First Protein Difference Between Humans and Primates That Correlates to Anatomical
Changes in the Early Hominid Fossil Record
(Philadelphia, PA) – In an effort to find the remaining genes that govern
myosin--the major contractile protein that makes up
muscle tissue--researchers at the University
of Pennsylvania School of Medicine have made
a discovery that may be central to answering key questions
about human evolution.
Published in the March 25 issue of Nature,
Penn researchers have found one small mutation that
undermines an entire myosin gene. Their estimated dating
for the appearance of this mutation places it at about
2.5 million years ago, just prior to a period of major
evolutionary changes in the hominid fossil record. These
include the beginning of larger brain size, so important
in making us human. While the characterization of this
mutation may better help understand such genetic diseases
as muscular dystrophy, this finding has potentially
wider implications for re-interpreting long-held notions
about the appearance and early evolution of the genus
Homo. Anthropologists have long debated how
humans evolved from ancestors with larger jaw muscles
and smaller brains. This newly discovered mutation seems
responsible for the development of smaller jaw muscles
in humans as compared to non-human primates. These converging
lines of evidence suggest the question: Did this genetic
mutation lift an evolutionary constraint on brain growth
in early humans?
In a classic case of scientific sleuthing, Hansell
Stedman, M.D., Associate Professor of Surgery,
Nancy Minugh-Purvis, Ph.D., Director
of Advanced Gross Anatomy, Department of Cell and Developmental
Biology, and colleagues took their discovery of a mutation
that prevents the expression of a variety of myosin
-- designated MYH16 on chromosome 7 -- to its
ultimate context: what makes humans different from other
“Around the lab, we jokingly call this the ‘room
for thought’ mutation, since we had to involve
scientists from several disciplines to make sense of
the possible domino effects,” says Stedman. “In
other words, we had to do a lot of experiments to connect
the dots from DNA to RNA to protein to muscle fiber
to whole muscle to boney attachment sites. Then in looking
at the modern and fossil skulls it dawned on us that
we just might have to look ‘outside of the box’
to appreciate the real significance of the initial findings.”
The study began with the discovery of an unexpected
similarity between an “anonymous” piece
of the human genome sequence and some previously studied
genes known to power muscle contraction. The surprise
came when a small, inactivating deletion was found in
this sequence, perhaps explaining why the computer programs
had previously passed by the area without recognizing
it as a gene.
To determine whether the mutation was a rare form of
an active gene and not a mistake introduced by the technical
nature of the investigation, the team tested DNA samples
from geographically disparate human populations. They
found the gene-inactivating mutation in all modern humans
sampled—natives of Africa, South America, Western
Europe, Iceland, Japan, and Russia. However, the mutation
was not present in the DNA of seven species of non-human
primates, including chimpanzees.
Additional studies showed that versions of this gene
in non-human primates bear the imprint of a critically
important function for the animal, which implies that
the mutation afflicts all humans, in one sense of the
word, with the same inherited muscle “disease.”
The intriguing questions became, what is the “disease”
and why is it so common?
To find out in which tissue the MYH16 gene
is normally activated, the investigators examined a
wide range of muscle types in the readily available
macaque monkey and humans. In macaques, they found the
MYH16 protein was only made in a group of related muscles
in the head, those involved principally with chewing
and biting. In humans, they found that messenger RNA,
which translates the genetic code into workaday proteins,
was still active in these muscles, but no protein was
being made by virtue of the mutation.
But how does this relate to the anatomical differences
seen in modern humans versus non-human primates? First,
the jaw muscles and their bony attachments in apes and
monkeys are much larger and more powerful than in humans.
At the tissue level, the researchers found that macaque
chewing and biting muscles are nearly ten times as large
as in humans, which correlates with the fact that MYH16
protein is made in macaques and not in humans. So maybe
the “disease” is a weaker bite, raising
a question as to why this mutated version of the gene
could have become so widespread among modern humans.
By comparing a portion of the MYH16 gene sequence
in humans to that in five other animals—quantifying
the so-called molecular clock—the researchers
calculated that the inactivating mutation appeared in
a hominid ancestor about 2.4 million years ago, after
the lineages leading to humans and chimpanzees diverged.
Shortly thereafter, roughly 2.0 million years ago, the
less muscled, larger brained skulls of the earliest
known members of the genus Homo start to appear
in the fossil record.
From this the investigators postulated that the first
early hominids born with two copies of the mutated MYH16
gene would show many effects from this single mutation—most
notably a reduction in size and contractile force of
the jaw-closing muscles, some of which exert tremendous
stress across and/or cause deposition of additional
bone atop growth zones of the braincase. “The
coincidence in time of the gene-inactivating mutation
and the advent of a larger braincase in some early Homo
populations may mean that the decrease in jaw-muscle
size and force eliminated stress on the skull, which
‘released’ an evolutionary constraint on
brain growth,” says Minugh-Purvis. Indeed, aspects
of the evolutionary trend of shrinking jaws and teeth,
resulting in the lighter, more delicate structure found
in humans today, roughly coincided with the increase
in brain size characterizing the evolution of Homo
over the past two million years.
Dr. Stedman is also a member of the Pennsylvania Muscle
Institute at Penn. Dr. Minugh-Purvis is also adjunct
assistant professor in Cell Biology and Anatomy at the
University of Pennsylvania School of Dental
Medicine; growth specialist in the Facial Reconstruction
Center, Division of Plastic Surgery, Children's Hospital
of Philadelphia; and a research associate at Penn’s
University Museum of Archaeology and Anthropology. Other
Penn researchers collaborating on this work are Benjamin
W. Kozyak, Anthony Nelson, Danielle M. Thesier, Leonard
T. Su, David W. Low, Charles R. Bridges, Joseph B. Shrager,
and Marilyn A. Mitchell.
The research was supported in part by grants from the
National Institutes of Health, Muscular Dystrophy Association,
Association Française contre les Myopathies,
Veterans Administration, and Genzyme Corporation. The
authors have no competing financial interest in this
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