A group of researchers from Harvard, Stanford, and the University of Waterloo have uncovered a surprising genetic link between height, arthritis, and the Out of Africa migration between 50,000 and 130,000 years ago.
A common mutation in a gene called GDF5, present in billions of people today, may have provided our ancestors with an evolutionary advantage against the extreme cold of the ice age by making us shorter. Unfortunately, the same gene responsible for shortening our limbs to conserve heat and protect us from frostbite is also associated with an increased risk for osteoarthritis.
“A genetic change to a single letter in our DNA can spread rapidly through the human population if it provides a biological advantage”, says co-author Andrew Doxey, a professor of biology at the University of Waterloo. “This mutation represents human evolution across thousands of years, which in this case was driven by a massive migration. The fact that this selection shows up so prominently in our genetic code is profound.”
The study was published this week in Nature Genetics.
Human evolution from a desktop
GDF5 was first identified a decade ago from genome wide studies on height, but it was the evolutionary signature that intrigued the team most.
Other studies have found similar positive selection hotspots such as the gene that produces the lactase enzyme in the human gut, an evolutionary adaptation that coincided with the origins of farming and milk consumption.“There are these signatures of selection all across our genome that seem to have swept through the population relatively quickly,” says Doxey. “Just a fraction of them have been studied and this is a new one. No one has ever examined the effect of this particular genetic variant before."
But bioinformatics only identifies the locations that have undergone this selective sweep, not what the genes do. That’s where Terence D. Capellini of Harvard University, the study’s lead, and David Kingsley, a professor at Stanford, provided additional experimental evidence on mice using CRIPSR technology to confirm that GDF5 had a strong influence on height and how it works to suppress limb growth.
“It takes lots of work and the use of variety of different, often complementary experimental techniques, to identify functional mutations in the genome.” says Capellini. “To date, there hasn’t been many discovered, especially those that influence height or arthritis, so this is the first step.”
From there, Doxey and his colleagues added a new dimension to the study by globally mapping the proportion of the population containing the GDF5 variant that makes humans shorter.
The results were striking: in Africa, hardly any groups possess the variant, but as you move away from Africa, the proportion of the population with an active GDF5 gene becomes increasingly higher. Over fifty percent of the European and the Middle Eastern population have the variant; some parts of Asia show near 100 percent prevalence.
“The idea that we can take this genomic data and get fundamental, functional and evolutionary insights by analyzing it on a computer shows how important computational methods are becoming in these types of studies,” says Doxey, who is also cross-appointed to Waterloo’s Cheriton School of Computer Science. “We’re no longer starting with experiments, but are looking for patterns in the genetic data to develop hypotheses.”
The long and short of human height
Although there are several factors that control height, the researchers found this particular mutation – a single change in one letter – is unique to humans.
“Thousands of genes and mutations across the genome contribute to our overall height, but GDF5 has a larger role to play than others,” says Doxey, who is also a member of the Centre for Bioengineering and Biotechnology. “If you have this mutation, you aren’t necessarily short, but you’re more likely to be shorter.”
Equally important to the researchers was how this gene seems to be associated with a 1.2- to 1.8-fold increase in the risk of osteoarthritis. This may be related to how the gene controls joint length versus the growing end of long bones.
“What was really surprising to us was that the genetic variant that influences height is not likely the same one that influences arthritis risk,” says Capellini. “However, because the variants sit in different switches, one for long bones and another for joints, and travel together on the same chromosome, selection on one brings along the other.”
This research was supported with funding from Natural Sciences and Engineering Research Council of Canada (NSERC), the Arthritis Foundation, National Institute of Health, the Milton Fund of Harvard, the China Scholarship Council, and the Jason S. Bailey Fund of Harvard.