Seeing evolution happening before your eyes
DNA enhancers more complex than thought

Date:
October 14, 2020
Source:
European Molecular Biology Laboratory
Summary:
Researchers have established an automated pipeline to create
mutations in genomic enhancers that let them watch evolution unfold
before their eyes.

Their findings on fruit flies may also be relevant to the
understanding of human diseases, requiring researchers to reassess
assumptions about how enhancers contribute to human health.



FULL STORY ========================================================================== Animal diversity and evolution are driven by changes in how our genetic
code is expressed. Specific DNA sequences called enhancers control where,
when and how strongly genes are expressed during development to create the respective organism. Studying enhancers and how they result in different patterns of gene expression therefore helps us to understand more about
how evolution takes place. In addition to driving the evolution of
species, enhancers are also relevant to disease: mutations in enhancers
are associated with over 80% of all human diseases.


========================================================================== "What we see in terms of biodiversity in nature is caused, to a large
degree, by changes in enhancers," explains Justin Crocker, group leader at
EMBL Heidelberg. "Understanding -- and subsequently trying to predict -- evolution in the time of climate change, where many animals are under the pressure to adapt quickly to fast changing environments, is an important
task." Despite broad relevance to evolution and disease, researchers
still struggle to understand how enhancers are coded in our genomes
and how easy it is to reprogram them, for example to prevent or treat
diseases. In an attempt to learn more about enhancers, the Crocker group
from EMBL Heidelberg performed an extensive study, published in Nature,
on a specific enhancer in the model organism Drosophila melanogaster,
a species of fruit fly. The group discovered that this enhancer -- which controls the patterns where hair grows on flies - - contains a lot more information than expected.

"Whenever we changed a single letter of the enhancer DNA sequence,
we created a significant change to the pattern of gene expression it
drove," explains Timothy Fuqua, PhD student at EMBL and first author of
the paper. "We also found that almost all mutations to the enhancer alter
the gene expression pattern in multiple ways. For example, one mutation controls not only where the expression pattern is within the fly, but
also when, and how much of the gene was expressed." These results
were surprising and contradict what had previously been known about
enhancers. Researchers thought that these complex gene expression patterns
were created by different proteins attaching to the enhancer. A first clue
that this might not be true came when Crocker and his team discovered
that artificially-produced enhancers did not work as designed. Their
most recent results provide support for this idea. "The results showed
that developmental enhancers encode a much higher level of information
than previously appreciated," Crocker says. "When we received the data,
I was honestly shocked! I couldn't believe it and we repeated everything,
as we assumed that there has been a mistake." Importantly, the density
of information encoded within the enhancer also constrains how animals
can evolve. The study also showed that each possible mutation has a
certain possibility for happening. This gives scientists insights into
where evolution could lead. "We can use this information to predict
patterns in wild fruit flies. Something which has been incredibly
difficult to do so far," Fuqua says. "Our results should encourage the community to reassess our assumption about how these regions contribute to human health." While studying enhancers is a well-established field in molecular biology, this study is unique in the sheer number of mutations
having been studied. The group created more than 700 unique, randomly
generated mutations within a single enhancer. "Nobody ever has studied
so many enhancer variants at this level of depth before. It was as if
evolution was happening before our very eyes!" highlights Fuqua. To
perform so many experiments, the team built -- assisted by the Janelia
Research Campus and the Advanced Light Microscopy Facility at EMBL --
a robot to handle the fly embryos used in the study, and an automated microscope pipeline to take images of each mutated line.

"Our study shows that what we have known about enhancers was
oversimplified. It shows we have to study enhancers at much greater
detail than ever before," Fuqua says. Therefore, in the next step,
the team not only wants to expand the pipeline and its throughput, but
also plans to study other enhancers and see if they can observe similar effects. "Can what we found be applied to other enhancers or not? We
don't know yet. But we plan to find out," concludes Crocker.


========================================================================== Story Source: Materials provided by
European_Molecular_Biology_Laboratory. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Timothy Fuqua, Jeff Jordan, Maria Elize van Breugel, Aliaksandr
Halavatyi, Christian Tischer, Peter Polidoro, Namiko Abe, Albert
Tsai, Richard S. Mann, David L. Stern, Justin Crocker. Dense
and pleiotropic regulatory information in a developmental
enhancer. Nature, 2020; DOI: 10.1038/s41586-020-2816-5 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201014114642.htm

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