Paleofantasy: What Evolution Really Tells Us about Sex, Diet, and How We Live (28 page)

Surprisingly, well over half of the human disease-related genes were very old, dating back to the origin of life itself. This is not simply because many of our genes themselves are ancient; 40 percent of our genes in total come from bacteria, but about 60 percent of the disease genes share their ancestry with bacteria. Less than half of 1 percent of the disease-related genes are so recent as to be shared only with the early mammals, which originated about 240 million years ago. The map does not allow assignment of particular ailments, but it can point to processes, such as the breakdown of food into usable elements within a cell, that are more likely to be associated with disease-related genes than with other types of genes.

Some of the media commentary on this work played up the potential practical application of our shared diseases, noting, as did Domazet-Lo
š
o and Tautz, that the existence of the genes in simple organisms like worms, insects, or bacteria means we could study diseases in animals that are much easier to experimentally manipulate than the currently popular rats and mice. But Domazet-Lo
š
o and Tautz also rather flatly note that “genetic diseases are an inescapable component of life.”
⁹
Their results point to the deeply rooted nature of disease itself. In an ideal world, natural selection would weed out those who cannot resist disease, but the only world we have is not ideal. It is just the one we have.

We carry our susceptibility to diseases with us, embedded in our genetic core, unable to be shed when our ancestors separated from worms and turtles, far before the time when we came down from the trees, left the savanna, and started carrying spears and babies. At the same time, natural selection constantly favors genes that make us healthier, particularly in response to the challenges of new diseases. This continuity between ancient and modern is further argument against our suddenly having wrenched our Stone Age selves into a jarring new environment to which we are not adapted. We are both always facing new environments, and always shackled by genes from the past. After all, those Paleolithic ancestors were still dragging around genes they shared with hamsters and bacteria.

The genes fight back

Saying we still carry old disease-causing genes tells only part of the story. We may have inborn vulnerability to illness that we cannot discard, but selection has not been completely slacking off. In addition to those older genes, we show many new ones, some of which arose well after the dawn of agriculture. And understanding those changes is leading to treatments for the most current of plagues: AIDS.

A gene with the catchy name of
CCR5
codes for a protein on the surface of white blood cells known as T cells, critical components of the ability to recognize and fend off foreign invaders such as viruses. Some people have a variant of the gene called
CCR5
-delta (the “delta” is usually represented by the Greek letter D). If they have one copy of the variant, they are resistant to the human immunodeficiency virus (HIV), which causes AIDS. Such people still become HIV-positive, but the actual disease manifests itself two to three years later in them than it does in people who have a different form of
CCR5
. People with two copies of
CCR5
-D are essentially immune to the virus—an extraordinary characteristic, given the usual destructive nature of HIV infection.
CCR5
genes in their usual form allow viruses to penetrate the outer membrane of cells, but individuals with the
CCR5
-D gene derail that entry before HIV can get through.

In 1998, a group of scientists led by J. Claiborne Stephens and Michael Dean from the National Cancer Institute surveyed 4,166 people from thirty-eight ethnic groups across Eurasia, Africa, and East Asia, as well as some Native American populations, for the presence of the
CCR5
-D gene.
¹⁰
The proportion of each population that carried the variant ranged from zero in the East Asian, Native American, Middle Eastern, and Georgian groups to over 13 percent in Sweden, Russia, and Poland. Relatively few Greeks bore the gene, but it was more common among eastern Europeans. In general, the gene occurs at higher frequency in northern countries than in southern countries.

Using a mathematical modeling technique, the researchers were able to estimate when
CCR5
-D is likely to have originated. They determined that the gene variant is about 700 years old, though it could be as young as 275 or as old as 1,875 years. Why do we see variation in the proportion of people in the different populations? Presumably, the gene rose in abundance because it was favored by natural selection. From that average starting point of 700 years ago, the scientists calculated how much selection had to favor the gene in different geographic locations in order to produce the proportions we see today. It turned out that selection had to have been quite strong, meaning that people carrying
CCR5
-D would have to have outreproduced those with the more common version of the gene by quite a wide margin.

What advantage could those people have had? HIV itself came on the scene only within the last several decades, but the association between
CCR5
and the immune system suggests that disease played a key role in the selection process. The obvious candidate seemed to be bubonic plague (the Black Death), a bacterial disease spread by rats harboring plague-infested fleas. During the Middle Ages, bubonic plague killed between 25 and 40 percent of the population of Europe, with some of the largest epidemics occurring—you guessed it—about 700 years ago. Later epidemics, though still destructive, killed a smaller proportion of the population, and plague declined in Europe after a pandemic in 1665 and 1666 called the “Great Plague.” The disease had all but disappeared from Europe by 1750. It would make sense for selection conferring resistance to bubonic plague to have driven the gene to high frequencies in a relatively short time.

This idea was at least tentatively accepted for several years following Stephens and colleagues’ publication, though the authors themselves were cautious in necessarily making plague the culprit, or hero, depending on your point of view. They suggested that the bacteria
Shigella
,
Salmonella
, and
Mycobacterium tuberculosis
, which all cause human diseases, were also suitable candidates. But in 2003, Alison Galvani and Monty Slatkin from UC Berkeley published a paper expressing skepticism about the plague hypothesis.
¹¹
Instead, they favored smallpox, another devastating disease, but one caused by a virus, not a bacterium, and one that is spread directly, from one person to another, rather than via a vector like the flea.

Plague and smallpox differ in many ways, but key to Galvani and Slatkin’s argument is the way that these diseases move through populations. Plague roars through like a wildfire, slaughtering victims of all ages and then disappearing, at least for a while. Smallpox is more low-key; its direct transmission means that it tends to persist at lower levels among children and young people, who pass it among themselves but then either die or survive with lifelong immunity to future infections. Selection from smallpox is therefore more continuous, rather than the intense but periodic carnage of plague.

