The spatio-temporal regulation of Hox genes in vertebrates has some fascinating offshoots. Marsupials like Tammar wallaby, Macropus eugenii , have delayed expression of posterior Hox genes, HoxA13 and HoxD13 , attributed to weaker hind limbs in newborn animals.
The forelimbs are relatively stronger, which helps them to climb the brood pouch of their parent. The delayed expression of the posterior Hox is yet another example of modularity and differential expression, possibly due to differences in clustering and accessibility of CRMs which can be accessed via the genome sequence available for marsupials Chew et al.
Similar variations of spatio-temporal regulation can be observed in simpler chordates like amphioxus. Despite being in a tight cluster, the spatially collinear expression of Hox genes is perturbed in Branchiostoma floridae. Hox6 , a central Hox gene, expresses almost ubiquitously across the neural tube, posterior to the cerebral vesicle. While Hox14 , a posterior Hox gene, is expressed in the most anterior cerebral vesicle. Furthermore, Hox14 mRNA is also detected in the pharyngeal endoderm.
Interestingly, levels of Hox6 vary greatly in closely related species. Unlike B. This indicates subtle modulations of HOX levels in closely related species and is similar to changes observed in invertebrates. Deep sequencing of flanking regions of Hox loci in multiple organisms along with a Bag-of-Motif analysis to understand protein-DNA interactions can shed light on putative regulatory mechanisms associated with the clustering of CRMs. In simpler organisms like annelids or mollusks, the arrangement of Hox thus seems to be dispensable, but with the evolution of complexity, clustering becomes a necessity for co-regulation.
The property of a system to separate and re-integrate its components to form a viable system is called modularity. Subtle changes in Hox expression can quickly orchestrate the evolutionary modularity. The studies are not limited to fruit flies. In an amphipod crustacean, Parhyale hawaiensis , the interplay between various Hox genes and their ability to act independently was comprehended by a series of sophisticated experiments involving manipulation of Hox levels Liubicich et al.
The amphipod is bilaterally symmetrical and has multiple segments with specialized appendages. A group of metameric segments evolved to perform a common function is called tagma, and the associated evolutionary process is called tagmatization Abzhanov and Kaufman, The arrangement of appendages in the order of their occurrence from anterior to posterior segments in Parhyale is as follows — feeding appendages mandible, Mn and maxillipeds Mx, or, gnathopods , claws T2—T3 , forward T4—T5 , and reverse T6—T8 walking legs pereopods , swimming appendages pleopods or swimmerets in the segments A1 to A3, and appendages for holding substrates uropods formed in A4—A6.
A simple representation of P. Figure 6. Interplay of different Hox genes in Parahyale hawaiensis. A Hox expression in Parhyale hawaiensis. Note that abd-A has overlapping regions of functioning with Ubx as well as Abd-B. B Ubx knock-out animals show anteriorization of forward walking legs. C abd-A knock-out animals show anteriorization of reverse walking legs and posteriorization of swimming appendages.
D Abd-B knock-out animals show anteriorization of swimming appendages into reverse walking legs and uropods in forward walking legs. Martin et al. This was as expected from previous studies in Drosophila that indicate the anteriorization of segments in the absence of posterior Hox ; a property called the posterior prevalence of Hox genes. This was an apparent effect of the additive function of Ph abd-A to regulate segment identity in either direction along the AP axis.
Ph Abd-B knock-out animals had derepression of Ph Ubx in the posterior segments, leading to extreme transformation into forward walking legs. The studies from the crustacean suggest that alongside collinear expression of Hox , the co-regulation, inter-regulation, and cross-talk between different HOX cause varying phenotypes.
The interplay between these genes brings about diversity in the animal kingdom Martin et al. Crustaceans such as P. This was done by injecting morpholinos for Ph Ubx knockdown in one of two-celled stage embryo cells. Each cell follows its fate separately across the LR axis of development. Although the system was utilized to compare wild type versus knockdown phenotypes in the same organism Browne et al.
In tune with this, in the Xenopus embryo, HoxC8 expresses asymmetrically along the left-right axis of development in the lateral plate mesoderm Thickett and Morgan, One interesting organism worth probing for Hox genes regulation and determination of the LR axis is the fiddler crab. It is a natural example of left-right asymmetry in appendage formation. The female fiddler crabs have similar-sized left and right feeding appendages.
In comparison, males have one of their feeding appendages extraordinarily enlarged. They use this appendage to fight competitors during mating and display handedness Pardo et al. A detailed understanding of Hox expression in these organisms can shed light upon the formation of segments in AP and LR axes of development.
Scorpions have undergone duplications of Hox genes, which are correlated to the heteronomy of the posterior segments Sharma et al. Arizona bark scorpion, Centruroides sculpturatus , has 19 Hox genes instead of 10 in its sister groups. The dual copies are expressed in varying degrees from antero-central to telson.
