The collective burden that salient genetic defects place on the human population is referred to as genetic load, and many quantitative attempts have been made to weigh this millstone. Representative summaries indicate that chromosomal abnormalities associated with medical ailments are displayed by about 1 percent of the human population, known single-gene disorders by another 1 percent, congenital genetic malformations by 2 percent, and other overt disorders with an evident genetic component by an additional 1 percent. Thus, at least 5 percent of the human population is known to be afflicted with obvious genetic disabilities. About 20 percent of infant deaths are attributable to genetic defects, as are nearly 50 percent of pediatric and adult admissions to hospitals. Apart from the tremendous burden to affected individuals, the costs to society are staggering.25
Although medically significant, these tabulations provide only a minimum estimate of genetic load because of serious downward recording biases. First, most of these figures exclude the vast majority of diseases for which hereditary components are suspected but ill-defined, including circulatory disorders, various cancers, and the multitudinous disorders of normal aging. These conditions typically have multifactorial genetic (and environmental) involvement, but the actions of individual genes in the complex nexus of causality can be difficult to pinpoint. Second, the figures exclude ubiquitous genetic defects that strictly speaking are not heritable because they are confined to somatic as opposed to germ cells. Many cancers qualify. Third, the figures fail to include genetic defects that go undetected because they merely lower fertility, or because they terminate life well before birth, yet these are precisely the biological arenas where the most serious selective action against compromised genotypes takes place. For example, chromosomal defects alone occur in about 20 percent of pregnancies, and genetic flaws appear to be responsible for more than 50 percent of all miscarriages.
The genetic gods produce a vast number of inborn errors of metabolism. This documented truth raises troubling epistemologi-cal issues for both religious (providential) and scientific discussion.
From a religious perspective, genetic malfunctions pose a number of ethical enigmas. Why would an omnipotent and loving god cut life terribly short, prolong suffering over decades, devise hideous self-torturing behavior, or send disease to only certain age groups or ethnic groups? How could a benevolent god countenance such horrific human suffering? Humans through the ages have proposed any number of reasons. Perhaps a god does not exist, or is less than all-powerful. Maybe a god possesses supreme powers but fails to exercise them. Perhaps a god purposefully designs genetic errors as a test of the afflicted's faith, or as finely tuned damnations for infractions of his will. However, the astonishing severity of many of the punishments, and their apparent quirkiness of allocation, fail to fit the crimes. Indeed, genetic punishment frequently is meted out to those normally perceived as most innocent: unborn fetuses, and the aged or already infirm. Perhaps an omnipotent god's concepts oflove, fairness, suffering, and morality all differ fundamentally from the usual meanings of these words to most of us.
Another class of providential explanation is that sufferings in this life are spiritual tolls for crimes committed in past lives. In quite a different sense, this explanation has an element of scientific truth. Many genetic defects in the present human population were inherited from our ancestors, and not generated de novo in the current generation. The genes in our hereditary blueprints do have past lives that can haunt us.
Inborn errors of metabolism pose profound explanatory challenges to scientific beliefs as well as to religious beliefs. Why do genetic mutations detrimental to fitness persist in human populations? Why hasn't natural selection's concern with reproductive performance eliminated the human suffering that surely has negative impacts on survival and reproduction? The scientific answers are clearer. Inborn errors of metabolism exist not because of the malfunctions they produce, but despite them.
Many of the rarer inborn metabolic disorders are encoded by mutations not yet eliminated by natural selection, either because the mutations are partially camouflaged, or because their harmful effects are modest in relation to the rate at which the mutations arise. Camouflaging can occur in at least three ways. Alleles responsible for many genetic diseases, such as alkaptonuria, have deleterious consequences only in homozygous individuals. In heterozygotes, these alleles are shielded from natural selection's view because their poor metabolic performance is compensated by the normal allele. Also, many genetic disorders such as Alzheimer disease have postreproductive onset. Contemporary natural selection is blinkered from the scrutiny of genetic defects whose consequences are postponed beyond reproductive age because these defects normally fail to lower an individual's reproductive fitness. In a sense, senescence and death themselves are inborn genetic diseases, and an important evolutionary question is how to account for the ubiquitous occurrence of these phenomena. A third form of evolutionary camouflaging arises because deleterious effects of some mutant alleles are evident only in some environments. Phenylketonuria is an autosomal recessive disorder characterized by severe mental retardation due to the accumulation of pheny-lalanine and related metabolites in the body. A mutation that knocks out the function of the enzyme phenylalanine hydroxylase is responsible. However, if the condition is diagnosed in early infancy, a diet low in phenylalanine can compensate for the enzyme's inactivity to the extent that some patients achieve normal intelligence.