Galvani and Slatkin mathematically modeled whether a disease like smallpox or one like plague would be more likely to produce the frequencies of
CCR5
-D that we see today.
¹²
They included several assumptions about how often mortality from either disease reached its highest level, how much disease resistance the gene would confer, and, perhaps most significant, the age structure of the group, meaning how many younger versus older people are in a given population. This last assumption is important because selection acts differently on organisms, depending on how much, if at all, they have already reproduced. Selection for resistance to childhood diseases takes a while to exert its effect, because of course the benefit of being resistant—namely, staying alive long enough to reproduce—won’t be seen until the resistant children reach sexual maturity. At the same time, such diseases can have a bigger effect on the population because they remove more “reproductive potential”—the modelers’ term for one’s promise of having babies. By contrast, someone who has a disease like plague that attacks all ages indiscriminately might already have donated plague-susceptible genes to the gene pool before being selected out of the population.

The calculations showed that bubonic plague was unlikely to have driven the increase in
CCR5
-D bearers that occurred between the thirteenth century and today. Smallpox, on the other hand, stays in the running. Although it did not wipe out as many people at a time as the plague, the total number of deaths caused by smallpox over the last 700 years is greater than those caused by plague, and it fits nicely into the other required criteria for causing the uptick in
CCR5
-D. Slow and steady wins the race, at least if by winning you mean putting more people into an early grave.

How did the
CCR5
-D gene variant spread across Europe and western Asia? Understanding the movement of the gene can help unravel the selection behind it. Along with John Novembre, Galvani and Slatkin tried to distinguish several possible ways the gene might have dispersed.
¹³
First,
CCR5
-D might have originated in northern Europe and been carried south, either through normal relatively slow migration or by the Vikings as they advanced through the continent in a more concentrated burst. Alternatively, the gene variant could have arisen in central Europe, becoming more common in the north because selection was stronger there. Yet another possibility is that although
CCR5
-D helps its bearers resist plague, it also has a cost in susceptibility to other diseases, and that cost was higher in southern regions, leading to a northern bias in the prevalence of the gene variant.

Again employing a series of sophisticated mathematical models (in another charming bit of jargon, they tried out a possible dispersal distribution called a “fat-tailed double exponential,” which sounds to me more like a rare type of bird than a mathematical element), the researchers were able to conclude that the “Viking hypothesis,” in which the Vikings took the gene with them as they moved through Europe, was consistent with the data. The gene variant probably arose either in Spain or northern Germany and spread outward from there before the Vikings moved it. The investigators also confirmed their earlier idea that selection on the gene must have been quite strong, meaning that the advantage it conferred was important enough to drive the rapid increase in the frequency of
CCR5
-D. That selection would have eventually increased
CCR5
-D in other populations besides the ones that exhibit it now, given enough time.

A final nail in the coffin of the Black Death hypothesis for
CCR5
-D (a little bit of plague humor there, if I may) comes from the tiny country of Malta, an island that was under Norman rule for over 400 years in the Middle Ages. Since the fourteenth century, Malta has suffered three major outbreaks of bubonic plague and several more minor ones. The Vikings or other Europeans would have had ample time to introduce the gene, and the epidemics would have placed its bearers at a considerable advantage. The Maltese, however, show virtually no evidence of
CCR5
-D, as a survey of 300 blood donors by Byron Baron and Pierre Schembri-Wismayer of the University of Malta determined, even though they would have been expected to be prime candidates for selection.
¹⁴

Being careful what you wish for

At this point one might conclude that it is good to have the
CCR5
-D variation, and because such disease resistance can arise and spread rapidly in human populations, one could further hope that even though agriculture has introduced new ailments, we will simply be able to adapt our way out of these newfound threats. Not so fast. Evolution often works by robbing Peter to pay Paul, such that an advantage in one situation means a disadvantage somewhere else. This is not intentional, of course; fatalistic superstition to the contrary, it is not as if Mother Nature penalizes those with robust immunity to smallpox by making them susceptible to warts. Instead, it is just that change in one part of the genome can have consequences elsewhere. Note that I did not say “unforeseen” or “unintended” consequences; as I have mentioned previously, everything about evolution is unintentional.

In the case of
CCR5
-D, one of those consequences could lie in susceptibility to another disease: West Nile virus, a mosquito-borne disease originating in Africa and first discovered in the United States in 1999. Many people harbor the virus without knowing it, but those who are immunocompromised—say, from HIV infection—are prone to develop a more serious form of illness. Complications of the central nervous system, particularly encephalitis, can in some instances even lead to death. In 2011, 690 cases of West Nile virus were reported to the CDC, with forty-three deaths.
¹⁵

Because of the immunity to AIDS that
CCR5
-D offers, medical researchers have attempted to mimic the effects of the gene variant in devising treatments for AIDS. If they can reproduce the change in the immune cells that
CCR5
-D confers, they should be able to reproduce the resistance as well. But in 2006, Philip Murphy and his colleagues from the National Institute of Allergy and Infectious Diseases discovered a snag.
¹⁶
Mice that were genetically engineered to have
CCR5
-D were unusually susceptible to West Nile virus. More troubling, symptomatic West Nile virus was much more common in blood samples from people with the
CCR5
-D variant than would be expected by chance. The mechanism for the heightened susceptibility is not yet clear, but in the meantime, altering
CCR5
as part of the treatment for AIDS or other diseases might not be a good idea, if it could have the side effect of increasing the risk of West Nile virus infection.