Quite predictably, sickle cell disease is not distributed evenly across human populations. After all, an SCD mutation that appeared in an individual living in a region relatively free of mosquitoes and malaria—say, Northern Europe—would confer no advantage on that individual. The allele would simply be a disease-causing mutation and would thus not persist. For this reason, sickle cell disease is almost unheard of in European populations. In fact, the geographic prevalence of sickle cell disease overlaps amazingly well with the geographic prevalence of malaria.
There’s an interesting final twist in the story of sickle cell disease. Researchers understood the push-pull of evolutionary pressure on the mutant code, but they initially could not understand why SCD persisted, because sickle cell disease is so much more deadly than malaria. They built computer models that predicted the opposite: SCD should have died out. But they overlooked a crucial factor stemming from the fact that many preagricultural human societies engaged in polygamy.
In most polygamous societies, a minority of men have multiple wives, meaning that males directly compete with one another for the privilege of reproducing with as many females as possible, with most males not reproducing at all. Among males, competition is quite fierce, and there is a direct and strong relationship between the number of offspring one leaves and one’s overall health, vitality, and virility. In this scenario, the push-pull of malaria versus sickle cell disease would likely doom males that had either two copies or no copies of the SCD alleles—these males would be either afflicted by sickle cell disease or vulnerable to the ravages of malaria. Most of the dominant and prolific males would thus be carriers. These alpha males (to borrow a loaded term) would reproduce with a large number of females and produce an even larger number of offspring. Many of those offspring wouldn’t make it to adulthood because, in addition to having the normal afflictions, infections, and deficiencies of premodern life, many of them would also have to contend with either malaria or sickle cell disease. That would have been perfectly okay, however, because the SCD carrier and his harem would constantly produce more babies.
Compared to binary marriage, polygamy substantially intensifies the selective pressures of health and survival because of the direct competition of males with one another. The heterozygote advantage is even stronger because a male must be in tiptop shape in order to fend off other males and earn a harem. Any predilection toward SCD or sensitivity to malaria would be a weakness he could ill afford. Although polygamy was never a universal human practice, it was common enough in certain places at certain times to facilitate the proliferation of the gene mutations that cause sickle cell disease. Many people whose ancestry traces to malaria-infested tropical regions still suffer from this genetic malady.
Other single-gene genetic disorders include cystic fibrosis, various forms of hemophilia, Tay-Sachs disease, phenylketonuria, Duchenne muscular dystrophy, and hundreds more. These genes are recessive, like the gene for SCD, so you must inherit the mutation from both parents in order to be afflicted. This makes each of these diseases fairly rare. However, collectively, genetic diseases are not uncommon; some estimates suggest that genetic disease affects around 5 percent of the human population. While not all of them will be lethal or even debilitating, we are still talking about hundreds of millions of people walking around our planet with errors in their genetic code. Most of those errors occurred generations ago, and many of the people who carry those errors don’t even know it because they are heterozygote carriers. Those who do suffer are the result of an incredibly unlucky pairing of two unknowing carriers.
A few genetic diseases are caused by a dominant mutation rather than a recessive one. This means that, instead of having to inherit a bad gene from each parent, just one from either parent is enough to cause the disease. These are much rarer for the obvious reason that they aren’t ever hidden; the selective pressure against a genetically dominant disease mutation is usually swift and unforgiving. However, a few of these mutations have persisted across generations, as have the genetic diseases they cause: for example, Marfan syndrome, familial hypercholesterolemia, neurofibromatosis type 1, and achondroplasia, the most common form of dwarfism. These conditions are often inherited from a parent, but even when the mutation occurs spontaneously in an individual with no family history of it (which actually happens quite often), the resulting disease will be passed on to 50 percent of that person’s offspring. Sadly, therefore, genetic diseases are just as persistent in the lineages of people who developed the mutation sporadically as they are in the lineages of individuals who inherited their condition from one of their parents.
