An ancient cluster of Wnt paralogues.

The recently completed sequences of the human and Drosophila genomes reveal an interesting conserved arrangement of a group of Wnt genes 1xWnt signaling: a common theme in animal development. Cadigan, K. and Nusse, R. Genes Dev. 1997; 11: 3286–3305Crossref | PubMed | Scopus (2001)See all References. There are seven Wnt family members in Drosophila and 19 in the human genome. I aligned their protein sequences using the ClustalW program (shown on http://www.stanford.edu/∼rnusse/genealigns/wntalign.html). The alignment confirmed an earlier phylogenic analysis2 of vertebrate and Drosophila Wnt proteins that indicated an orthologous relationship between WNT1 and Drosophila Wingless 3xThe Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Rijsewijk, F. et al. Cell. 1987; 50: 649–657Abstract | Full Text PDF | PubMed | Scopus (554)See all References (Wg); between WNT7 and DWnt2; and between WNT5 and DWnt5. Three recently identified Drosophila Wnt proteins also have orthologs in the human genome and are therefore called DWnt6, DWnt8 and DWnt10.In the Drosophila genome, the paralogous genes wg, DWnt6 and DWnt10 are immediately adjacent to each other at position 27F on the second chromosome, transcribed in the same orientation and with no recognizable gene in between them. This order is conserved in the human genome. Human chromosome 12q13 contains WNT1 and WNT10B immediately adjacent to one another, although they are transcribed in the opposite orientation. Human chromosome 2q35 has WNT6 next to WNT10A, expressed from the same strand with no gene in between. WNT10A and WNT10B are closely related to each other, and the result of recent duplications occurred during the evolution of the jawed vertebrate lineage 2xDiversification of the Wnt gene family on the ancestral lineage of vertebrates. Sidow, A. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 5098–5102Crossref | PubMed | Scopus (114)See all References. It seems probable, therefore, that there was a common ancestral cluster of Wnt genes containing WNT1, WNT6 and WNT10 pre-dating the last common ancestor of arthropods and deuterostomes. This cluster has been preserved during arthropod evolution. In the lineage leading to vertebrates, the cluster was duplicated, leading to the WNT1–WNT6–WNT10A and WNT1–WNT6–WNT10B groups now on human chromosomes 12 and 2 (Fig. 1Fig. 1). After this duplication, WNT1 was lost from one cluster and WNT6 from the other.Fig. 1A primordial cluster of three Wnt genes is present in the Arthropod lineage and in Drosophila. The human genome contains duplicated copies of the same cluster but WNT6 is deleted from 12q13 and WNT1 is deleted from 2q35. Because the common ancestral cluster pre-dates the last common ancestor of arthropods and deuterostomes, it is ∼500 Myr old.View Large Image | Download PowerPoint SlideThis conservation of gene order is reminiscent of the evolutionary conservation of the Hox complex 4xColinearity and functional hierarchy among genes of the homeotic complexes. Duboule, D. and Morata, G. Trends Genet. 1994; 10: 358–364Abstract | Full Text PDF | PubMed | Scopus (323)See all References and could be similarly ancient (500 Myr old). None of the remaining Wnt genes in either the fly or the human are organized in a similar way. Although the Drosophila Wnt4 gene is close to wg, there is one gene (CG13785) in between. The DWnt2, DWnt8 and DWnt5 genes are at separate locations. In the human genome, there are some additional examples of closely linked Wnt genes (WNT3A–WNT14 on 1q42; WNT2–WNT16 on 7q31; and WNT3–WNT15 on 17q21), but there are intervening genes in each case. The conservation of the WNT1–WNT6–WNT10 cluster might imply that these genes are, like Hox gene clusters, coordinately regulated.