Surveys of protein-coding sequences for signatures of positive selection in humans and chimpanzees have flagged surprisingly few genes known to be involved in neural or nutritional processes 1-5 , despite the pronounced differences between humans and chimpanzees in behavior, cognition, and diet 6-8 . It may be that most such differences are due to changes in gene regulation rather than protein structure 9 . Here, we present the first survey of promoter (5 -flanking) regions, which are rich in cis-regulatory sequences, for signatures of positive selection on the human lineage. Our results indicate that positive selection has targeted the regulation of many genes known to be involved in neural development and function, both in the brain and elsewhere in the nervous system, and in nutrition, particularly glucose metabolism.Cognitive, behavioral, and dietary differences are among the most conspicuous differences between humans and their closest relatives, chimpanzees and other great apes. For example, even in the absence of written language or agriculture, human communication and tools are much more complex than those of chimpanzees 6,7 , and humans consume a far wider range of foods than chimpanzees 8 . These traits are essential to many aspects of human ecology, such as the broad range of habitats humans occupy 8 , and although assessing the adaptive significance of a trait is often challenging, it is plausible that many human cognitive, behavioral, and dietary traits are adaptations. Consistent with this, the protein-coding sequences of several genes known to function in neural or nutritional processes have been shown to bear signatures of positive selection (natural or sexual selection for novel alleles) in humans 10,11 . Surprisingly, however, such genes are not prominent in surveys of coding sequences for evidence of positive selection in humans and chimpanzees [1][2][3][4][5] . Instead, these surveys have flagged many genes known to function in immunity, olfaction, and spermatogenesis, among other processes. Neural-related genes in particular show little sign of positive selection in these surveys 3, 4 .One possible explanation, first suggested by King and Wilson 9 , is that many phenotypic differences between humans and chimpanzees may be due to changes in gene regulation rather than protein structure. In particular, the genetic bases of human neural and nutritional adaptations may reside primarily in cis-regulatory sequences (DNA where proteins bind sequence-specifically to regulate transcription), very few of which lie within coding sequences 12 . Several recent studies point in this direction. First, of the two most thoroughly investigated cases of positive selection on cis-regulatory sequences in humans, one, PDYN, is neural-related 13 , and the other, LCT, is nutrition-related 14 . Second, two surveys of linkage disequilibrium among single-nucleotide polymorphisms for signatures of very recent positive selection within human populations, embracing both coding and noncoding sequences, found excesses of s...

Surveys of protein-coding sequences for signatures of positive selection in humans and chimpanzees have flagged surprisingly few genes known to be involved in neural or nutritional processes 1-5 , despite the pronounced differences between humans and chimpanzees in behavior, cognition, and diet 6-8 . It may be that most such differences are due to changes in gene regulation rather than protein structure 9 . Here, we present the first survey of promoter (5 -flanking) regions, which are rich in cis-regulatory sequences, for signatures of positive selection on the human lineage. Our results indicate that positive selection has targeted the regulation of many genes known to be involved in neural development and function, both in the brain and elsewhere in the nervous system, and in nutrition, particularly glucose metabolism.Cognitive, behavioral, and dietary differences are among the most conspicuous differences between humans and their closest relatives, chimpanzees and other great apes. For example, even in the absence of written language or agriculture, human communication and tools are much more complex than those of chimpanzees 6,7 , and humans consume a far wider range of foods than chimpanzees 8 . These traits are essential to many aspects of human ecology, such as the broad range of habitats humans occupy 8 , and although assessing the adaptive significance of a trait is often challenging, it is plausible that many human cognitive, behavioral, and dietary traits are adaptations. Consistent with this, the protein-coding sequences of several genes known to function in neural or nutritional processes have been shown to bear signatures of positive selection (natural or sexual selection for novel alleles) in humans 10,11 . Surprisingly, however, such genes are not prominent in surveys of coding sequences for evidence of positive selection in humans and chimpanzees [1][2][3][4][5] . Instead, these surveys have flagged many genes known to function in immunity, olfaction, and spermatogenesis, among other processes. Neural-related genes in particular show little sign of positive selection in these surveys 3, 4 .One possible explanation, first suggested by King and Wilson 9 , is that many phenotypic differences between humans and chimpanzees may be due to changes in gene regulation rather than protein structure. In particular, the genetic bases of human neural and nutritional adaptations may reside primarily in cis-regulatory sequences (DNA where proteins bind sequence-specifically to regulate transcription), very few of which lie within coding sequences 12 . Several recent studies point in this direction. First, of the two most thoroughly investigated cases of positive selection on cis-regulatory sequences in humans, one, PDYN, is neural-related 13 , and the other, LCT, is nutrition-related 14 . Second, two surveys of linkage disequilibrium among single-nucleotide polymorphisms for signatures of very recent positive selection within human populations, embracing both coding and noncoding sequences, found excesses of s...

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