Sickle-cell trait is perhaps the best known of many genetic conditions that are correlated with ancestry. As another example, malaria is also common in parts of Southeast Asia, yet sickle-cell trait is less common in these regions. In this part of the world, natural selection has favored a different set of derived variants that confer resistance to malaria, variants that do not cause sickle-cell trait or sickle-cell anemia. Instead, when homozygous, several of these variants cause serious, often fatal, blood-related conditions called thalassemias. Symptoms include extreme weakness and a tendency to become tired very quickly, jaundice (skin yellowing), swollen abdomen, bone deformities, and delayed growth. A person who is heterozygous, having inherited just one copy of one of these variants, however, has increased resistance to malaria and does not have symptoms of thalassemia. Because of natural selection, thalassemias are some of the most common inherited conditions in people whose ancestry is from regions of Asia plagued by malaria, especially Southeast Asia. Thalassemias, however, are far from exclusive to people with Southeast Asian ancestry. They are due to a large number of different variants found in human populations throughout the world. The prevalence, however, is greatest in people whose ancestry traces to regions with malaria, due to natural selection favoring resistance to malaria in their ancestors.
An additional example of a frequent and serious genetic condition associated with geographic ancestry is cystic fibrosis. The symptoms of this condition vary among people who have it; they often include thickened mucus that causes chronic coughing and wheezing, susceptibility to lung infections, and digestive problems. Derived variants in a gene called CFTR cause it, and a person must inherit these derived variants from both parents (in other words, must be homozygous) to have cystic fibrosis. Those who have just one derived variant are called heterozygous carriers, and they may pass the variant on to their children, but they have no symptoms. The majority of cystic fibrosis cases result from homozygosity for the same derived variant, called delta F508, that lacks three base pairs when compared to the ancestral variant:
The word delta here stands for “deletion,” meaning that a mutation deleted three base pairs to create the derived variant. Evidence in the DNA surrounding this variant indicates that its originating mutation happened only once in human history, so everyone who inherits this variant, be it one copy or two, traces her or his ancestry for this part of their DNA to the same ancient person. This variant is so ancient that it is difficult to trace where this person lived. He or she probably lived somewhere between central Asia and Europe more than thirty thousand years ago, and the distant descendants of this person colonized much of Europe generations later.9 The relatively high proportion of people with European ancestry who carry this variant is probably a consequence of natural selection. Heterozygous carriers of the variant are less likely to become severely dehydrated by diarrhea; thus, they are better able to survive cholera infections and possibly more resistant to typhoid fever. This survival advantage probably hastened the spread of this variant and contributed to its prevalence in ancient Europe. Hence, cystic fibrosis appears most frequently (albeit not exclusively) in people who have European ancestry, and, for this reason, it is the most common genetic disorder in Europe, Canada, Australia, and the United States, as well as other countries with high proportions of people who have predominantly European ancestry.
All of these examples—sickle-cell trait, sickle-cell anemia, thalassemias, and cystic fibrosis—are genetic conditions caused by identifiable derived variants. The causal relationship of each of these conditions is clear and absolute, understood in detail at the molecular, cellular, and physiological levels. And we could examine many similar examples.
More difficult to identify, however, are variants that do not necessarily cause a condition or disease but, rather, confer susceptibility to it. For example, type 2 diabetes, heart disease, obesity, rheumatoid arthritis, Alzheimer's disease, Parkinson's disease, autism, various types of cancer, and many other health-related conditions tend to run in families but do not display clear-cut patterns of inheritance like cystic fibrosis or sickle-cell anemia do. Some of these conditions, like type 2 diabetes, heart disease, obesity, and types of cancer, are not entirely genetic but also dependent on diet, physical activity, exposure to chemical substances and environmental pollutants, and other nongenetic factors—an interaction of inheritance and environment.
