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Neurochemical Individuality:  Genetic Diversity Among Human Dopamine and Serotonin Receptors and Transporters

Anibal Cravchik, MD, PhD; David Goldman, MD
Arch Gen Psychiatry. 2000;57(12):1105-1114. doi:10.1001/archpsyc.57.12.1105.
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Behavioral variation in human beings encompasses wide differences in personality and susceptibility to psychiatric illness arising from both genotype and experience. Long-lasting behavioral differences generally have heritabilities of 30% or more, and such inheritance is ultimately attributable to functional variants of genes programming brain development and function. The sequencing of the human genome is revealing a pattern of gene sequence variation. The ability of sequence variants to affect neural function either alone or in concert may reveal effects of behavioral selection on the human genome over evolutionary time frames. Dopamine and serotonin are phylogenetically ancient neurotransmitters intrinsic to brain function and behavior. Dopamine and serotonin receptor and transporter genes have been an early focus for efforts to identify and functionally characterize sequence variation. The purpose of this article is to present a preview of a developing new perspective in human behavior: the genetic variation of the brain or neurochemical individuality.

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Figure 1.

Phylogenetic trees for human dopamine (D) and serotonin (5-HT) G protein–coupled receptors. A, Phenogram representing genetic distances. This analysis supports the suggestion that dopamine, 5-HT1, 5-HT5, 5-HT7, and 5-HT4 receptors evolved from a common ancestor after the initial divergence of the 5-HT2 and 5-HT6 receptor subtypes.11 B, Most parsimonious tree. The 3 major divisions in the evolutionary topology correspond to a signal transduction mechanism rather than ligand specificity: coupling to Gq proteins (leading to increased phosphoinositol), Gs proteins (increased cyclic adenosine monophosphate [cAMP]) and Gi proteins (decreased cAMP). The 5-HT5A–signalling mechanism remains unclear, and this is convergent with its position in the evolutionary topology based on sequence. PI indicates phosphoinositol; AC, cAMP; ↑, increase; and ↓, decrease.

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Figure 2.

Putative membrane topography of a consensus protein sequence for all the human dopamine (D) and serotonin (5-HT) G protein–coupled receptors. Functionally conserved residues are color coded. Receptor protein variants are also depicted in different colors according to allele frequency. NH2 indicates the amino group; COOH, carboxyl group; bp del, base pair deletion; aa, amino acid; A, alanine; R, arginine; N, asparagine; D, aspartic acid; C, cysteine; E, glutamic acid; G, glycine; I, isoleucine; L, leucine; K, lysine; M, methionine; F, phenylalanine; P, proline; S, serine; T, threonine; W, tryptophan; Y, tyrosine; and V, valine.

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