The Genes We Lost Along the Way

In a 1972 paper, geneticist Susumu Ohno, an early leader in the field of molecular evolution wrote: “The earth is strewn with fossil remains of extinct species; is it a wonder that our genome too is filled with the remains of extinct genes?” And while this was decades before we sequenced the human genome, Ohno was right. Buried inside your genome right now are molecular fossils - bits of DNA that are so broken that they no longer work. One of these can be found on your 8th chromosome. It’s called GULOP and it used to do something pretty important for our early primate ancestors. It gave them the ability to make their own vitamin C. But that all ended around 61 million years ago in the middle of the Paleocene Epoch, when something happened in the DNA of one of those early primates. That gene effectively died, becoming a ‘pseudogene,’ a non-functional molecular fossil. And this was a key moment for our lineage. Now, our more distant primate cousins on the other major branch of the family tree, like the lemurs, can still make their own vitamin C, like most other vertebrates. Their branch split off from ours before GULOP became a pseudogene. But ever since the death of GULOP, our side of the primate family tree - the tarsiers, monkeys, and apes - have had to get vitamin C from the food we eat, instead. Without that vitamin in our diets, we risk suffering from diseases like scurvy. And GULOP isn’t the only dead gene we carry with us. There are thousands of them, and we’ve only just begun to unravel their stories. But one thing is already clear: we’re not just defined by the genes that we’ve gained over the course of our evolution, but also by the genes that we’ve lost along the way. Over 90% of our genome doesn’t actually code for anything. And embedded in all this non-coding DNA, like bones in rock, are fossilized pseudogenes -- sequences that were once active, but are now basically dead, with a few rare exceptions. We’ve now found around 20,000 of them in our genome. This rivals the number of genes we have that are still active! And we know where a lot of these pseudogenes came from. In many cases, they’re the result of ancient gene duplication events. This happens when a gene is duplicated into two identical daughter genes, and one copy dies, leaving one functional copy behind. Others, like GULOP, are ‘unitary’ pseudogenes - there was only one of them in the genome and when it died there was no back-up copy, so its function was lost. So how do genes die? Well, the short answer is mutations. Mutations occur randomly in our DNA all the time. They’re totally normal and a source of new variation. And variation is the raw material for evolution. Occasionally, mutations occur at particular spots in a gene that inactivate it, which prevents the instructions it carries from being translated into a protein. And that’s what happened to GULOP, around 61 million years ago. A mutation inactivated it, turning off its ability to make an enzyme that’s a key part of making vitamin C. Without that enzyme, our ancestors couldn’t produce the vitamin. And this is part of the bigger picture of how evolution works, too. If a mutation that inactivates a gene reduces fitness, or the ability of an organism to survive and reproduce, natural selection will get rid of it by selecting against the individuals that carry the mutation. This process keeps useful genes free of mutations. But if the loss of the gene doesn’t reduce fitness, then this mutation can spread throughout a population. This can happen either through a random process called genetic drift, or through natural selection. Eventually, the mutated gene can become ‘fixed,’ meaning it’s the only version of that gene left in a species’ gene pool. In the case of GULOP, we don't know if its death increased fitness, but it probably didn’t reduce it. When it became inactive, our early ancestors were likely already getting a lot of vitamin C from eating fruit. This resource was becoming more abundant as tropical forests expanded throughout the Paleocene and fruiting plants continued to diversify. It’s been suggested that the loss of their vitamin C gene wasn’t a big deal for those primates, because they could get it easily from the environment instead. So gene death isn’t necessarily bad. It creates opportunities for evolution and can even be good, depending on the environmental and ecological context in which it happens. And GULOP definitely wasn’t our last broken gene. About 44 million years later, in the early Miocene Epoch, our hominoid ape ancestors lost another gene: UoX This gene coded for a protein called uricase - an ancient enzyme produced by organisms from bacteria to mammals. Apes like us are the odd exception. The function of the uricase enzyme is to break down uric acid, a waste product of metabolism. When UoX became a pseudogene - around 17 million years ago by molecular dating estimates - apes lost this enzyme. Now, all that’s left of UoX is its molecular fossil, which is entombed in our 1st chromosome. And, like GULOP, its loss has some consequences for us even today. For example, humans and the other living apes all have high uric acid levels in our blood. They’re between 3 and 10 times higher than other mammals, who still have functioning uricases and can break the acid down effectively. Which means that we can get diseases like gout - when uric acid builds up in our blood, forms crystals, gets deposited in our joints, and causes painful swellings. So how and why did we lose such a useful gene? To figure it out, in 2014 a team of researchers studied ancient mammalian uricase enzymes using a technique called ‘ancestral sequence reconstruction’. By comparing both the gene and protein sequences of uricase enzymes found in mammals living today, they were able to reverse-engineer what the sequences of ancient uricase genes and proteins would have been at different points in the past. Then - and brace yourself because this sounds like science fiction - they physically resurrected these ancient uricase proteins, by building them in the lab! They then performed a series of experiments on the resurrected proteins to see if they worked. And they found that the oldest uricase protein they’d resurrected - dating back 90 million years - was really good at processing uric acid. But uricases from around 40 million