Among the most well-known genetically dominant diseases is Huntington’s, an especially cruel disease. Symptoms don’t usually appear until the victim is in his or her early forties to late fifties. Following the onset of the disease, patients suffer a slow deterioration of the central nervous system, beginning with muscle weakness and poor coordination and progressing to memory loss, mood and behavior changes, loss of higher cognitive functions, paralysis, vegetative state, and eventually coma and death. The deterioration is excruciatingly slow, taking five to ten years, and as of now there is no cure or even treatment to slow the progression. The patients and their loved ones are powerless, fully aware of the nature of the impending decline.
The cause of Huntington’s disease, like all genetic diseases, is a mutation in the genome. However, if a genetic disease persists instead of being eliminated by natural selection, there must be a reason, as we saw with sickle cell disease. This is especially true in the case of a genetically dominant condition like Huntington’s, which has no carriers—only victims. Around one in every ten thousand people in Western and Northern Europe has the dominant and lethal Huntington’s mutation (with the highest rates in Scandinavia and the British Isles). That may not sound like much, but it adds up to hundreds of thousands of people in these regions alone. Although the percentage of Huntington’s mutations in Asian populations is much lower than it is in Europe, the total number of people who are affected by the disease is much higher, given how much more populous Asia is. This begs the question: How can Huntington’s disease be so common if it is also so deadly?
The answer is almost as cruel as Huntington’s itself. By the time Huntington’s strikes, the sufferer is past prime reproductive age and so may have already passed the disease gene on. Rather than taking the disease allele with them when they die, the victims leave it behind with their offspring as a grim genetic legacy.
The genetics behind Huntington’s disease wasn’t even discovered until the late nineteenth century. Before then, no one had any idea that it was passed on in such a simple manner. Of course, it seems obvious now, but the nature of Huntington’s was partly obscured by the fact that, until the past two or three centuries, most people died before reaching age forty. The disease didn’t track as cleanly in a family tree as it does now because people were dying of so many other afflictions and infections before they reached the ripe old age of two score years. In addition, in earlier times, both women and men tended to begin their reproductive lives earlier than people in the developed world do now. When someone did live to be forty years old, he or she was likely to be an aged grandparent, and a disease like Huntington’s, with its slow start and nonspecific early symptoms, was mistaken for dementia or just old age.
Because of its late onset, Huntington’s can be passed on with natural selection having little to say about it. Selective forces can operate only on inherited traits that directly or indirectly affect reproduction or survival—that is, survival through reproductive age. Beyond that, one’s genes have already been passed on to the next generation’s gene pool. An affliction like Huntington’s doesn’t much affect the number of successful offspring one produces, so it is largely in natural selection’s blind spot.
Genetic diseases are shockingly common in the human population and are often deadly or debilitating. Most are inherited, and whether they have persisted for generations or are the
result of a sporadic mutation, they all come down to errors in our DNA blueprints. Chromosomes break, DNA is mutated, and genes are destroyed. And evolution is sometimes powerless to stop it.
As if that weren’t bad enough, there is another onslaught that our genomes must endure: viruses.
Our Viral Graveyards
Just as it’s populated with pointless pseudogenes and harmful disease genes, the human genome also contains the remnants of past viral infections. Strange as this may seem, these viral carcasses are widespread; as a percentage of the total DNA letters in your body, you have more viral DNA than genes.
You have ancient viral DNA in all of your cells thanks to a family of viruses called retroviruses. Of all the kinds of viruses that infect animal cells, retroviruses may be the most nefarious. The life cycle of a retrovirus includes a step in which its genetic material is actually inserted into the genome of the host cell, like a parasite made of pure DNA. Once ensconced in the tangles of genetic material, it waits for the perfect time to strike—and when it does, the results can be catastrophic.