In science, it is often a challenge to distinguish causation from mere correlation. Although correlation is often a result of causation, a cardinal rule of science is that correlation in and of itself does not provide sufficient evidence for causation. As a simple and obvious example, Utah has one of the highest rates in the United States of malignant melanoma, the most dangerous and lethal form of skin cancer.10 Utah also has the lowest rate of tobacco smoking.11 Yet no legitimate scientist would recommend that people take up smoking to prevent malignant melanoma because there is no scientific reason to presume any causal relationship between the two. Indeed, if there were any causal relationship, it should be the reverse.
By contrast, the causal relationships for many genetic associations are evident based on a clear understanding of how genes function and how variants in them alter their functions. If a variant causes a change in the function of a gene related to a particular condition, and a genetic variant in that gene is correlated with the incidence of that condition, the correlation probably represents at least a partial causal relationship between the two. We can extend the example we just examined—the relatively high incidence of melanoma in Utah—as a case in point. Utah has the second-highest rate of malignant melanoma, and Vermont has the highest. These two states have relatively high proportions of people with northern European ancestry (in fact, Vermont's is the highest in the United States). Utah also has relatively high ultraviolet light radiation, due to the high elevation where most of its population lives (an environmental risk). As we've already seen, people with predominantly northern European ancestry typically carry derived variants that confer low skin pigmentation, which increases their susceptibility to malignant melanoma when exposed to sunlight. Therefore, susceptibility to malignant melanoma and variants that cause reduced skin pigmentation are causally correlated. This same correlation is evident on the other end of the spectrum. In the United States, malignant melanoma is lowest within the District of Columbia (Washington, DC), which has the highest proportion of people with predominantly African ancestry and high skin pigmentation, and, therefore, ancestral variants that confer protection against this type of cancer.
Correlations between diseases and the variants conferring susceptibility to them are not absolute. Malignant melanoma is an example. People who are genetically susceptible to it because of lower skin pigmentation can reduce the probability of malignant melanoma by avoiding overexposure to the sun and protecting their skin with clothing and sunscreen.
Among the most researched genetic susceptibilities associated with ancestry is predisposition to alcohol dependence, popularly known as alcoholism, which affects large numbers of people of all ancestral backgrounds in every part of the world. Humans, as well as many other species of animals, have genes whose products metabolize alcohol to protect them from its harmful effects (in excessive amounts, alcohol is toxic, even fatal, to humans). These gene products act mostly in the liver, which is why people who consume large amounts of alcohol over long periods during their lifetimes often suffer from liver disease. When someone consumes alcoholic beverages, the alcohol is quickly absorbed into the bloodstream and soon affects the brain and nervous system. It initially causes sensations of well-being, including the so-called buzz, followed by drunkenness with increased consumption. The liver metabolizes the alcohol through a two-step process, beginning with conversion of ethanol (the type of alcohol in alcoholic beverages) to an intermediate substance called acetaldehyde. The second step is converting acetaldehyde to acetate, a substance that causes the sour taste in vinegar. In fact, the process that happens in the liver is
similar to the chemical process that naturally converts wine to vinegar when wine is exposed to oxygen in the air.
Variants in the genes that govern this process may alter the body's ability to metabolize alcohol. Which combination of these variants a person carries may either increase or decrease that person's susceptibility to alcohol dependence. The genetic condition is a case of susceptibility because alcohol dependence is not entirely genetic but also influenced by behavior. Obviously, strict abstinence from alcohol consumption prevents alcohol dependence regardless of which genetic variants a person carries. But for those who regularly consume alcohol, susceptibility to alcohol dependence may vary depending on genetic constitution, as well as on how often and how much alcohol they consume.
