By RANDOLPH M. NESSE take off my glasses and gaze at the sud-

denly blurry scene out my window. Peo-ple walk by, but I can't recognize them.The leaves on the trees look as though

they have been colored by a child with a thick green crayon. Like me, a full quarter ofthe population in modern societies is nearsighted. We get along fine today, but how wouldwe have fared in the ancestral environment? Many of us would probably have survived assecond-rate hunters and gatherers, but some would likely have become tiger food, andothers would have slowly starved because we could not see our prey. By now, the genesthat contribute to nearsightedness should have been strongly selected against. Yet some-how they have persisted.

Why do the genes that cause disease persist? Is natural selection so weak that it cannot

eliminate the genes that contribute to nearsightedness, heart attacks, and cancer? This

hardly seems likely for an evolutionary force that has shaped such exquisite and sturdy

creations as the heart, the ear, and the eye. Furthermore, as geneticists have long shown,

selection forces should rapidly eliminate genes that cause serious disease. If all members ofa population have one copy of a recessive gene that is lethal when homozygous (that is,

when two copies occur in the same person), that gene will, after just eight generations,

be present in only 10 percent of the population. After 65 generations, the single copy of

the gene will be present in less than 1 percent of the population, and the disease will

affect only 1 out of every 10,000 people. Deleterious genes that are dominant-meaning

that disease occurs in people with only one copy-are weeded out much faster. Natural

selection is not weak-it eliminates most disease-causing genes far faster than they are cre-

ated by mutation. How, then, can we explain their persistence?

An evolutionary perspective

offers new insights about disease and why it persists.

.~~..

J

itb a Woman, 1941d Constellations in love wrt by Joan Mir6: Ciphers {/II

..e?roponents of a new approach called Darwinianmedicine are trying to explain why these genes are socommon as part of a broader quest to discover why ourbodies aren't more reliable. The emerging answers yielda richer view of the human body. Increasingly, we areseeing the body less as a Platonic ideal and more as abundle of evolutionary compromises. We are learningthat our vulnerability to each disease is a trait that per-sists in the face of natural selection for very specific rea-sons. As biomedical researchers develop technologies foridentifying and altering disease-causing genes, ourunderstanding of these reasons clearly assumes a greatlyenhanced practical importance.

OLD ANSWERS ARE INADEQUATE

~t is true, of course, that the genes that cause somet7 abnormalities may persist because people with theabnormality have just as many children as other peo-ple. The genes that predispose a person to manic-depres-sive illness, for instance, may not decrease his or herreproductive success and could, according to some, evenincrease it. But what about disease that causes earlydeath? Some have argued that the relative safety of mod-ern life can explain the prevalence of many diseasesbecause it weakens natural selection. To the extent thatsome forces of natural selection are now weaker, this hashappened only extremely recently in evolutionary terms.Even genes that now have no effect on reproductive fit-ness will not, by chance, become common in just a fewgenerations.Another common supposition is that DNA replica-

tion is so inexact that new errors accumulate faster thannatural selection can eliminate them. To be sure, somediseases do seem to be caused simply by mutations-new errors in the DNA code that arise as fast as natu-ral selection eliminates them. In fact, there are thousandsof unusual genetic diseases that are caused by rare reces-sive genes. Such genetic mistakes are difficult for naturalselection to eliminate entirely. For instance, if 1 of every100 people carry such a gene, then 1 in 10,000 will con-tract the disease, while if 1 in 1,000 people carries thegene, only 1 in 1,000,000 people will get the disea e.As the gene becomes increasingly rare, the force of selec-tion fades even faster, so natural selection cannot elimi-nate the gene completely. For diseases that affect fewerthan 1 in 20,000 people, this may be a sufficient expla-nation. But when we turn to the more common geneticdiseases, mutation does not occur often enough to out-

RANDOLPH M, NESSE teaches in the Department of Psychiatry at theUniversity of Michigan. He is coauthor, with George Williams, of Why WeGet Sick: The New Science of Darwinian Medicine (rimes Books, 1995).

