The first challenge is to specify whether the object of explanation is a trait universal in the species or variation in a trait (Q1). Attempts to explain universal traits, such as the narrow birth canal, wisdom teeth, and synthesis of bilirubin, proceed very differently from attempts to explain variations in traits, such as skin color, ability to digest lactose, or vulnerability to malaria.
Other universal traits are facultative adaptations such as the capacities for skin tanning, adaptation to high-altitude, callus formation, cough, and fever. Natural selection shaped these protective responses in conjunction with regulation mechanisms that express them when they are likely to be useful. The time scale of such responses can range from instantaneous to a lifetime. Tissue damage arouses pain immediately. Cold causes shivering in minutes. Callus formation and skin tanning take weeks.
Some responses have a longer horizon. When early experiences shape the long-term developmental trajectory of an individual, this is usually described as developmental plasticity (Stearns 1989; West-Eberhard 2003). One classic example remains inadequately documented; babies whose spend their earliest months in hot climates have more sweat glands as adults (Kawahata and Sakamoto 1951). A similar finding in voles is well established; those born at the end of summer have thicker coats (Lee et al. 1987). A review of such environmental influences during human development emphasizes the important distinctions among developmental disruptions (such as from folate deficiency), immediately adaptive responses (such as premature birth to escape an infected uterus), and predictive adaptive responses, such as those that use intrauterine cues to adjust behavior and metabolism to varying environments (Gluckman et al. 2005a,b).
Predictive adaptive responses are an important research area in evolutionary medicine (Gluckman et al. 2005a,b). Responses to cues of two kinds have been studied extensively. Mothers exposed to severe stress give birth to offspring with increased responses to stress (Meaney et al. 2007). Mothers exposed to limited nutrition give birth to offspring prone to obesity, hypertension, diabetes, and atherosclerosis if they grow up in nutritionally rich environments (Gluckman et al. 2005a,b; Barker 2007). In each case, the change is in the direction that would conceivably increase the fitness of an offspring living in environmental conditions similar to those experienced by the mother. Work is ongoing to determine whether these mechanisms are indeed facultative adaptations. In both cases, explication of the epigenetic mechanisms that mediate the effects will likely provide useful guidance, as will data on the prevalence and fitness effects of nutrition availability during pregnancy (Rickard et al. 2010).
Human genes are obvious targets for evolutionary explanation, and population genetics offers reliable methods (Childs 1999; Lewontin et al. 2000). Attention usually focuses on variations, but fixed or very common genes deserve attention also. For instance, most vertebrates have the enzyme uricase, but the hominid line lost the responsible gene in the Miocene, leaving us with high levels of uric acid and vulnerability to gout (Varela-Echavarria et al. 1988; Johnson et al. 2010; Keebaugh and Thomas 2010). Is this because of the antioxidant properties of uric acid, its effect on blood pressure, some other benefit, costs associated with the gene, or just chance? The active reabsorption of uric acid in the kidney suggests some adaptive function, but a definitive answer remains elusive (Álvarez-Lario and Macarrn-Vicente 2010). The answer is important, because it may help to explain the relationship between modern diets, obesity and atherosclerosis (Johnson et al. 2010). A proximate view that assumes uric acid is merely a metabolic byproduct neglects the important possibility that high uric acid levels may also offer fitness advantages.
Genes that give a reproductive advantage can go to fixation even if they harm health. Men would, on average, live 7 years longer if their metabolism and behavior were like that of women. Why aren’t they? Competitive ability increases fitness more for males than females in a polygynous species, while ability to repair tissues increases fitness relatively more for females. Data from multiple species, and from diverse human groups across the past century, support this hypothesis (Kruger and Nesse 2006).
Could genes that make human mood regulation systems vulnerable to mania have become fixed because they give selective advantages, separate from mania, that more than counter-balance the disadvantages of illness experienced by some people? This purely hypothetical example illustrates the possibility that alleles can improve fitness at the expense of health. Of course, the focus is usually on genetic variation and on why individuals with a variant might have advantages as well as disadvantages; this has been proposed for manic depressive illness (Wilson 1998).