As a specific example, certain combinations of variants in genes called ADH1B, ADH1C, and ALDH2 cause acetaldehyde, the product of the first step, to accumulate to excessive levels when a person consumes alcohol. Some variants increase the rate of the first step (conversion of ethanol to acetaldehyde); others reduce the rate of the second step (conversion of acetaldehyde to acetate). In either case, the result is similar: acetaldehyde accumulates to high levels, causing a reaction named facial flushing syndrome or alcohol flush reaction. The word syndrome is appropriate because the combination and degree of symptoms often vary, depending on the individual's genetic constitution and the amount of alcohol consumed. Symptoms may include facial reddening, redness in other parts of the body, nausea, headache, confusion, dizziness, and blurred vision, often with a reduction in the pleasant effects that come with the initial stages of inebriation. People who suffer from facial flushing syndrome after alcohol consumption are often hesitant to consume large amounts of alcohol, so the syndrome decreases their susceptibility to alcohol dependence. Some medications used to treat alcohol dependence cause facial flushing syndrome, creating an unpleasant sensation when alcohol is consumed as they inhibit conversion of acetaldehyde to acetate.
Some common terms for facial flushing syndrome are “Asian glow,” “Asian blush,” and “Asian flush” because this syndrome is more common in people with ancestry from east Asia, especially eastern China, Japan, and the Korean Peninsula. Like many other genetic conditions, it is not exclusive to people with a certain ancestry, simply more frequent among them—a fact that led the author of a popular article in Yale Scientific to conclude: “Maybe it's time, then, to think of a new name for ‘Asian glow.’”12
Several of the variants that cause the syndrome originated anciently in east Asian populations and have spread among their descendants. One of the best-studied examples is a derived variant in the ADH1B gene. This variant increases the conversion of ethanol to acetaldehyde by about a hundredfold compared to the ancestral variant.13 It is unusual because most derived variants reduce or eliminate the function in the products they encode when compared to the ancestral variant, whereas this one increases its function. Like many of the examples we've already discussed, it originated from a single base-pair change:
The original geographic distribution of this variant is very distinct, abruptly changing along an ancient north-south linguistic and cultural divide in east Asia. The region where it is most prevalent is on the eastern side of this divide, including what is now eastern China, the Korean Peninsula, and Japan.14 People who carry this variant are susceptible to facial flush syndrome. A second variant in this gene, which arose against the background of this first variant, is found in localized populations in extreme eastern China, the Korean Peninsula, and Japan. It further exacerbates facial flush syndrome in people who carry both variants. And there is evidence in DNA that natural selection has favored these two variants together, perhaps because they strongly inhibit alcohol dependence.15
Both of these variants arose in the east Asian ancestors of the linguistic and ethnic groups that occupied this region in ancient times. Geographic and cultural restrictions on mating account for the fact that these two variants are largely associated with historic ethnic populations in well-defined parts of east Asia. These restrictions inhibited, but did not entirely prevent, the spread of these variants beyond the cultural boundaries of these populations. Because of emigration during modern times, these same variants are now present in many people elsewhere in the world who have ancestry from eastern China, Japan, and the Korean Peninsula.
Associations of alcohol dependence with several different variants in the genes that govern alcohol detoxification are apparent in different populations throughout the world, detected in people with Asian, African, European, Middle Eastern, and Native American ancestry, among others.16 Considerable attention has been directed toward Native Americans who reside on reservations in the United States, where alcohol dependence has been an extremely serious issue ever since reservations were created, afflicting the majority, and often the vast majority, of adults who live on reservations.
