Hox Cluster Duplications and the Opportunity for Evolutionary Novelties

PERSPECTIVE Hox cluster duplications and the opportunity for evolutionary novelties Gunte P. Wagner*†, Chris Amemiya‡, and Frank Ruddle* *Yale University, New Haven, CT 06520-8106; and ‡Benaroya Research Institute, Virginia Mason Research Center, Seattle, WA 98101 Hox genes play a key role in animal body plan development. These genes tend to occur in tightly linked clusters in the genome. Ver- tebrates and invertebrates differ in their Hox cluster number, with vertebrates having multiple clusters and invertebrates usually having only one. Recent evidence shows that vertebrate Hox clusters are structurally more constrained than invertebrate Hox clusters; they exclude transposable elements, do not undergo tandem duplications, and conserve their intergenic distances and gene or- der. These constraints are only relaxed after a cluster duplication. In contrast, invertebrate Hox clusters are structurally more plastic; tandem duplications are common, the linkage of Hox genes can change quickly, or they can lose their structural integrity completely. We propose that the constraints on vertebrate Hox cluster structure lead to an association between the retention of duplicated Hox clusters and adaptive radiations. After a duplication the constraints on Hox cluster structure are temporarily lifted, which opens a window of evolvability for the Hox clusters. If this window of evolvability coincides with an adaptive radiation, chances are that a modiﬁed Hox cluster becomes recruited in an evolutionary novelty and then both copies of duplicated Hox clusters are retained. Contributed by Frank Ruddle, October 15, 2003 ince their discovery, Hox genes, a found that the Hox genes tend to occur fishes is intriguing because it is associ- family of linked transcription- in tightly linked clusters that exhibit spa- ated with the teleost radiation, which factor genes sharing a DNA-bind- tiotemporally coordinated expression gave rise to the largest taxon of extant S ing domain (the homeobox) (1), along the anterior–posterior axis. In all vertebrates of about 24,000 species. It is have confronted biologists with surpris- bilaterian animals these Hox genes are currently not possible to draw a close ing riddles. The first so-called Hox para- responsible for patterning the main body association between these two events, dox was the discovery that homologous axis (1). In addition, Hox genes have cluster duplication and teleost radiation, genes ‘‘code’’ for fundamentally differ- been recruited into secondary areas of however, because the Hox cluster situa- ent body plans. It is now widely ac- expression, most notable the cranial tion among basal ray-finned fishes is not cepted that the divergent body plans are neural crest in vertebrates, fins, and known. Currently, available data suggest based more, but not exclusively, on dif- limbs and other organs. All invertebrate that the cluster duplication happened ferences in the regulation of a con- taxa extensively examined so far have before the most recent common ances- served set of genes rather than different only a single Hox cluster (reviewed in tor of euteleosts and after the most re- gene complements (2–4). This commen- ref. 7). In sharp contrast, it was found cent common ancestor of the sturgeons tary discusses a second Hox paradox: that every major taxon of vertebrates and teleosts (K. Takahashi, J. Yoder, Why is it that in the evolution of chor- has at least three if not up to eight such C.-h. Chiu, C.A., D. Nonaka, and dates (vertebrates) the number of Hox clusters (Fig. 1). First, it was shown that G.P.W., unpublished work). Although gene clusters has increased several times mammals have four Hox clusters, called the data for jawless vertebrates and car- (Fig. 1), often in association with major A, B, C, and D (8), a condition which tilagenous fishes (sharks and relatives) radiations (5, 6), whereas no evidence seems to be true for all tetrapods. The are still incomplete, the most parsimoni- exists for such a trend in invertebrates closest relative of vertebrates, Am- ous scenario also associates the earlier (7)? It is hard to believe that this differ- phioxus, has a single Hox cluster with 14 Hox cluster duplications, leading to the ence should be due to differences in the genes, although this number might not four clusters found in humans, with ma- frequency of genome and chromosome be the ancestral condition for the verte- jor adaptive radiations (5, 19). One du- duplications between vertebrates and brate Hox gene number (9, 10). Re- plication might have occurred before the invertebrates. In this commentary, we cently, it was shown that the jawless ver- radiation of jawless vertebrates and one argue that vertebrate Hox clusters, in