Many genetic disorders typically are not discussed as disorders at all because their harmful expression is confined to environments viewed as aberrant. For example, our genetic inability to produce vitamin C is of no health consequence when ascorbic acid from fresh fruits and vegetables is available. However, scurvy results when dietary access to vitamin C is limited, as often was true for European sailors on prolonged voyages during the fifteenth to nineteenth centuries. Conversely, some genetic conditions such as postanesthetic apnea and many disorders of the elderly have become increasingly visible in our modern environment.
In conjunction with genetic, developmental, and environmental camouflaging, recurrent mutation also contributes to the maintenance of deleterious alleles in human populations. The theory of mathematical population genetics shows that the expected frequency of a harmful allele at any gene is influenced by a balance between the origination rate of that allele by mutation (m) and the selection-mediated loss of the allele due to its fitness-reducing effects. Over the long term, the tug of war between the forces of recurrent mutation and purifying selection tends toward an equilibrium population frequency for the deleterious allele.26 These allele frequencies are low but nonzero for realistic mutation rates (which are typically 10-5 or lower for point mutations per gene per generation). The balance achieved between deleterious mutations and cleansing natural selection accounts for the observed frequencies of many rare genetic disorders.
For example, a recessive lethal allele that arises at mutation rate m = 10-5 achieves a mutation-selection balance at a population frequency of about q = 0.0032. Death results when two copies of the defective allele appear together in an individual, an occurrence expected with probability q2 = 10-5. In other words, in a population of size 1,000,000, about ten people per generation are expected to die from this hereditary disorder, a rather typical figure for many serious genetic diseases. Some gross chromosomal disfigurations, such as loss of the Y or the presence of three copies of chromosome 21, occur spontaneously at higher frequency (e.g., m — 10-2 - 10-3), thus accounting for the higher incidences in human populations of genetic disorders such as Turner and Down syndromes.
In some cases, natural selection itself acts in a manner that maintains high frequencies of genotypes that at first examination appear deleterious. An example involves the most common human enzymopathy known: glucose-6-phosphate dehydrogenase (G6PD) deficiency, which affects more that 400 million people worldwide. This genetic condition, inherited on the X chromosome, can result in severe hemolytic anemia following an infection, ingestion of certain drugs, or consumption of particular foods.
Why hasn't natural selection scrupulously culled such deleterious alleles from the human gene pool, driving them to a low frequency balanced only by recurrent mutation? The answer appears to be that the G6PD deficiency simultaneously confers upon its bearers a startling reduction (46-58 percent) in susceptibility to malaria, an evolutionary benefit that has compensated for the cost of the deficiency.27
Another genetic polymorphism related to malarial resistance involves a hemoglobin gene. Under low oxygen conditions, the red blood cells of individuals homozygous for the "S" allele assume a rigid configuration, clog blood capillaries, and produce a painful and life-threatening sickle cell disease. The S allele reaches frequencies of 20 percent in some African populations, far higher than anticipated from recurrent mutation alone. An explanation long has been known. The S allele has attained high frequency because it also affords heterozygous individuals an increased resistance to malaria. Thus, in malarial regions, heterozygotes have a fitness advantage over normal (A/A) homozygotes, and they also have an advantage over S/S homozygotes by virtue of a near freedom from sickle cell disease. Natural selection operates so as to retain both alleles in frequencies determined by the relative fitnesses of the two homozygous classes.28 Under the rules of Mendelian inheritance and sexual reproduction, heterozygotes do not automatically pass these advantages directly to their offspring, and in each generation new homozygotes are produced. This produces a segregational load that contributes to the total genetic burden that humans bear.
In summary, mutational and selective influences provide the proximate scientific explanations for why humans are burdened with inborn errors of metabolism. These processes are oblivious to pain and suffering—they are both mindless and amoral. But why do these natural evolutionary processes themselves exist? Why do harmful mutations arise? Why are they shuffled and redistributed through sexual reproduction in a seemingly random fashion? How can the genetic gods (or any other gods) play such games of dice with our lives? As we shall see, science has provisional answers to these questions as well.
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