# Convergent Evolution of Two Dopamine Receptor Genes: Repeated Evolution of Exon 6 Skipping in Drd2, and Repeated Deletion of Exon 6 in Drd3

## TL;DR

This paper explores how two dopamine receptor genes, Drd2 and Drd3, evolved in different ways across species, with Drd2 skipping a specific exon and Drd3 deleting it.

## Contribution

The study reveals convergent evolution of exon skipping in Drd2 and exon deletion in Drd3 across diverse vertebrate lineages.

## Key findings

- Exon 6 skipping in Drd2 evolved convergently in derived tetrapod lineages.
- Exon 6 deletion in Drd3 occurred randomly across various species.
- Exon 6 is not essential for dopamine signal transduction.

## Abstract

Drd2 dopamine receptor mRNAs are alternatively spliced in rodents and primates by skipping exon 6 to produce the D2S protein, or including exon 6 to produce the D2L protein. These protein isoforms have differing roles in pre- vs. post-synaptic signaling, cytoplasmic vesicle processing, and calcium-mediated desensitization. Genetic alteration in the D2S/D2L ratio affects human behavior and cognition at multiple levels, including working memory. Here we show that exon 6 originated early in vertebrate evolution, after the duplication and divergence of D2 and D4 dopamine receptor genes, but before the duplication and divergence of D2 and D3 dopamine receptor genes. Exon 6 encodes a relatively conserved sequence in the third cytoplasmic loop of the D2–D3 receptor. Its amino acid sequence is relatively short (24–33 amino acids), and is not strictly necessary for dopamine signal transduction. Exon skipping of Drd2 exon 6 was not detectable in the brains of cyclostomes, sharks, fish, relatively primitive amphibians (Xenopus, Notophthalmus), relatively primitive reptiles (turtles), relatively primitive birds (ostrich), or relatively primitive mammals (monotremes and marsupials). However, exon skipping of Drd2 exon 6 did occur at significant levels in the brains of more derived amphibians, reptiles, birds and mammals. Thus, skipping of Drd2 exon 6 arose convergently and specifically in the more derived tetrapod lineages, none of which deleted this exon. In contrast, exon 6 was convergently deleted during Drd3 evolution in an apparently random subset of the species of sharks, fish, amphibians, reptiles, birds, and mammals.

The online version contains supplementary material available at 10.1007/s00239-025-10255-7.