34 MAY/JUNE 1995

weigh the force of natural selection. Other explanationsare necessary.The simplest is that some genes are especially vulner-

able to mutation. For instance, the gene that causesDuchenne's muscular dystrophy is damaged by muta-tion 10 to 100 times more frequently than most othergenes, undoubtedly because it is huge-many times thelength of the average gene, with some 2 million basepairs that take up almost 1 percent of the X chromo-some (as compared with the typical gene, with closer to1,000 base pairs.)Nonetheless, new mutations cannot begin to explain

the continuing prevalence of something as common andharmful as cystic fibrosis-a fatal hereditary respira-tory disease that occurs in childhood. Quite simply, intrying to explain the persistence of disease, the oldanswers look less and less adequate.

GENETIC QUIRKS

("j/he genes that contribute to the bulk of modemV human disease were not harmful in our ancestralenvironment. Some genes that cause atherosclerosis, orso-called hardening of the arteries, for instance, wouldbe harmless if our diet was 15 percent fat instead of 40percent. Because these genes were harmless, or evenhelpful, in our original environment, we call them"quirks" to remind us that they are not really deficits-that is, until they interact with altered environmentalfactors.

earsightedness (myopia), is a good example. Itundoubtedly has a genetic component. According to aUniversity of California study, the prevalence of myopiain late childhood is 12.2 percent if both parents aremyopic, 8.2 percent if one parent is affected, and only2.7 percent if neither parent is affected. Genes are not,however, the entire explanation. earsightedness warare in Eskimos prior to this century, as it is in mosthunter-gatherer populations today. But in the decadesafter Eskimo children began attending school, the rateof myopia quickly increased to the same 25 percentprevalence found in most modern societies. Myopia, itseem ,is completely dependent upon both environmen-tal and genetic factors. If you have the genes and go toschool in childhood, you will almost certainly become

Art by Joan Mira: Personages, Birds, Stars, 1946

myopic. But if you don't have the genes, school won'thurt your eyes, and if you don't go to school, the geneswill cause no harm.What exact environmental factors cause myopia?

Investigations into the responsible mechanism revealone of the wonders of the body. When researcherplace cloudy lense over the eyes of young chicks ormonkeys, these animals' eyeballs keep growing longeruntil they are profoundly near ighted. The exact mech-anisms have yet to be completely understood, but itappears that natural selection has shaped a biologicalystern that induces growth in the eye whenever theretinal image is blurry. Thi is u eful indeed. The mech-anism that automatically focuses slide projectors is sim-ilar, except of course, that it can go back and forth.

TECHNOLOGY RIWIEW 35

HIDDEN BENEFITS

Eyes, unfortunately, can onlygrow, not shrink. If the systemhappens to overshoot, perhapsbecause of unnatural exposureto close work at an early age,the resulting nearsightednesslasts a lifetime.Why do some people have

genes that make them especiallyvulnerable to nearsightedness?Perhaps they would have aslight advantage in a naturalenvironment, where they mightexperience short periods ofblurry vision during childhood.Or perhaps the gene is a "quirk"that has no effect on fitness inthe natural environment. Ineither case, such an evolutionaryremnant or genetic quirk isdetrimental to people in mod-ern society.Many genes that contribute

to the current epidemic of heartdisease seem to be quirks thatare dangerous only when peo-ple eat a high-fat diet. Theywould likely be harmless forhunter-gatherers who exercisedmuch of the day in their effortsto gather vegetables (with highfiber) and hunt meat (that wasonly 10 percent fat). Likewise,according to Emory Universityresearcher Boyd Eaton and col-leagues, some genes that con-tribute to the enormous frequency of breast cancer inwomen in modern societies may have had few harmfuleffects in societies in which women became pregnantsoon after puberty, breast-fed their babies for years, andthen quickly became pregnant again.Some adult-onset diabete may be caused by genes

that were once useful. Geneticist James Neel discoveredI

that the Pima Indians in the Southwestern United Stateexhibit a marked tendency toward obesity and adult-onset diabetes-but only since they abandoned theirtraditional diet for a modern, Western one. Neel pos-tulates that today's extraordinary incidence of adult-onset diabetes in this group-approaching 50 percentof the population over the age 35-eould be due to thesame "thrifty genotype" that stored calories and onceconferred an advantage in an environment wherefamine was a strong force of selection.