tebrate, Petromyzon marinus, the sea probably occurred before the radiation the absence of duplication, are structur- lamprey, has at least three clusters (11) of the jawed vertebrates. ally less evolvable than their inverte- (12). These clusters are, however, not This pattern of Hox cluster number brate counterparts. The constraint on orthologous to those in the mammals expansion in vertebrates is in striking Hox cluster structure may be tempo- and have thus originated by an indepen- contrast to the stasis of Hox cluster rarily lifted after cluster duplication, dent duplication event (13). From the number in invertebrates. Yet, inverte- which may make an association between horn shark, Heterodontus francisci,two brates experienced even more dramatic Hox cluster duplications and adaptive Hox clusters have been described based episodes of adaptive radiation and in- radiations more likely in vertebrates on complete Hox cluster sequences (14), novations of body design. More than than in invertebrates. but more are likely to exist (unpublished 20 major clades of invertebrates differ Hox genes were first discovered data). Teleost fishes are the pinnacle of so radically in body organization that through their effects on Drosophila de- Hox cluster evolution, with at least they were formerly known as ‘‘phyla.’’ velopment. Mutations cause dramatic seven Hox clusters in zebrafish (15) and The largest metazoan radiation of all is transformations of the identity of spe- Takifugu and Spheroides (16). Incom- that of insects, which gave rise to Ϸ1 cific body segments to those of different plete data from other teleosts are con- Mio of described species with wildly body segments, called homeotic trans- sistent with the hypothesis that all tel- formations. Eventually these genes were eosts may have more Hox clusters than characterized as coding for transcription the mammals [killifish (17), tilapia (6), †To whom correspondence should be addressed. E-mail: factors from the family of homeobox- and striped bass (18)]. The expansion of [email protected]. containing genes. Furthermore, it was Hox cluster number in higher ray-finned © 2003 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.2536656100 PNAS ͉ December 9, 2003 ͉ vol. 100 ͉ no. 25 ͉ 14603–14606 Downloaded by guest on September 27, 2021 consistent with this model (see next paragraph). Conservation of noncoding sequences is another feature strongly affected by Hox cluster duplication. A detailed comparison of intergenic sequences between the HoxA clusters of shark and human shows extensive regions of strong se- quence conservation, which is largely absent in the zebrafish (23) and fugu (24). It can be expected that the cis- regulatory elements of genes get modi- fied when two copies are retained to resolve genetic redundancy (26). Sur- prisingly, however, conservation is also lost when only one paralog is retained in the zebrafish, which by inference is expected to be necessary to maintain the ancestral gene function. Apparently, this function was important enough to conserve those very same sequences Fig. 1. Number of Hox clusters in chordate phylogeny. The inferred numbers of Hox clusters are since the most recent common ancestor superimposed on the phylogeny. Asterisks indicate taxa under investigation whose Hox clusters have been of sharks and humans, at least for the isolated but not yet completely characterized. In the Agnatha, only lampreys have been investigated to HoxA cluster. But functional studies of date, and their Hox clusters appear to have originated by an independent duplication event(s); i.e., their zebrafish Hox genes show that even the Hox cluster duplicates are not orthologous with those in mammals (11–13). It should be noted that, notion of retained ancestral functions is although the increasing number of Hox clusters through phylogeny is consistent with Ohno’s prediction misleading in the Hox genes. Prince and (45) of genome duplications and vertebrate complexity, it is not entirely consistent with his proposed collaborators have shown that the ze- stepwise (2R) model. brafish ortholog of the mammalian Hoxa-1, Hoxa-1a, is not expressed in the different adaptations. If one includes phioxus also has a comparatively large hindbrain, but its function has been crustaceans, spiders, and some minor Hox cluster (Ϸ450 kb; C.A., unpub- taken over by Hoxb-1b. In contrast, in taxa, any other phylogenetic event in lished work). The Hox A cluster of the mouse the Hoxb-1 gene is not essen- animal phylogeny pales in comparison shark and mammals is very similar and tial for hindbrain development (27). with the radiation of arthropods. Based much smaller than the Amphioxus clus- These findings suggest that, after du- on that evidence, Sean Carroll has ar- ter, Ϸ100–120 kb. Most of

Load more