The textbook exemplar is the sickle cell hemoglobin allele. Individuals with two copies get sickle cell disease. Individuals homozygous for ordinary hemoglobin are vulnerable to malaria. Heterozygote individuals have decreased vulnerability to malaria and limited symptoms of sickle cell disease; their relative fitness advantage explains the persistence of the sickle cell allele where malaria is prevalent (Livingstone 1960; Wiesenfeld 1967; Piel et al. 2010). This explanation is solid, but it is by no means a generalizable exemplar for evolutionary medicine. The variation is in a single base pair, it is of recent origin, and almost all other documented examples of balancing selection have also been shaped by malaria (Evans and Wellems 2002).
This has not inhibited attempts to propose heterozygote advantage as an explanation for other traits. As the most common fatal disease caused by a recessive allele, carried by 4% of European Americans, cystic fibrosis is a good candidate. While 70% of cases arise from the Delta F508 allele, 1400 other causal mutations have been identified (Collins 1992). Heterozygote mice are protected from dehydration caused by cholera toxin (Bertranpetit and Calafell 1996), and their intestinal cells are resistant to penetration by Salmonella typhi (Pier et al. 1998). Does this explain the high prevalence and diversity of the cystic fibrosis allele? It does not fit well with epidemiologic data showing higher frequencies in northern climates, where death from diarrhea may be less common, but this is weak counter-evidence. Attempts to understand the prevalence of cystic fibrosis illustrate the human tendency to think of alleles as either normal or abnormal, as if they were components in a designed machine. Mutation-selection balance, and mutation vulnerability of the allele, may account for most of the prevalence of the cystic fibrosis, with frequencies perhaps increased because of selective advantages in certain circumstances.
Recessive alleles causing Tay Sachs and other diseases of sphingolipid metabolism in Askanazi Jews have also been attractive targets (Zlotogora and Bach 2003), but definitive conclusions have been hard to find. Analysis of new genetic evidence shows positive selection in Askanazi Jews for ability to metabolize alcohol and lactose, but the frequency of sphingolipid diseases seems better accounted for by bottleneck effects (Bray et al. 2010). Another review considers the general difficulties of reaching firm evolutionary conclusions about the evolutionary significance of recessive alleles and the excessive attention associated with hypotheses about heterozygote advantage (Valles 2010). This review also documents the prevalence of confusion arising from failure to specify the exact object of explanation, and it provides a useful taxonomy of evolutionary explanations for alleles that cause disease (see Table 2).
Table 2. Evolutionary explanations for high frequencies of disease-causing alleles (Valles 2010, 185).
|1||Elevated mutation rate|
|4||Founder effects and genetic drift|
|5||Heterozygote advantage (overdominance)|
Such sophisticated analysis is needed and welcome; however, many mistakes are much more fundamental. For instance, untenable hypotheses based on naïve group selection are published remarkably often. Hypotheses about Mendelian defects such as color blindness (Yokoyama and Takenaka 2005) are especially likely to rely on group benefits that are inconsistent with modern evolutionary theory.
The null hypotheses for increased prevalence of a rare genetic variant in a subpopulation are founder effects and drift; however, selection effects are being confirmed. Lactase is the best-studied example. Alleles that allow lactose digestion in adulthood have dramatically different prevalence in different geographic areas; nearly absent in Asia, they are almost uniformly present in northern Europe (Simoons 1978). Inability of adults to digest lactose is the ancestral state, so alleles for lactose intolerance should not be considered defective. New genetic data show mutations for lactase persistence arising and being selected for repeatedly (Tishkoff et al. 2006). The story is not, however, as simple as strong selection increasing frequencies of lactase alleles in dairying cultures. It now appears that such cultures in Europe expanded quickly, with a selective advantage perhaps as high as 20%, so subpopulations migrated north, carrying along alleles for adult expression of lactase (Ingram et al. 2009).
Still unaddressed is the question of why lactase synthesis in adults is inhibited in most human populations. Is the selection force simply the cost of manufacturing an enzyme that is usually unnecessary? Does the presence of lactase increase vulnerability to certain pathogens? Does inability to digest milk prevent older children from competing with younger siblings? Or, does lactase inhibition arise from drift of a mutation that is neutral in most populations? These questions have been surprisingly neglected.