36 MAYI]UNE 19')5

(j> enetic quirks that cause harm only in the modern& environment make up just one category in a Dar-winian framework. Sometimes continuing, but oftenhidden, benefits from the genes associated with a diseasecan help explain why these genes have persisted over thecour e of generations. The most widely recognized phe-nomena in this category are genes that may offer a so-called heterozygote advantage-an advantage, in otherwords, that occurs when a person has only one copy ofa given gene where two are needed to cause disease.Take, for instance, the case of sickle cell disease. Indi-

viduals who have two genes (homozygotes) for sicklecell hemoglobin (HbS) produce rigid, sickle-shaped cellsthat can clog small blood vessels. These individuals haveepisodes of terrible bone pain, and they die very young.

Arl by Joan Mira: Dancer, 1925

Itwould seem that selection should eliminate a gene thatso drastically decreases fitness, but it doesn't. Sickle celldisease affects 1 in every 500 African Americans in theUnited States, and 8 percent of the black population inthe United States carries the gene.An explanation for the prevalence of sickle cell dis-

ease was first suggested in 1949 by the great Britishbiologist and evolutionist WB.S. Haldane, who notedthat the gene for HbS occurred in up to 14 percent ofpeople in areas of Africa where malaria had been preva-lent, and that the frequency of the gene, as plotted on amap of Africa, matched the frequency of malaria. Hethen wondered if heterozygotes (people with one nor-mal hemoglobin gene and one for HbS) might be pro-tected against malaria and thus have a higher fitnessthan either people with two versions of the gene fornormal hemoglobin or those with two copies of HbS.The evidence for this heterozygote advantage is now

overwhelming. African individuals with sickle cell trait

Livingstone has documented through studies of agri-cultural methods and the frequency of malaria, becausehuman slash-and-burn agricultural methods opened upbodies of stagnant water to the sunlight required by thespecies of mosquito that serves as the principal vectorfor malaria.For other genetic causes of disease, the explanations

become more complex and uncertain. Consider, forexample, cystic fibrosis, a fatal disease that affects 1out of every 2,500 newborns of European origin. Giventhis incidence, we can calculate that the disease-causingrecessive gene must be present in lout of every 25 peo-ple from this group. This is an enormously high fre-quency for a gene that causes a fatal genetic disease-one that cannot be explained simply by mutationsalone. There must be some benefit.The recent discovery of the specific gene associated

with cystic fibrosis has revealed further information.About 70 percent of cases are accounted for by a single

are less likely to get malaria and less likely to die from it,and volunteers with sickle cell trait who received amalaria inoculation became ill less often and had fewercomplications than people with normal hemoglobin.When malaria is no longer present, selection tends todecrease the frequency of the HbS gene, as has alreadyhappened in the United States even in the short periodsince Africans first arrived.Sickle cell trait has become the exemplar of a u eful

gene that also cause disease, and the phrase "heterozy-gote advantage" has become almost a synonym forexplanations of the persistence of a gene that causesdisease. In fact, however, the sickle cell case is somewhatunusual even as a case of heterozygote advantage. Itsbenefits are limited to certain locations (where malariais prevalent). Also, it consist of a single mutation.Finally, this mutation seems to have arisen in only thepast 10,000 years, probably, as anthropologist Frank

mutation, but a myriad of other mutations can alsocause the problem. According to Francis Collins, direc-tor of the Human Genome Project, the multiple varia-tions suggest that they may have conferred orne het-erozygote advantage in the Northern European popula-tion. And, in fact, recent studies by Sherif Gabriel andcolleagues at the University of North Carolina suggestthat the cystic fibrosis gene may protect against deathfrom cholera. When injected with cholera toxin, micethat have one copy of the gene have half as much diar-rhea as ordinary mice, and mice with two copies of thegene do not get diarrhea.Many other genes need similar investigation to look

for possible benefits. For instance, up to 10 percent ofAshkenazi Jews (from Eastern Europe) carry the genefor Tay-Sachs, a disease in which the lack of a particularenzyme (called hexosamidinase A) causes progressiveneurological deterioration and death in childhood. Data

