Commentary In our genes

T D4 dopamine receptor (DRD4) locus may be a model system for understanding the relationship between genetic variation and human cultural diversity. It has been the subject of intense interest in psychiatry, because bearers of one variant are at increased risk for attention deficit hyperactivity disorder (ADHD) (1). A survey of world frequencies of DRD4 alleles has shown striking differences among populations (2), with population differences greater than those of most neutral markers. In this issue of PNAS Ding et al. (3) provide a detailed molecular portrait of world diversity at the DRD4 locus. They show that the allele associated with ADHD has increased a lot in frequency within the last few thousands to tens of thousands of years, although it has probably been present in our ancestors for hundreds of thousands or even millions of years. There is a repeat polymorphism in exon III of the gene at which a variable number of 48-bp motifs can occur. The common and probable ancestral allele has four repeats (4R), whereas the allele associated with novelty seeking and ADHD has seven (7R). Ding et al. (3) show that there are essentially two allele classes at the locus: most variants are easily derived from 4R by simple recombinations or mutations, whereas 7R differs from 4R by a minimum of seven events. This means either that the coalescence of the 4R and 7R allele classes is ancient or that 7R was generated by an extremely improbable mutation and recombination event more recently. At any rate the allelic diversity within the 4R class and the lack of linkage disequilibrium with markers around it show that it has been the common variant in our species for a long time. 7R alleles, with little diversity within the class and high linkage disequilibrium with neighboring markers, must have a recent common ancestor. If the 7R class has been rare for a long time, coalescence within the class could be recent, whereas coalescence between the 7R and 4R classes could be ancient. This curious pattern, an allele that has been in the population for a very long time at a very low frequency, suggests that some kind of balancing selection has been maintaining 7R, but preventing it from becoming common until recently. An alternative is that 7R was incorporated from another hominid species during the expansion of modern humans. It is clear from association studies with childhood ADHD that the allele affects behavior, but it is not so clear what it does. The recent positive selection for 7R denies that it causes pathology in any evolutionary sense. Adaptive genetic variants cannot be the cause of fitness-reducing mental illness unless that illness in some way is a product of recent environmental change or is compensated by other increases in fitness as in classical balanced polymorphisms. Natural selection would have purged common alleles that induce crippling disorders such as schizophrenia in premodern conditions. On the other hand, it is entirely possible that some psychological traits are adaptive yet, because they are irritating or undesirable, are called mental illness. There is an important distinction to be made between fitnessreducing mental illnesses, behaviors that can never have been adaptive, and psychological syndromes that we happen not to like (4). Another hint that 7R does not cause pathology in an evolutionary sense is the finding that children diagnosed with ADHD often show specific neurological deficits, whereas children bearing 7R and diagnosed with ADHD do not show such deficits (5). Neurotransmitter receptors are especially good candidates for genetic variation that modulates behavior. The polymorphisms we see in dopamine metabolism all seem to be in receptor and transporter molecules rather than in the dopamine molecule itself. Dopamine is involved in a wide spectrum of functions, acting through five different receptors. Any change that affected all of those systems at once would almost certainly be maladaptive. A mutation that affects a smaller range of systems, by changing a single dopamine receptor or transporter, has a better chance. The same principle may apply to other neurotransmitters, which typically have a number of different receptors. We know that serotonin, for example, has 14 (6). Evidence of adaptive genetic variation affecting human psychology should be of interest to evolutionary psychologists, particularly because they have argued that it cannot exist. For example Tooby and Cosmides (7) claim that there are only two kinds of human nature, male and female, and that apparent variation in personality is either facultative response to environmental cues or nonadaptive. They argue that complex adaptations require the coordinated action of many genes, and that if individuals of a sexually reproducing species differed in the genes required to build these adaptations, sexual reproduction would disrupt the necessary gene complexes. They also argue that there has been insufficient time since the advent of modern humanity for the development of significant novel mental adaptations. As has been pointed out by D. Wilson (8), their arguments are unconvincing. They imply that no sexual species should have heritable adaptive morphs, whereas in fact many examples are known, such as the male morphs of the side-blotched lizard Uta stansburiana that act out a scissors–paper–rock game, in which morph A beats morph B, morph B beats morph C, and morph C beats morph A (9). The ‘‘insufficient time’’ argument is probably just incorrect; considering the measured heritability of psychological traits and the expected response to mild selection over hundreds of generations, it is instead surprising that we seem to have changed little over historical time. Even if 40 or 50 thousand years were too short a time for the evolutionary development of a truly new and highly complex mental adaptation, which is by no means certain, it is certainly long enough for some groups to lose such an adaptation, for some groups to develop a highly exaggerated version of an adaptation, or for