Subfunctionalization of duplicated zebrafish pax6 genes by cis-regulatory divergence.
Gene duplication is a major driver of evolutionary divergence. In most vertebrates a single PAX6 gene encodes a transcription factor required for eye, brain, olfactory system, and pancreas development. In zebrafish, following a postulated whole-genome duplication event in an ancestral teleost, duplicates pax6a and pax6b jointly fulfill these roles. Mapping of the homozygously viable eye mutant sunrise identified a homeodomain missense change in pax6b, leading to loss of target binding. The mild phenotype emphasizes role-sharing between the co-orthologues. Meticulous mapping of isolated BACs identified perturbed synteny relationships around the duplicates. This highlights the functional conservation of pax6 downstream (3') control sequences, which in most vertebrates reside within the introns of a ubiquitously expressed neighbour gene, ELP4, whose pax6a-linked exons have been lost in zebrafish. Reporter transgenic studies in both mouse and zebrafish, combined with analysis of vertebrate sequence conservation, reveal loss and retention of specific cis-regulatory elements, correlating strongly with the diverged expression of co-orthologues, and providing clear evidence for evolution by subfunctionalization.
Kleinjan
Dirk A
DA
Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom.
Bancewicz
Ruth M
RM
Gautier
Philippe
P
Dahm
Ralf
R
Schonthaler
Helia B
HB
Damante
Giuseppe
G
Seawright
Anne
A
Hever
Ann M
AM
Yeyati
Patricia L
PL
van Heyningen
Veronica
V
Coutinho
Pedro
P
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D005124:Eye Abnormalities / Q000196:embryology / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D020440:Gene Duplication; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D017930:Genes, Reporter; D005816:Genetic Complementation Test; D008040:Genetic Linkage; D018398:Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D015027:Zebrafish / Q000002:abnormalities / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics*
D017931:DNA Primers; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D029961:Zebrafish Proteins