years ago, in the mid-Eocene Epoch, had already picked up mutations that made them less efficient. And over the next 20 million years, primate uricases from the Oligocene and early Miocene Epochs were even less efficient. So the UoX gene becoming inactivated around 17 million years ago was actually only the final step in a series of mutations stretching back tens of millions of years. Why uricase gradually stopped working over time is still mysterious. But, there is evidence to suggest that the final stages of UoX’s decline may have given our ancestors an evolutionary advantage. You see, UoX’s death happened at a time when the Earth’s climate was cooling. For our fruit-eating ape ancestors, this was a bad thing. It meant that fruit was no longer available year-round - sure, there’d be plenty during summer, but very little in winter. Enter uric acid. One of the few advantages of having a lot of uric acid is that it stimulates the creation and accumulation of fat from fructose - a sugar commonly found in fruit. And it’s been hypothesized that having less active, and eventually inactive, uricase enzymes, made our ape ancestors better able to store fat during times when fruit was abundant, and to survive off those fat stores during leaner times. To test this idea, the researchers inserted the resurrected ancient uricases into human cells in the lab. As expected, they found when the cells were given fructose, they were worse at turning the sugar into fat, compared to normal human cells with no working uricases. So there's evidence that the loss of the UoX gene and the enzyme it coded for may have given our lineage a survival advantage. Sometimes in genetics, less is more. And if you’ve noticed that all of the genes we’ve talked about so far are linked to food, well, there’s a good reason for that. Food availability is one of the most important and rapidly changing pressures that living things face. So shifts in our diets have played a huge part in molding our genomes. We see this again in our taste receptors - a dynamic group of genes in vertebrates that allow us to perceive different tastes. Their birth and death is tightly linked to changes in the diet of a species. In the genomes of carnivores with all-meat diets for example, we often see that sweet taste receptor genes have died, becoming pseudogenes. As omnivores, we humans have a relatively well-rounded set of taste receptor genes. We can pick up on all of the major taste groups pretty well - sweet, sour, umami, salt, and bitter. And it's in that group of bitter taste receptors that we find some of our most recent pseudogenes. Right now, our DNA contains 25 working bitter taste receptor genes. Each of them is thought to be associated with tasting specific families of compounds. And for millions of years, they’ve helped our ancestors tell which plants are good to eat, and which might be toxic. But we’ve also lost quite a few. We carry 11 dead bitter taste receptor pseudogenes. And two of them died relatively recently in our evolution, sometime after our last common ancestor with chimpanzees and bonobos. And we know that these two genes died before we split from the Neanderthals and Denisovans, around 500,000-600,000 years ago. Because! Their genomes also contain the same two pseudogenes, with the exact same inactivating mutations. So these genes very likely died in a common ancestor of ours, and their molecular fossils were inherited by all three groups. So what happened to these two bitter taste receptors? Well, the last few million years of our evolution saw huge changes in our eating habits. We started eating more meat and eventually learned to cook with fire, which often makes plant foods less toxic. Our cultural knowledge of food sources became more and more sophisticated, and we became able to transmit this information through language. And all of these changes might have meant that the ability to tell the difference between bitter plant compounds became less and less important as time went by. When these two bitter taste receptor genes mutated and died, there wasn’t enough evolutionary pressure to save them. And their pseudogenes became molecular fossils shared by our species and our closest cousins. Evolutionary genomics is still a young science, and our understanding of the thousands of dead genes we carry with us will only grow with time. But it’s already clear that the genome is more than just a recipe book for building an organism. It’s also a historical record, a molecular fossil bed filled with "extinct genes", preserving our evolutionary legacy in the form of the As, Ts, Cs, and Gs that make up our DNA. Our taste receptors have helped us humans out a lot over the years - like bitter helping us figure out the toxicity of plants, but what about umami and sour? To find out, watch our episode, “How We Figured Out Fermentation”. Thanks to this month’s Eontologists for staying active in the Eons genome : Sean Dennis, Jake Hart, Annie & Eric Higgins, John Davison Ng, and Patrick Seifert! Become an Eonite at patreon.com/eons to get fun perks like submitting a joke for us to read. Like this one from Stephen O'Leary: "Fossilization is a Sediment-al Journey." That's pretty cute And as always thank you for joining me in the Konstantin Haase studio. Subscribe at youtube.com/eons for more evolutionary escapades.

Channel: PBS Eons

Views: 1,157,913

Rating: 4.9491463 out of 5

Keywords: dinosaurs, dinos, paleo, paleontology, scishow, eons, pbs, pbs digital studios, hank green, john green, complexly, fossils, natural history, genome, genus, molecular fossils, pseudogene, chromosome, GULOP, DNA, unitary, mutations, UoX, uricase, evolution, uric acid, fructose, ancestral sequence reconstruction, resurrection, taste receptors, vitamin C

Id: 6Vc2bM2aQsw

Length: 12min 48sec (768 seconds)

Published: Wed Feb 24 2021

Reddit Comments

[u/MapChap]

All animals can except for humans, guinea pigs, fruit bats, and maybe a few others.

[u/Boo_Owl]

I watched the whole video. Very interesting!

[u/ObiMemeKenobi]

PBS Eons is fucking awesome

[u/No-Pizda-For-You]

If they produced their own gravy, I might be interested. Seriously though, very interesting and thank you for posting!

[u/Ianbeerito]

Yeah but can they make Sunny-Delight?

Didn’t think so!

[u/giltwist]

So using gene therapy to restore UoX might help solve our obesity epidemic?