HIV is the best understood retrovirus. When HIV enters a human T cell, the virus consists of little more than a few genes made of RNA (another genetic-code molecule closely related to DNA) and an enzyme called reverse transcriptase, or RT. After the virus unpackages itself to begin the infection, the RT enzyme makes a DNA copy of the viral RNA. This DNA copy then nestles inside the host cell’s DNA on some unsuspecting chromosome. Once it is integrated, it can lie in wait indefinitely, perfectly hidden within the endless strands of As, Cs, Gs, and Ts of the host cell. It can pop out and pop back in at will. When it pops out, it engages in an active phase of viral attack. When it pops back in, the virus goes dormant. This is why people with HIV can have occasional bouts of severe illness followed by periods of relative good health.
This is why HIV is still impossible to cure. It lives in the DNA. There is no way to kill the virus without also killing the host cell. Killing all T cells is not an option because then we wouldn’t have working immune systems. Instead, recent therapies that have had great success in treating HIV are targeted at simply keeping the virus in the dormant phase for the rest of the patient’s life.
Of course, the virus is not passed from parents to children genetically (although cross-infection can occur between mother and child during childbirth or before). The reason it’s not inherited is that the virus infects only T cells, which have no role in passing genes from parents to children. Only sperm and eggs do that. However, if a retrovirus were to infect one of the cells that give rise to sperm or eggs, a child could literally inherit a viral genome from one of her parents. She would be born with a virus hidden inside the chromosomes found in every single cell of her body, like trillions of tiny Trojan horses waiting to unload their malicious contents on their unsuspecting host. Her parent had the virus only in a sperm- or egg-producing cell. She has it everywhere!
This inherited viral DNA need not produce an active infection in order to be propagated. In fact, it doesn’t need to produce any actual viruses at all. The genome of the virus, once inside the core DNA, will be passed on no matter what. For the virus, this is an absolute victory; it doesn’t have to do any other work in order to spread.
This is precisely what has taken place countless times in human history, and the resulting viral carcasses are still with us. Thankfully, they’re now heavily mutated after all this time, to the point that almost none of them are able to create infections. (Although, as we’ll see, even dead viral DNA can and does do harm.)
Around 8 percent of the DNA inside every single cell of your body consists of remnants of past viral infections, nearly a hundred thousand viral carcasses in all. Humans share some of these carcasses with cousins as distant as birds and reptiles, meaning that the viral infections that originally created them took place many hundreds of millions of years ago and these viral genomes have been passed along, silently and pointlessly, ever since.
Truly, most of these viral corpses serve no function whatsoever, even as the body dutifully copies each one of them hundreds of millions of times a day. The good news is that all or nearly all of our parasitic viral genomes have quieted down to a truly carcass-like state, never doing any work such as, um, releasing active viruses into our cells. (Here’s a premise for a sci-fi thriller: An evil genius discovers how to turn on the ancient, dormant viruses skulking in our DNA. Our bodies would destroy themselves from within, probably in a hurry.)
Yet while they’re mostly dormant, these genetically inherited viruses do have a blood-soaked past—one that occasionally seeps into the present. They have surely killed innumerable individuals over the years due to their tendency to disrupt other genes. Retroviral genomes can jump around and insert themselves randomly into chromosomes; like a bull in a china shop, they cause all kinds of damage because, even though they can’t make viruses anymore, they retain their pop-in, pop-out abilities, and if they pop into an important gene, they can do great harm. As if this weren’t odd enough, it turns out that pieces of our own DNA can also jump around through the genome.
Jumpy DNA
I have saved perhaps the most perplexing, and certainly the most abundant, type of pointless DNA for last. Lurking in our genomes are regions of highly repetitive DNA called transposable elements (TEs). TEs are not genes; they are pieces of chromosomes that can actually get up and move around, changing position during cell division, not unlike the retroviral genomes discussed above.
