Genomic surveys in humans identify a large amount of recent positive selection. Using the 3.9-million HapMap SNP dataset, we found that selection has accelerated greatly during the last 40,000 years. We tested the null hypothesis that the observed age distribution of recent positively selected linkage blocks is consistent with a constant rate of adaptive substitution during human evolution. We show that a constant rate high enough to explain the number of recently selected variants would predict (i) site heterozygosity at least 10-fold lower than is observed in humans, (ii) a strong relationship of heterozygosity and local recombination rate, which is not observed in humans, (iii) an implausibly high number of adaptive substitutions between humans and chimpanzees, and (iv) nearly 100 times the observed number of highfrequency linkage disequilibrium blocks. Larger populations generate more new selected mutations, and we show the consistency of the observed data with the historical pattern of human population growth. We consider human demographic growth to be linked with past changes in human cultures and ecologies. Both processes have contributed to the extraordinarily rapid recent genetic evolution of our species.HapMap ͉ linkage disequilibrium ͉ Neolithic ͉ positive selection H uman populations have increased vastly in numbers during the past 50,000 years or more (1). In theory, more people means more new adaptive mutations (2). Hence, human population growth should have increased in the rate of adaptive substitutions: an acceleration of new positively selected alleles.Can this idea really describe recent human evolution? There are several possible problems. Only a small fraction of all mutations are advantageous; most are neutral or deleterious. Moreover, as a population becomes more and more adapted to its current environment, new mutations should be less and less likely to increase fitness. Because species with large population sizes reach an adaptive peak, their rate of adaptive evolution over geologic time should not greatly exceed that of rare species (3).But humans are in an exceptional demographic and ecological transient. Rapid population growth has been coupled with vast changes in cultures and ecology during the Late Pleistocene and Holocene, creating new opportunities for adaptation. The past 10,000 years have seen rapid skeletal and dental evolution in human populations and the appearance of many new genetic responses to diets and disease (4).In such a transient, large population, size increases the rate and effectiveness of adaptive responses. For example, natural insect populations often produce effective monogenic resistance to pesticides, whereas small laboratory populations under similar selection develop less effective polygenic adaptations (5). Chemostat experiments on Escherichia coli show a continued response to selection (6), with continuous and repeatable responses in large populations but variable and episodic responses in small populations (7). These results are explained by a model in...

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This paper elaborates the hypothesis that the unique demography and sociology of Ashkenazim in medieval Europe selected for intelligence. Ashkenazi literacy, economic specialization, and closure to inward gene flow led to a social environment in which there was high fitness payoff to intelligence, specifically verbal and mathematical intelligence but not spatial ability. As with any regime of strong directional selection on a quantitative trait, genetic variants that were otherwise fitness reducing rose in frequency. In particular we propose that the well-known clusters of Ashkenazi genetic diseases, the sphingolipid cluster and the DNA repair cluster in particular, increase intelligence in heterozygotes. Other Ashkenazi disorders are known to increase intelligence. Although these disorders have been attributed to a bottleneck in Ashkenazi history and consequent genetic drift, there is no evidence of any bottleneck. Gene frequencies at a large number of autosomal loci show that if there was a bottleneck then subsequent gene flow from Europeans must have been very large, obliterating the effects of any bottleneck. The clustering of the disorders in only a few pathways and the presence at elevated frequency of more than one deleterious allele at many of them could not have been produced by drift. Instead these are signatures of strong and recent natural selection.

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Literature on schizophrenia and other mental illnesses has emphasized the compatibility of evidence with genetic causation without adequately considering alternative hypotheses of disease causation. Although some studies from the mid-20th century reported associations between certain pathogens and schizophrenia, only recently has the possibility of infectious causation of schizophrenia again become an active focus of research. Infectious causation of schizophrenia is still, however, generally regarded as less well demonstrated than genetic causation. This article evaluates the evidence that has been used to support genetic and infectious causation. Our consideration of infectious causation focuses on the protozoan Toxoplasma gondii but also assesses other pathogens that may contribute to the development of some of the illnesses currently categorized as schizophrenia. Although evidence generally accepted as demonstrating genetic causation can be readily explained by hypotheses of infectious causation, some of the evidence implicating infectious causation cannot be similarly explained by genetic causation. This asymmetry indicates that a scientific approach to the causation of schizophrenia needs to put a greater emphasis on tests that distinguish hypotheses of genetic causation from those of infectious causation.

Evolutionary considerations implicate infectious causation of atherosclerosis and help to resolve different risk factors as parts of an overall process of disease causation. An evolutionary approach also provides insight for the timing of research efforts to provide better control of pathogen evolution. In particular, evolutionary considerations emphasize the need to understand the transmissibility of Chlamydia pneumoniae from systemic infections in order to control the evolution of antibiotic resistance.