The genes that made us truly human may also make us ill

By Jasmin Fox-SkellyFeatures correspondent

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."

Bigger brains

Humans underwent a series of rapid evolutionary changes that allowed us to grow bigger brains, with more neurons devoted to the outer cerebral cortex – the area responsible for higher order cognitive reasoning. In fact, human brain size nearly quadrupled in the six million years since Homo sapiens last shared a common ancestor with chimpanzees.

However, many of the genetic tweaks which enabled these changes are now associated with disorders such as autism and schizophrenia, according to recent research.

For example, in 2018, two teams of researchers identified a gene family, Notch2NL, that appears to play an important role in cortex development in humans, and may have been a driving force in the evolution of our large brains.

The Notch signalling pathway is an ancient system used in all animals to control the fate of stem cells in the embryo, directing whether they divide and grow to form new stem cells, differentiate into more specialised cells, or die. However, the specific Notch2NL gene is found only in humans, and is absent from the DNA of chimpanzees, orangutans, and other great apes.

"What's fascinating about the history of Notch2NL is that there actually was an original event that happened in our common ancestor with gorilla, where the original Notch2 gene was duplicated," says Sofie Salama, professor of molecular, cellular and developmental biology at the University of California Santa Cruz, who was involved in one of the research studies.

Segmental gene duplication is a process by which a section of the genome gets copied. The new copy is then moved to another spot in the genome, leaving behind two very similar sections of DNA.

"It seems based on our analysis that that initial duplication event was kind of like a dead-on-arrival thing, and that the new gene either couldn't get expressed, or created an unstable protein," says Salama.

Then in the human lineage around three to four million years ago the gene was altered again through a process known as gene conversion. This time the new copy – Notch2NL –was functional.

"That is an interesting time in our evolutionary history, because if you look in the fossil record that was right before there was this exponential increase in brain size," says Salama.

So how could Notch2NL lead to bigger brains? The gene delays stem cells in the cortex of the brain from turning into neurons. Instead, the stem cells carry on dividing and producing more stem cells. This ultimately leads to more neurons being produced, and bigger brains.

Notch2NL isn't the only example where genes have been duplicated in humans. Scientists have identified more than 30 gene duplications that are unique to our species. Some believe these duplications could be responsible for some of our uniquely human traits.

For instance in 2012, researchers at Columbia's Zuckerman Institute discovered that humans have a unique, duplicated form of the SRGAP gene, which they named SRGAP2C.

SRGAP genes play a crucial role in controlling the number of connections, known as synapses, that a neuron makes with its neighbouring cells. The more synapses a neuron has, the more information it can process. The new, human-specific SRGAP2C gene essentially allows humans to form more synapses, and stronger and denser connections between neurons.

Although they may explain our species' unmatched brainpower, gene duplications such as those that resulted in SRGAP2C and Notch2NL may have left us vulnerable to developing neuropsychiatric disorders. For instance, mutations in the region of the genome where Notch2NL is found are associated with a range of neurodevelopmental disorders, including ADHD, schizophrenia, autism spectrum disorder, and intellectual disability, according to Salama and colleagues.

"If you want to make more of a gene, a really easy way to do it is copy and duplicate the gene so there are multiple copies that can all be turned on at once," says Tony Capra, professor of epidemiology and biostatistics at the University of California, San Francisco.

"But of course, once you have that more complex control there are more ways it can go wrong."

For instance, if the sequence in the newly copied gene is very similar to its predecessor, it can sometimes confuse the machinery that makes copies of our genomes, leading to genes being moved around, inserted in different places, or combined in different, maladaptive ways. Duplicated genes also contain repetitive sequences that make them more prone to additional deletions and duplications.

It's also possible that some of the "genes that made us human" may be in areas of the genome that are prone to high mutation rates, making us susceptible to disease. In a 2022 study, Craig Lowe, professor of molecular genetics and microbiology at Duke University, analysed the human genome to find the places that had changed the most since our ancestors diverged from chimpanzees. He found that many of the regions – known as Haqers ("human ancestor quickly evolved regions") – were involved in regulating the developing brain, for example by inducing the growth of more neurons.

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These regions also tended to be in areas with high mutation rates, which, according to Lowe, could lead to problems further down the evolutionary branch.

"These quickly mutating regions of the genome are like evolution's cauldron – the places where everything comes together and gets mixed up," says Lowe.

Lowe found that mutations in many Haqers he discovered are associated with schizophrenia and bipolar disorder.

It's possible such genes now making us ill because evolutionary trade-offs are pulling our bodies in different directions. Our risk of developing cancer seems to be inversely related to our risk of developing Alzheimer's, Parkinson's and Huntington's disease. Cancer involves the uncontrolled growth of new cells, while these diseases are linked to cell death.

It's also true that it is often the most recently evolved regions that are often vulnerable to dysfunction, suggesting that we might not have had time to evolve compensatory buffers to protect ourselves.

Alternatively, it could be that the environment we now find ourselves living in is very different to that of our ancestors.

"We have been able to change and remodel our environments so quickly, and often much more quickly than the evolutionary process can keep up with," says Capra.

"This could create an evolutionary mismatch where adaptations that have been shaped over tens of thousands of years are no longer suited to our modern lives."

It's possible that understanding how certain genes lead to diseases could help inspire new treatments. Some even say it could even help us move towards a new era of personalised, precision medicine: where targeted drugs could be used for each unique genetic profile. However, others are more cautious.

"I think evolution is a really useful lens in which to view what goes wrong, and when, how and why," says Capra.

"But the major driver of variation in disease occurrence across humans is whether people have access to healthcare, healthy food, and clean water – those are the places I think we should be focusing efforts first."

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