Adaptation to low oxygen pressure at high altitudes offers another example; fitness-enhancing haplotypes went from rare to over 80% prevalence in just 4000 years in Tibetan Highlanders (Simonson et al. 2010; Yi et al. 2010). The responsible gene, EPAS1, inhibits hypoxia-induced hemoglobin synthesis, and thereby decreases medical complications at high altitudes. In the Andes, by contrast, the same environmental challenge has shaped very different physiologic mechanisms that are similarly effective (Beall 2007). Strong selection causes changes, but it is hard to predict what they will be.
Variations at the ApoE locus also have medical relevance; those with the ApoE 4 allele have high risks of heart disease and Alzheimer’s disease. These variations are especially appropriate for evolutionary examination given marked geographic differences in frequency and near-fixation of Apo-E 4 in our primate ancestors (Finch 2010). These alleles may give advantages to meat eaters, but the exact trade-offs remain unclear (Finch and Stanford 2004).
Searches for the adaptive significance of specific alleles are most fruitful when selection forces are specific to a particular geographic area. For instance, the absence of Duffy antigen makes it harder for Plasmodium falciparum to enter blood cells, giving a potent fitness advantage where malaria is prevalent. However, it also seems to increase vulnerability to other infections and to predispose to more malignant prostate cancer (Shen et al. 2006). Similarly, the rare individuals who lack the CCR5 antigen are also protected against pathogens entering cells, in this case, HIV, but they are more vulnerable to other infections, including West Nile Fever (Ahuja and He 2010). Both examples illustrate trade-offs that help to prevent thinking of an allele as all good or all bad.
Attempts to propose natural selection as the explanation for geographic distribution of rare polygenic diseases illustrate the perils of advocating for one hypothesis without fully considering all possibilities. For instance, the increased prevalence of Type I diabetes in northern versus southern Europe has been used to support the hypothesis that genes predisposing to diabetes were selected for during the ice age because high levels of glucose protect against tissue damage from freezing (Moalem et al. 2005). However, the predisposing genes do not directly increase glucose levels; they mediate autoimmune reactions that destroy pancreatic beta cells, leading, in the absence of exogenous insulin, to early death. Even if not fatal, Type I diabetes results in extravagant caloric loss via glucose in the urine. It seems most unlikely that cold conditions in northern Europe 14 000 year ago selected for genes predisposing to Type I diabetes. Much more likely are drift and selection driven by infectious agents.
Cell lines undergoing somatic evolution
Evolution occurring in somatic cell lines poses different challenges and opportunities. These have been studied mostly in immune cells and tumors, but somatic evolution has also been recognized in neurons (Edelman 1987). Diverse applications in cancer are proving important (Greaves 2000). Tumors can be viewed as ecosystems in which cells compete for resources, with more successful cells displacing others, thus changing the genetic signature of a tumor as it evolves (Merlo et al. 2006). Apoptotic cell death after telomere shortening protects against cancer at a cost of faster aging (Newbold 2002), and apoptosis more generally is essential in development, and in coping with pathogens and stressors (LeGrand 1997).
A significant proportion of cancer arises from mutations early in development resulting in mosaicism (Frank 2010), and positive selection in antagonistic co-evolutionary processes may account for maintenance of alleles that confer cancer vulnerability (Crespi and Summers 2006). Some genetic abnormalities in laboratory-maintained cancer cell lines are now recognized to result from the peculiar selection forces acting on cells grown in bottles. The evolutionary genetics of subpopulations of cells has been used to understand metastasis (Nguyen and Massague 2007) and to stage cancers. Evolutionary analysis of cancer cell lines has enormous clinical significance.
The above six objects of explanation are not necessarily all-inclusive; however, specifying the object of explanation carefully can help prevent mistakes. While an appropriate object of explanation is always something that can be influenced by evolution, this does not necessarily mean natural selection; mutation, drift and migration need full consideration.