TECHNOLOGY REVIEW 3

on infection rates and population distributions suggestthat heterozygotes may have been protected againsttuberculosis, a major force of selection in AshkenaziJews. Jared Diamond, a physiologist at the Universityof California at Los Angeles, further notes in a recentdiscussion in the journal Nature that this group is alsoespecially vulnerable to two other congenital metabolicdiseases called Gaucher and Nieman-Pick. All three dis-eases involve disruptions of the same class of enzymes,and this supports the possibility that all may be selectedbecause of similar functions.Geneticists have long held that if a disease is caused by

multiple different versions of a gene, this strongly sug-gests that natural selection has played a role in main-taining the mutations. Geneticist Victor McKusick ofJohns Hopkins School of Medicine made such a case in1979 for Tay-Sachs, noting that if two or more versionsfor the Tay-Sachs mutation were discovered, it would be"a powerful argument for selection." Left to chance,McKusick and others explain, multiple versions wouldnot be likely to rise to significant frequencies. In 1989,two distinct common mutations were found in patientswith Tay-Sachs disease. In the case of Gaucher's dis-ease, five common mutations account for almost all thecases. With these important clues in hand, we now needto investigate further the selection force--perhaps resis-tance to tuberculosis-that has maintained these genesin Ashkenazi Jews.

GE ES THAT BOTH HARM A D BENEFIT THE BEARER

("jLor practitioners of Darwinian medicine, the pic-JT ture becomes significantly more complex withthe important realization that some genes harm thesame person they benefit. Such an understanding isoften lost in the common misperception that an indi-vidual gene erves only a single purpose. The fact is thatmany genes are well known to be pleiotropic-that is, tohave multiple effects. If one of the effects of a pleiotropicgene i beneficial, then the gene may be selected fordespite its other harmful effects.Some of the best examples may be some genes

related to aging. In a theoretical, but nonetheless clas-sic, example offered in 1957, biologi t GeorgeWilliams noted that a gene causing calcium to bedeposited in the arteries might be selected for if it alsocaused bones to heal more quickly. Because every pop-ulation has more young people than old, the force ofselection is stronger earlier in life, and a small benefitin youth can thus outweigh a ubstantial or even fatalharm late in life.Physiologist Jared Diamond has proposed an expla-

nation for some diabetes that may depend on this

38 MAY/JUNE 1995

--~•

mechanism. A gene called DR3 has been shown to bevery common in children with diabetes. If one copy ofthe gene is present in only one parent, one-half of theoffspring should have the gene. But the observed rate isdose to two-thirds, ostensibly defying the laws ofgenetics. Diamond explains this discrepancy by not-ing that as many as eight out of ten conceptions rou-tinely end in miscarriages, many of which are nevernoticed. The DR3 gene in a fetus, he postulates, maygreatly decrease the miscarriage rate and thus perpet-uate itself despite causing severe diabetes. If confirmed,this will perhaps be the ultimate example of apleiotropic gene that is selected because of benefitsearly in life despite the fact that it causes severe prob-lems later.A genetic tendency to gout, a painful joint disease,

may arise in a converse manner. Gout is caused by pre-cipitation of uric acid crystals in the joint fluid.Researchers have observed that the blood levels of uricacid in a wide variety of species are directly related tothe species' life pan. While the mechanisms are still ill-understood, many believe that uric acid's function asan antioxidant may prevent some effects of aging. Wehumans, with our long life-span, have higher level ofuric acid than other species-so high that gout some-

times results. An evolutionary perspective suggeststhat the genes that cause these high uric acid levelspersist because they give most of us longer lives.

