Why We Get Sick (16 page)

It is 2010, and Mary, a woman who was in elementary school in 1995, has just found out she is pregnant. “Well, you are pregnant, all right, Mary. Congratulations! The nurse will be here in a minute to explain the normal procedures, but I do need to find out if you want the standard gene screen. I presume so.”

“Well, what does it involve?”

“The risks are nonexistent these days, but it is expensive unless you have executive-level health benefits.”

“We do have the high-benefits package, but what will the tests tell me?”

“The basic screen identifies forty serious genetic diseases, and then you can get the supplement to look for things like nearsightedness and attention deficit disorder and susceptibility to alcoholism. Most people think it’s worth it.”

“But what if it shows a problem?”

“Yes … well … then we will have to talk about what to do. Probably you wouldn’t want to terminate just for an increased likelihood of alcoholism or something like that, but it is better to know early. At any rate, it is better to find out now rather than after the problem arises, don’t you think?”

“Well, I suppose so, but what am I supposed to do if, say, my baby is going to be nearsighted?”

“Well …”

I
t will be a few years before the comprehensive testing imagined above is available, but we already know the chromosomal locations of many genes and the code sequences of some. The goal of the controversial Human Genome Project is to unravel the
entire code, to find the order of As, Cs, Gs, and Ts that make up the hundred thousand or so genes. When we have the code in hand, we will be able to compare the genes of any individual to those in the standard sequence, thus making it much easier to find abnormal genes.

But is there a “normal” human genetic makeup, as our term
standard sequence
might imply? We are not, of course, all identical. About 7 percent of human genes can differ from individual to individual. For most proteins the variation is low, about 2 percent, while for certain groups of enzymes and blood proteins, 28 percent of genes may have multiple versions. Often, as far as we can tell, different versions of the gene function identically. In other cases, one version (one
allele
) is normal, while the other is defective. In many cases the defective allele is
recessive
, meaning that it has no noticeable effect if paired with the normal allele. If the defective allele is
dominant
, however, even one copy will cause disease.

The problem for an evolutionist is to explain why there is genetic disease at all. Was the professor who gave the myopia lecture right? Are our bodies “bundles of genetic flaws” with legions of disease-causing genes that have not been eliminated by natural selection? Not exactly. There are many genetic defects that are so rare that natural selection has not been able to eliminate them, but they cause relatively little disease compared to more common genes that are, paradoxically, selected for even though they cause disease. We will soon explain how genes that cause disease can be selected for, but first we need to consider how genes work and the rare genetic abnormalities.

All it takes is a single error in the DNA of a sperm or an egg, a C instead of an A, or perhaps a single missing T, to cause a fatal genetic disease. Such errors arise from copying mistakes, from chemical damage, or from ionizing radiation. The wonder is that such errors are not more common. It is estimated that the likelihood of any given gene being altered is one in a million per generation. This means that, on average, about 5 percent of us start life with at least one brand-new mutation found in neither parent. In most cases such mutations have no detectable effects; in others they cause minor effects; in a few they are fatal.

As the individual develops from a single cell to an adult with about ten trillion cells, many more mistakes will creep in. Those that occur after most of the cells in the body have formed are likely to
have little effect. Many mutations code for a protein that works about as well as the original or for a protein that is not even expressed in the kind of cell that has the mutation. If the mutation is fatal to the cell, even that will likely be of no consequence since there are usually plenty of other cells available to do the same job. A mutation in a single cell can, however, cause major problems if it knocks out some crucial part of the machinery that regulates cell growth and division. It takes only a single cell multiplying out of control to create a tumor that jeopardizes the whole organism. This hazard is countered by the multiple mechanisms discussed in
Chapter 12
.

Apart from the difficulties arising from an occasional mutation, how can even an enormously long sequence of only four chemical symbols manage to code for a complete human being? We know quite a bit about how DNA reproduces itself, how it produces RNA, how RNA produces protein molecules, and how these molecules combine to produce microscopic chains or two-dimensional sheets. Beyond that is a vast sea of ignorance in which there are scattered islands of understanding. For instance, we know about some cause-effect relationships and even some details of the machinery of hormonal regulation of tissue development. These isolated points of enlightenment, however, are only the beginnings of a general understanding of animal and plant development.

Even though developmental genetics is still largely mysterious, patterns of genetic transmission are well worked out. At conception, each of us got a copy of each gene at each locus on each chromosome from each parent. A single complete complement of genes (collectively a
genome
) is a random sample of a gene from each locus of the two complete genomes of each parent. So each of us, having two parents, must have two copies of each gene, two complete genomes that together constitute the
genotype
. What we observe in organisms is the
phenotype
, the expression of the genotype as influenced in the course of individual development by many subtle environmental factors. Sexual reproduction is a random shuffling of the genotypes of parents to provide the unique genotype of each offspring. If the shuffling, at a particular locus, gives identical copies of the same gene from both parents, the offspring is
homozygous
at that locus. If it gets a different contribution from each parent, it is
heterozygous
.

