Functional evolution of the trace amine associated receptors in mammals and the loss of TAAR1 in dogs

Abstract

Background: The trace amine associated receptor family is a diverse array of GPCRs that arose before the first vertebrates walked on land. Trace amine associated receptor 1 (TAAR1) is a wide spectrum aminergic receptor that acts as a modulator in brain monoaminergic systems. Other trace amine associated receptors appear to relate to environmental perception and show a birth-and-death pattern in mammals similar to olfactory receptors.

Results: Across mammals, avians, and amphibians, the TAAR1 gene is intact and appears to be under strong purifying selection based on rates of amino acid fixation compared to neutral mutations. We have found that in dogs it has become a pseudogene. Our analyses using a comparative genetics approach revealed that the pseudogenization event predated the emergence of the Canini tribe rather than being coincident with canine domestication. By assessing the effects of the TAAR1 agonist beta-phenylethylamine on [3H]dopamine uptake in canine striatal synaptosomes and comparing the degree and pattern of uptake inhibition to that seen in other mammals, including TAAR1 knockout mice, wild type mice and rhesus monkey, we found that the TAAR1 pseudogenization event resulted in an uncompensated loss of function.

Conclusion: The gene family has seen expansions among certain mammals, notably rodents, and reductions in others, including primates. By placing the trace amine associated receptors in an evolutionary context we can better understand their function and their potential associations with behavior and neurological disease.

Figure 1

Phylogeny of mammalian TAAR genes. Branch length is proportional to nucleotide divergence. d_N/d_S ratios for all branches can be found in Additional file 1.

Figure 2

Phylogeny of primate TAAR genes. Branch length is proportional to nucleotide divergence. Pseudogenes are identified in blue.

Figure 3

Phylogeny of mammalian TAAR1. Branch length is proportional to nucleotide divergence. Lineage-specific d_N/d_S values are displayed. Note that the d_N/d_S value associated with the cat terminal branch extends to the last common ancestor between Carnivora and Cetartiodactyla.

Figure 4

Simplified phylogeny of Carnivora. Green (open) circles denote TAAR1 open reading frames. Blue (closed) squares denote TAAR1 pseudogenes.

Figure 5

Modulation of [³H]dopamine uptake by β-PEA in brain striatal synaptosomes. Synaptosomes from wild-type mouse (n = 3), TAAR1 knockout mouse (n = 3) and dog (n = 1) were exposed to 10 nM [³H]dopamine alone or 10 nM [³H]dopamine plus 100 nM β-PEA for the indicated times. Uptake values are percentage of the maximal uptake. Note the reduction in dopamine uptake during β-PEA challenge in wild-type mouse as compared to TAAR1 knockout mouse and dog. Data are presented as mean ± S.E.M.

Figure 6

Table depicting the Genbank accession numbers for all the genes used in this study. A cladogram depicting species relationships is presented above the table. Pseudogenes are in bold.