Yale: Thousands of genetic “dimmer” switches, regions of DNA known as
regulatory elements, were turned up high during human evolution in the
developing cerebral cortex, according to new research from the Yale
School of Medicine.
Unlike in rhesus monkeys and mice, these
switches show increased activity in humans, where they may drive the
expression of genes in the cerebral cortex, the region of the brain that
is involved in conscious thought and language. This difference may
explain why the structure and function of that part of the brain is so
unique in humans compared to other mammals.
The research, led by James P. Noonan, Steven K. Reilly, and Jun Yin, is published March 6 in the journal Science.
In
addition to creating a rich and detailed catalogue of human-specific
changes in gene regulation, Noonan and his colleagues pinpointed several
biological processes potentially guided by these regulatory elements
that are crucial to human brain development.
“Building a more
complex cortex likely involves several things: making more
cells, modifying the functions of cortical areas, and changing the
connections neurons make with each other. And the regulatory changes we
found in humans are associated with those processes,” said Noonan,
associate professor of genetics, an investigator with the Kavli
Institute for Neuroscience, and senior author of the study. “This likely
involves evolutionary modifications to cellular proliferation, cortical
patterning, and other developmental processes that are generally well
conserved across many species."
Scientists have become adept at
comparing the genomes of different species to identify the DNA sequence
changes that underlie those differences. But many human genes are very
similar to those of other primates, which suggests that changes in the
way genes are regulated — in addition to changes in the genes themselves
— is what sets human biology apart.
Up to this point, however, it
has been very challenging to measure those changes and figure out their
impact, especially in the developing brain. The Yale researchers took
advantage of new experimental and computational tools to identify active
regulatory elements — those DNA sequences that switch genes on or off
at specific times and in specific cell types — directly in the human
cortex and to study their biological effects.
First, Noonan and
his colleagues mapped active regulatory elements in the human genome
during the first 12 weeks of cortical development by searching for
specific biochemical, or “epigenetic” modifications. They did the same
in the developing brains of rhesus monkeys and mice, then compared the
three maps to identify those elements that showed greater activity in
the developing human brain. They found several thousand regulatory
elements that showed increased activity in human.
Next, they
wanted to know the biological impact of those regulatory changes. The
team turned to BrainSpan, a freely available digital atlas of gene
expression in the brain throughout the human lifespan. (BrainSpan was
led by Kavli Institute member Nenad Sestan at Yale, with contributions
from Noonan and Pasko Rakic, a co-author on this study.) They used those
data to identify groups of genes that showed coordinated expression in
the cerebral cortex. They then overlaid the regulatory changes they had
found with these groups of genes and identified several biological
processes associated with a surprisingly high number of regulatory
changes in humans.
“While we often think of the human brain as a
highly innovative structure, it’s been surprising that so many of these
regulatory elements seem to play a role in ancient processes important
for building the cortex in all mammals, said first author Steven Reilly.
“However, this is often a hallmark of evolution, tinkering with the
tools available to produce new features and functions.”
Next,
Noonan and colleagues plan to investigate the function of some of the
regulatory changes they identified by introducing them into the mouse
genome and studying their effects on mouse brain development.
The
research was funded by the National Institutes of Health (GM094780,
DA023999, NS014841, GM106628) and a NSF Graduate Research Fellowship. It
was conducted in collaboration with Pasko Rakic, director of the Kavli
Institute at Yale and one of the world’s leading experts on the
development of the human cortex. Other authors were Deena Emera, Jing
Leng, Justin Cotney and Richard Sarro in the Noonan lab and Albert E.
Ayoub in the Rakic lab.