms, are in fact unique to humans and could help explain how our
species came to exist.
These genes code for a class of proteins known as transcription
factors, or TFs, which control gene activity. TFs recognize specific
snippets of the DNA code called motifs, and use them as landing sites to
bind the DNA and turn genes on or off.
Previous research had suggested that TFs which look similar across
different organisms also bind similar motifs, even in species as diverse
as fruit flies and humans. But a new study from Professor Timothy Hughes‘ lab, at the Donnelly Centre for Cellular and Biomolecular Research, shows that this is not always the case.
Writing in the journal Nature Genetics, the researchers
describe a new computational method which allowed them to more
accurately predict motif sequences each TF binds in many different
species. The findings reveal that some sub-classes 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,” says 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
“This means they are likely to have novel functions by regulating
different genes, which may be important for species differences,” he
Even between chimps and humans, whose genomes are 99 per cent
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,” says Lambert, who won the
Jennifer Dorrington Graduate Research Award for outstanding doctoral
research at U of T’s Faculty of Medicine.
To reanalyze motif sequences, Lambert developed new software which
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,” says Hughes,
who is also a professor in U of T’s Department of Molecular Genetics and
Fellow of the Canadian Institute for Advanced Research. “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,” says 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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