Notedly, the telson is formed posterior to terminalia anus. It would be interesting to delete one or multiple copies of each of these Hox genes and observe the changes in body patterning. The tagmatization could be affected to the extent that the body form might become less elongated, as is the case with Opiliones, harvestmen, or instigated to form a telson-less scorpion Sharma et al. The opposite spectrum of body formation is seen in Tardigrades, in which deletion of several Hox genes correlates with their compact body plan with simpler, repetitive, and less four number of segments Smith et al.
Other than the levels of HOX, structural modifications in the transcription factors can help in diverse functions. Recent experiments with flies provided evidence of functional conservation of mouse Hox genes. Singh et al. The ortholog-specific interaction leads to differential occupancy of HoxA1 across the genome.
This study strongly supports the notion of evolutionary modularity in Hox complex by causing structural changes in HOX that lead to similar yet functionally divergent protein products Singh et al. An ordered arrangement of Hox could have played an important role in their sequential co-regulation along the AP axis, as indicated by our understanding of BX-C regulation.
One can consider Hox genes as switches to control different electrical equipment at home. They can be present anywhere across the house and can still function, as is the case of an octopus. But clustering on a switchboard gives quick, precise, and perhaps, robust control over the spatio-temporal regulation of Hox genes. This modularity could have been one reason for arthropods to surpass mollusks as the richest bio-diverse species on our planet Benton, Many genes are co-regulated in different organisms Snel et al.
Overall, clustering is more abundant in vertebrates than invertebrates Elizondo et al. Nevertheless, in addition to clustering, the ordering is an important property of Hox complexes that need to be pondered upon.
Understanding them in the context of gene clusters, including Hox complexes, will be riveting. The Hox genes have a tremendous potential to modulate diversity by teaming up with multiple partners and setting a stage for downstream players in various axes. Different combinations of cis- and trans- regulators together bring about manifold changes that can drive evolution. Classically, mutations in Hox genes are associated with the homeotic transformation of one body segment into another, a process called homeosis Lewis, These mutations transformed embryonic segments, and therefore the Hox genes were established as the regulators during embryonic development Pradel and White, Recent studies opened new horizons to understand the role of Hox genes in an organism.
A rising number of articles suggest their role beyond homeotic functions and embryonic development Wang et al. The three genes of the bithorax complex, Ubx , abd-A , and Abd-B , have defined anterior limits of expression in Drosophila larvae.
The larva undergoes metamorphosis during pupal stages of development, ultimately eclosing as adults. One key event during this process is autophagy of most of the larval tissues, including the fat body, salivary glands, and trachea. This is further coupled with the differentiation of adult tissues that goes on till eclosion. Down regulation of Ubx is accompanied by developmental and starvation-induced autophagy, whereas sustained expression of the Hox gene inhibits autophagy and delays metamorphosis Banreti et al.
Like the larval fat body, larval epithelial cells LECs also undergo apoptosis during metamorphosis. Further, another group of cells called histoblast nest cells HNCs differentiates to form adult abdominal epithelial cells during pupation.
Moreover, HNC proliferation is hindered by abd-A down regulations, and the cells fail to form a complete epithelium in abd-A knocked down pupae. Similar reports for Abd-B were observed in testis development, where it remains active in pre-meiotic spermatocytes. Tissue-specific knockdown of Abd-B in adult testes leads to a loss of maintenance of the stem cell niche required to produce normal sperms. This is because ABD-B has direct binding sites on src42A and sec63 , members of Boss signaling involved in testes formation and sperm differentiation.
Abd-B also has an extended effect on the orientation of centrosomes and the division rates of germline stem cells Papagiannouli and Lohmann, Obtaining tissue-specific cells for further studies of Hox was a Herculean task a couple of years back, as one had to do neck-breaking dissections to get ounces of desirable material.
Although now, endogenous tagging of Hox genes has solved a lot of such problems. Cell sorting of fluorescently labeled HOX expressing tissues followed by multi -omics experiments can help us understand the genome-wide effects of HOX in adult tissues. Domsch et al. They utilized this resource to establish the role of Ubx as a major repressor of factors involved in alternate fate development in mesodermal cells.
In their recent work, Paul et al. The extraembryonic roles of Hox are more distinct in vertebrates. As early as , it was evident that Hox genes play a role in non-homeotic fashion owing to the near-complete loss of hair formation in mice deficient for HoxC Although the mouse also had patterning defects, hair growth was uniformly reduced across the body Awgulewitsch, Recent reports showed several HoxC genes in the dermal papilla and associated it with regional follicle variation.
In a mutant mouse line called Koala mutant, a 1 Mb inversion encompassed disintegration of HoxC4 to HoxC13 from the main complex leading to their misexpression.
Similar deletion studies have identified the role of HoxA genes in mammary gland formation during specific transition developmental periods Lewis, Owing to their multifaceted roles during and after development, levels of Hox proteins need to be tightly regulated. Misexpression of these genes has been observed in various cancers like breast cancer, melanoma, bone cancer, blood cancer, and colorectal cancer Shah and Sukumar, Central and posterior Hox genes, HoxA5 and HoxD9 , have been implicated in esophageal squamous cell carcinoma.
