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 primates.
"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 work.
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