SEXUAL ANTAGONISTS AND OUTLAWS

4full accounting of the evolutionary forces thatVl/ maintain the frequencies of genes that cause dis-ease must also take several other factors into account.For one thing, some genes that benefit women mayharm men, and vice versa. Hemochromatosis, forinstance, a metabolic disease leading to liver damage

and diabetes, is caused by a recessive gene that vastlyincreases the efficiency of absorption of iron from thegut. The excess iron damages men's livers by middle age,but women need more iron to compensate for the bloodthey lose with each menstrual period and thus oftenshow no symptoms until late in life. So far, we don'tknow why this disease persists, but it is quite possiblethat the ability to absorb extra iron during the repro-ductive period confers an evolutionary benefit towomen who carry this gene.Oxford geneticist David Haig has recently investi-

gated the possibility that the divergent genetic interests

An by Joan Mir6: Dragon with Red Tipped Wings in Pursuit of a Serpent Spiraling Touwd a Comet, 1951 TECHNOLOGY REVIEW 39

of men and women may have shaped several subtle yetpowerful genetic competitions that cause disease dur-ing pregnancy. He begins with the observation that theoptimal size of a baby that will maximize a female'sgenetic interests is smaller than that for her mate. Thisis not so much because of the dangers of bearing a largeoffspring, but because the female maximizes her repro-ductive success by reserving some nutritional resourcesfor her next offspring, while the male gets no benefitfrom such farsightedness, because his mate s next off-spring may not be his.Haig has found another powerful example of this sort

of conflict in mice. Insulin-like growth factor IT(IGF II)i secreted by the placenta and makes the baby bigger.If the gene is missing, the offspring will be 40 percentsmaller but otherwise normal. The gene that makes thisfactor is active only if it comes from the father. The samegene, if it is transmitted to the fetus from the mother, is"imprinted," that is, chemically changed in a way thatmakes it inactive in that generation so her own IGF IIgene will not make her offspring larger than is in herinterests.When an active copy of the gene comes from the

father, how does the mother defend herself against itseffects? She has another gene that makes another sub-stance, insulin-like growth factor receptor (IGFr), whichspeeds the degradation of IGF IT,thus making her off-spring smaller. The gene that makes IGFr is, sure

40 MAY/JUNE 1995

enough, imprinted in the opposite way from IGF II. Itis inactive if it comes from the father, just what youwould expect from a gene that represents the mother'sinterests in the conflict fathers and mothers wage overthe optimal offspring size. So far, this battle has beenconfirmed only in mice, but something similar may welloccur in humans.Despite benefits that may be conferred dispropor-

tionately between men and women, genes in a givenindividual usually cooperate to create a body that willmanage to insert copies of themselves into future gener-ations. It is useful, however, to note that certain genesadvance their own interests even at the expense of theindividual. The best known of several examples is theso-called T locus on chromosome 17 in mice. Male micewith two copies of this gene always die very young, butabout 25 percent of wild mice carry this genetic trait.The males carrying the trait (the heterozygotes) have areproductive advantage: the gene impairs the ability ofsperm with a normal chromosome 17 to fertilize eggs,so the trait becomes preferentially transmitted. Conse-quently, the proportion of heterozygous males' offspringthat carry the gene is not the expected 50 percent butalmost 90 percent. This increased transmission of thegene more than makes up for the severe decreases inindividual fitness.There is little question that many genes that cause

disease are selected for because of their benefits to theindividual, to other individuals who carry the gene indifferent combinations or environments, or evenbecause of benefits to the gene itself. Can such evolu-tionary insights offer practical help to medical practi-tioners in treating disease? Today's technology is clos-ing in on the sequence of the entire human genome. Thisinformation will doubtless provide a wellspring forfuture study of human biology and for cures of diseasesthat were thought incurable. But the study of evolu-tionary influences on disease reveals our bodies as richand interwoven biological systems. This perspectivesuggests a cautious approach to human gene therapy.For example, a full knowledge of the pleiotropic func-tions of the gene associated with cystic fibrosis-suchas the protection it may confer against cholera-mayomeday give us enough confidence to eliminate it solong as cholera is controlled. But before we alter othergenes, such as tho e that cause aging, we will certainlywant to know the evolutionary forces that su tain them.By studying such evolutionary links, Darwinianmedicine can offer important clues to some of the bio-logical mechanisms that cause disease-dues that couldwell accelerate new kinds of treatments for disparate dis-eases as well a helping to protect us from ill-consid-ered intervention .•

An by Joan Mlr6: Spanish Dancer. J945