Genes That Make Us Humans: Upright Man

 

The changes in our genes since our ancestors and apes evolved from a common ancestor helped us develop bigger brains and upright walking. But did they also have a downside?

Over the past 15 million years, our ancestors acquired the genetic changes that eventually made us human, and separated us from our closest living relatives – the chimpanzee and other great apes.

Our ancestors' brains quadrupled in size, allowing greater behavioural flexibility, while modifications to the tongue and vocal cords contributed to the development of human speech and language. Ancient humans acquired skeletal, muscle and joint modifications which allowed them to walk upright, move across large distances, and grasp and throw projectile weapons.

However, although these rapid genetic changes may once have helped us adapt to our environment, scientists now believe they may have increased the risk of developing diseases such as Alzheimer's, schizophrenia, bipolar disorder, diabetes, and osteoarthritis.

When you think of what it means to be human, one of the first things that jumps to mind is bipedalism. Walking upright on two legs gave our ancestors an advantage, helping them to carry food and use tools, and to track and hunt migrating animals across long distances. Humans evolved the ability to walk on two legs quite rapidly after their split from the last common ancestor of chimpanzees. By the time that Homo erectus inhabited East Africa 1.9 million years ago, humans were fully bipedal.

However, some anatomical adaptations in the knee were necessary before our ancestors could walk on two legs. The human knee is thicker than a chimpanzees, and reinforced by lots of extra bony surfaces and cartilages to make it stronger.

"The knee joint of chimpanzees is completely different to ours as they are knuckle walkers – they don't stand up on two legs, and their weight is differently distributed," says Terence D Capellini, professor of human evolutionary biology at Harvard University.

"Our centre of mass is right over our hips, so the weight goes right down through our legs and to our knees. Our knees are built for having weight loaded straight down."

Capellini believes that, as the knee is so important to humans, it should be possible to find traces of its evolution in the genome. In a 2020 study, his team took cartilage cells from developing mouse and human embryos. The cartilage was taken from the exact place, and at the exact time, that the knee is beginning to develop and form its shape in the embryo. They then sequenced the DNA of the cells, looking for something known as "human accelerated regions", or Hars.

Hars are places in the genome where the sequence is exactly the same – or very similar – in chimpanzees, orangutans and other primates, but very different in humans. In other words, they are good places to look for "the genes that made us human".

Capellini's study found an abundance of Hars located in the regulatory switches that control the shape and biology of the developing knee. Rather than coding for proteins directly, regulatory switches control the expression of other genes.

"If a gene is like a lightbulb, the regulatory switch is like a light switch," says Capellini.

As a control, they also sequenced the DNA of cells from other areas of the developing skeleton, such as the elbow, ankle, and shoulder. Much fewer Hars were found in these regions. This suggest that the switches that control the shape of the knee underwent rapid evolution in humans compared to the switches that control other areas of the skeleton.

However, it seems that after this burst of evolution, the switches stopped mutating rapidly. When Capellini looked at the genomes of living humans, there was very little genetic variation in these "knee shape switches". That makes sense, because having a functional knee was vital to our ancestor's ability to walk. Once evolution arrived at a good knee shape, further changes were undesirable.

So what does this have to do with human diseases? Well, in the final piece of the puzzle, Capellini and his graduate student Daniel Richard reviewed previous studies that had mapped the genome of patients with osteoarthritis, a degenerative condition which causes joint pain and stiffness. They found that the exact same genes that control the shape of the knee in developing embryos were mutated in patients with osteoarthritis compared to the general population. In other words, the very same genes that help us walk on two legs are now associated with a heightened risk of developing osteoarthritis.

"The blueprints for building a knee have been subjected to intense selection to build a knee correctly, and further excessive mutations aren't tolerated," says Capellini.

"However sometimes small, minor mutations in those switches cause those shapes to be slightly different, or they alter knee biology only subtly. And that altered biology is tolerable when you are young, as you have strong neuromuscular coordination and you can walk just fine. But when you get older and you've gained some weight or you're a little weaker in your muscles, potentially those shape differences start making an impact."

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- Author: Jasmin Fox-Skelly, BBC