If that sounds weird to you now, imagine how absurd it seemed when first proposed by Barbara McClintock in 1953. Her theory was the only explanation she could find for the bizarre genetic phenomenon of haphazardly inherited colored stripes on corn leaves. The scientific community was completely incredulous and dismissed her ideas with barely a second thought, but she worked tirelessly to refine and advance her theory anyway, putting it to the test in hundreds of painstaking experiments with corn plants. More than twenty years after she first proposed the existence of TEs, they were discovered in bacteria, and this time by more “traditional” research groups (I use these quotes cynically, to mean “led by men”). This forced the scientific community to take another look at McClintock’s work and admit that she was right. In 1983, she was awarded the scientific community’s highest honor—the Nobel Prize.
One particular TE, called Alu, offers a good example of how these curious elements of our genomes—these “jumpy” bits of DNA—have come to be what they are. We know the most about the Alu element because it is the most abundant TE in humans and other primates. There are one million copies of it in the human genome. These copies have been dispersed all over the place, on every chromosome, within genes, between genes—everywhere. The story of how they ended up in the human genome is both incredible and completely improbable.
Once upon a time, in the genome of a creature that inhabited the earth over a hundred million years ago, a gene called 7SL did something strange. Every living cell in every organism today, from bacteria to fungi to humans, has a version of 7SL, which helps build proteins. However, in a sperm or egg cell of some ancient mammal, a molecular mistake was made. Two 7SL RNA molecules were fused together, head to tail. Coincidentally, a retrovirus infection was ravaging the same cell, and one of the viruses inadvertently grabbed this misshapen double-7SL RNA molecule and started making DNA copies of it. These DNA copies then inserted themselves back into the genome of this anonymous mammal’s cell, creating multiple copies of 7SL: one normal version (which we still have), and many of the fused copies. Not knowing it was anything unusual, the cell transcribed the fused 7SL genes into RNA as if they were normal genes. The retrovirus again took the RNA products and made DNA copies from them. Some of those copies inserted themselves into the genome, and the cycle continued over and over again, amplifying exponentially each step of the way. We cannot know how many 7SL-fused elements, which we now call Alu, that the cell and virus initially made, but it was certainly thousands.
Through pure chance
, the offspring that resulted from that sperm or egg cell became the ancestor of a whole group of mammals called the supraprimates, which include all rodents, rabbits, and primates. We know this because all those animals contain many hundreds of thousands of copies of the bizarre Alu element but no other animals do.
You’d be forgiven for thinking that a molecular accident of this magnitude—one resulting in hundreds of thousands of copies of a freakishly deformed gene being scattered throughout an organism’s genome—would have had serious, negative ramifications for the animal in which it occurred. The fact that supraprimates are here means, of course, that it didn’t, at least not right away. Most of these copies and insertions fell harmlessly into sections of DNA that simply don’t matter much, if at all. The Alu sequences spread from this originating organism to its offspring, eventually becoming fixed in that ancient species and all its descendants. Alu has since taken on a life of its own, continuing to copy, spread, mutate, insert itself, reinsert itself, and just generally bumble its way through the genome. Most of that bumbling is harmless, but occasionally it can wreak havoc.
In fact, we don’t have to look deep into our evolutionary past to identify the harm that one million random insertions can do when they rip through the genome. To this day, genetic damage caused by rogue Alu insertions makes humans more susceptible to a variety of diseases. For instance, Alu and other TEs created the “broken” gene alleles responsible for hemophilia A, hemophilia B, familial hypercholesterolemia, severe combined immunodeficiency, porphyria, and Duchenne muscular dystrophy. Alu went crashing into these important genes and either completely destroyed or severely disabled them. Disruptions by Alu or other TEs have also created genetic susceptibilities to type 2 diabetes, neurofibromatosis, Alzheimer’s disease, and cancer of the breast, colon, lung, and bone. These are genetic susceptibilities, meaning that the gene was weakened rather than completely destroyed. Nonetheless, this genetic damage has undoubtedly killed millions of humans just in the past few generations.
Human Errors Page 9