News stories, public protests, a documentary film, a class-action lawsuit, blogs, and books have made Whiteclay, Nebraska, infamous for alcohol abuse. As is the case on several reservations, alcohol cannot be sold on the Pine Ridge Indian Reservation, which is located immediately north of Whiteclay across the Nebraska–South Dakota border. Chris Hedges and Joe Sacco, in their book Days of Destruction, Days of Revolt, offer a stark description of the town:
Whiteclay, an unincorporated village that exists for only a block and a half before vanishing into the flatlands of the surrounding prairie, has only five or six permanent residents. It exists to sell beer and malt liquor. It has no town hall, no fire department, no police department, no garbage collection, no municipal water, no town sewer system, no parks, no benches, no public restrooms, no schools, no church, no ambulance service, no civic organizations, and no library…. The liquor stores dispense the equivalent of 4.5 million 12-ounce cans of beer or malt liquor a year, or 13,500 cans a day…. Whiteclay's clients, however, are some of the poorest people in the country. They are Native Americans from the Pine Ridge reservation that is less than 200 feet away, just over the state line in South Dakota.17
That social issues—such as poverty, unemployment, discrimination, substandard health care, poor living conditions, and diminished educational opportunities—contribute to alcohol dependence on reservations is beyond question. However, is there evidence that genetic variants inherent to Native Americans confer increased susceptibility to alcohol dependence? Thus far, genetic analysis of several variants in alcohol-metabolizing genes among Native Americans who reside on reservations shows some statistically reliable correlations of alcohol dependence with certain variants. In some cases, the association is negative; the derived variants protect against alcohol dependence.18 Other research suggests that alcohol dependence may be associated less with alcohol-metabolizing genes and more with variants in other genes that confer a generalized craving for addictive substances, including alcohol, methamphetamines, and cocaine.19 The correlations identified thus far, however, are relatively mild. The evidence collectively indicates that, although genetic constitution may contribute some degree of either predisposition or protection, deplorable social and economic conditions on reservations are the overriding factors responsible for the rampant abuse of alcohol and other addictive substances.
Many of the variants we've examined so far arose from mutations that originated less than twenty thousand years ago in localized populations and have spread beyond their regions of origin more recently. However, even the most ancient variation that arose in Africa and is retained in people worldwide is associated with geographic differences in health.
One of the best-studied examples is the AGT gene, which regulates blood pressure. A derived variant is associated with lower blood pressure, which confers lower incidence of heart disease in people alive today. This variant is very old, having first appeared in Africa before the ancient out-of-Africa migrations. Both variants are now present in populations throughout the world but are distributed unevenly. The ancestral variant is more common in Africa, as well as in some regions of
the world outside Africa. The derived variant bears the marks of a selective sweep in several places where it is more prevalent, outside Africa.20 One possible explanation for the uneven distribution is natural selection for salt regulation. This gene regulates the amount of salt retained by the body, and the ancestral variant tends to cause salt retention, a trait that was advantageous in parts of the world where dietary salt was in short supply, which was the case in much of Africa. Other parts of the world have abundant salt, however, and in these regions, salt retention can be a liability because excess salt increases blood pressure. Ancient diets probably varied in the amount of salt they had, resulting in different effects of natural selection.
These examples of health issues are just a very small sampling of hundreds associated with variants in DNA dispersed among the world's people. Ancient African variants as well as more recent variants are distributed unevenly throughout the world's human population, and the incidence of diseases influenced by these variants is often correlated with geographic ancestry. A combination of factors is responsible for this nonuniform distribution of variants, including where and when mutations originated, emigration and settlement patterns of ancient humans, historic mating and cultural practices, geographic barriers and topography, climate, random fluctuations in variant frequencies from one generation to the next, and the influence of natural selection.
Throughout much of human history—including recent history, right up to the present—false assumptions about the relationship of race, ancestry, health, and inheritance have abounded. In some cases, racist misconceptions reinforced these false assumptions. Perhaps nowhere is this more evident than with the history of sickle-cell disease in the United States. Sickle-cell anemia has been known as a specific disease for little more than a century, first identified in 1910 in an African Caribbean young man who was a student in the United States.21 In the ensuing years, additional cases of sickled cells in blood were identified, some associated with outward symptoms of sickle-cell anemia but most without symptoms (the genetic distinction between sickle-cell trait and anemia remained unknown until 1949), which contributed to a plethora of false assumptions prior to that time.22 According to two physicians writing in 1930 about what later was identified as sickle-cell trait, “the sickler who presents even mild anemia is a subnormal individual and even though he may not be regarded as an active case of sickle cell anemia, he is still ill equipped to withstand the vicissitudes of life.”23
Everyone Is African Page 9