A gene will have some average effect over the large number of individuals in which it finds itself over the course of generations, but its
effect in any given individual may be quite different from the average. Genes interact with one another and with the environment in determining the features of a phenotype. So a sexually produced individual is unique in many ways and may differ strikingly from either parent. The development of one fertilized egg into two offspring (identical twins) is an asexual reproductive process that produces two individuals with the same genotype.

O
f the thousands of serious genetic diseases, the vast majority are rare, affecting fewer than one in ten thousand people. Most of these diseases result from recessives, genes that don’t cause any trouble except in individuals unlucky enough to get two copies, so there is no normal allele at that locus. This misfortune becomes more likely if you marry a relative, who will have more genes identical to yours than a non-relative will. This is why marriages between close relatives are more likely to produce abnormal babies.

It is hard for natural selection to eliminate a deleterious recessive gene. If, as is likely, people heterozygous for a rare recessive have no disadvantage, the rate of adverse selection may be so small that natural selection cannot depress the gene frequency further. If a gene is present in one in a thousand individuals and people normally marry nonrelatives, then on average only one in a million will be homozygous. Even if all of these unfortunate people die early in life, the effect of selection is weak. In this situation, new mutations can often create the defective gene as fast as natural selection eliminates it, because as the gene frequency decreases, the prevalence of homozygous individuals decreases even faster. A lethal recessive gene that is created by mutation in one out of a million pregnancies will stabilize in frequency at about one in a thousand individuals. This is indeed a situation in which the power of natural selection is limited.

Dominant genes are another matter. If you have even one copy of a dominant gene that causes a disease, you get the disease and, on average, so will half your children. One of the best known such genes causes Huntington’s disease. Most people with this disease have no
symptoms until their forties, when their memory fades and their muscles begin to twitch. Some of their nerve cells steadily degenerate until these people cannot walk, remember their own names, or care for themselves. This disease is a particularly vivid example because of its devastating effects and because all known cases can be traced to a small number of European families in the 1600s. One of the men migrated to Nova Scotia. The gene and the disease have been passed on to hundreds of his descendants, including the folk singer Woody Guthrie. In the 1860s a Spanish sailor from Germany, Antonio Justo Doria, settled on the western shores of Lake Maracaibo in Venezuela. His descendants now form the greatest concentration of people with Huntington’s disease. Steady detective work and fabulous luck have enabled geneticists to pinpoint the Huntington’s gene on the short arm of chromosome 4.

This brings us back to the mystery: Why hasn’t this devastating gene been eliminated? The answer is that it usually causes little harm before age forty and thus cannot substantially decrease the number of children born to someone who later develops Huntington’s disease. In fact, some studies have suggested that women who later develop Huntington’s disease may have more than the average number of children. The reproductive rate of men is somewhat decreased, but net selection against the gene in modern societies must be very slight. Studies estimate that one out of twenty thousand people in the United States have the gene for Huntington’s disease.

This disease again illustrates a principle emphasized in
Chapter 2
: natural selection does not select for health, but only for reproductive success. If a gene does not reduce the average number of surviving offspring, it may remain common even if it also causes a devastating illness. There are genes that cause disease but may possibly increase reproductive success (at least in modern societies)—notably the genes that cause manic-depressive illness. During mania some patients become sexually aggressive, while others accomplish feats that make them successful and thus attractive. If a gene increases the rate of successful reproduction—by whatever mechanism—it will spread.

Table 7-1 offers a classification, based on the beneficiary, of genes that cause disease. While there are many diseases that result from mutation and the limitations of natural selection, they account for relatively little sickness. In most cases the story is more complicated and interesting.

T
ABLE
7-1 B
ENEFICIARIES OF
G
ENES
T
HAT
C
AUSE
D
ISEASE

The individual with the gene:

Other individuals:

The gene at the expense of the individual:

S
ickle-cell anemia is the classic example of a disease caused by a gene that is also useful. The gene that causes sickle-cell disease occurs mostly in people from parts of Africa where malaria has been prevalent. A person who is heterozygous for this gene gets substantial protection from malaria because the gene changes the hemoglobin structure in a way that speeds the removal of infected cells from the circulation. Homozygotes, however,
get sickle-cell disease. Their red blood cells twist into a crescent or sickle shape that cannot circulate normally, thus causing bleeding, shortness of breath, and pain in bones, muscles, and the abdomen. People with this disease suffer terribly in childhood, and until recently all of them died before reproducing. An individual homozygous for the normal allele has perfectly good red blood corpuscles but lacks the special resistance to malaria. The sickle-cell gene thus illustrates
heterozygote advantage
. Because of their resistance to malaria, heterozygotes are favored over both kinds of homozygotes: Homozygotes for the sickle-cell allele have low fitness resulting from sickle-cell disease, while homozygotes for the normal allele have low fitness resulting from their vulnerability to malaria. The relative strength of these two selective forces determines the allelic frequencies. Thus, a gene that causes a lethal childhood illness and a gene that makes one susceptible to malaria can both be maintained at high frequencies in the population.