Strikingly, they were found to localize more in the cytoplasm of the mucosa cells in esophageal cancer than in the nucleus in normal cellular conditions Takahashi et al.
Overexpression of posterior Hox genes, particularly HoxA, HoxB13, and HoxC10, is linked to the onset and tumor progression of ovarian, cervical, and prostate cancers Jung et al. Hox-associated cancer is not limited to genetic mutations. Rauch et al. The study highlighted epigenetic misregulation as a putative cause for Hox-related lung tumors.
Likewise, promoter methylation of HoxA5 and downregulation of HoxA10 are associated with progressive breast carcinoma. Misexpression studies in Drosophila confirmed the causal effect and established flies as a model to study Hox-associated oncogenesis. The outcome of the study was the ability of Dfd , Ubx , and abd-A genes to be leukemogenic when overexpressed in fat body and lamellocytes Ponrathnam et al. Detailed understanding of Hox genes expression and interaction during embryogenesis, tissue formation, organogenesis, and cellular homeostasis is required to delineate their functional modalities.
Due to their overarching involvement in multiple processes of body formation, patterning, and evolution, Hox genes occupy a prime position in our quest toward understanding these processes in depth. A long-debated topic in the field of Hox genes was their presence in the form of clusters and the property of spatio-temporal collinearity.
Some recent developments also demonstrated the functioning of Hox independent of clustering. However, coordinated functioning is better when they are clustered together, as implied by the open for business model of the bithorax complex.
Alterations of CRMs throughout the Hox led to a myriad of homeotic transformations. Similar genomic alterations across evolution might have experimented with Hox modules and their expression to bring about the enormous diversity we see today. Hox come together to set up the primary and secondary axes and provide constant inputs in different tissues, therefore orchestrating the developmental design sublimely. In vivo experiments with the latest genome editing tools and a better understanding of non-coding DNA become important for comprehending the conductors of this symphony.
RKM and NH conceived the design of the article and edited the manuscript. Both authors contributed to the article and approved the submitted version. NH is a fellow of the Department of Biotechnology, Govt. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Soujanya, Sonu Yadav, and Lorraine Teron for carefully reviewing the manuscript. The authors would also like to extend gratitude toward Surbhi Lambhate for continuous discussions and suggestions while preparing the manuscript.
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BioRxiv 1— Drewell, R. Deciphering the combinatorial architecture of a Drosophila homeotic gene enhancer. Duboule, D. The rise and fall of Hox gene clusters. Elizondo, L. Genomics 10, 64— Through binding site occupancy, it may interfere with the functions of other homeoproteins normally involved in digit morphogenesis, as for example HOXA13, leading to alterations more severe than those due to Hoxd inactivation alone 28 , That heterozygotes for the Hoxa null mutation in the mouse show defects that are apparently less severe than those seen in the hand-foot-genital syndrome supports the previous suggestion that the HOXA mutation results in a protein exerting a dominant negative effect 31 X.
Warot, C. Fromental-Ramain, P. Chambon, and P. Several studies have revealed roles for other Abd-B- related Hox genes in the developing genitourinary tract and terminal part of the digestive tract. Both male and female Hoxa null mutants are hypofertile.
Mutant male subjects exhibit cryptorchidism, caused by abnormal formation of inguinal canal and by a failure of shortening of the gubernaculum 33 , In addition, they display a malformation of the vas deferens that resembles a partial homeotic transformation to an epididymis Partial homeosis of the vas deferens to an epididymis-like morphology is also observed in Hoxa null mutants Interestingly, Hoxa null mutant females display an anterior transformation at a corresponding level of the reproductive tract, because the proximal part of the uterus is transformed into an oviduct-like structure Indeed, Hoxd and Hoxd null mutants display a disorganization of the smooth muscles layers forming the internal anal sphincter, resulting in rectal prolapsus in some mutants Hox genes in hindbrain patterning and craniofacial development.
The hindbrain or rhombencephalon, is transiently divided along its anteroposterior axis into a series of segments seven in mice and man called rhombomeres This segmental organization of the hindbrain determines the segmental migration of the NCC from the neurectoderm to populate and pattern the pharyngeal arches.
In situ hybridization analyses have revealed that, in general, part of the combination of Hox gene expressed in a given rhombomere is also expressed in the NCC migrating from that rhombomere, suggesting that Hox genes may be instrumental in the patterning of the branchial region of the head reviewed in Ref.
To validate this hypothesis, we and others functionally inactivated the Hoxa-2 gene 40 , NCC emigrating from the first two rhombomeres and caudal mesencephalon normally populate the first or maxillomandibular arch where they give rise to the dentary, maxilla, squamosal, tympanic, malleus, and incus bones and to the Meckel's cartilage.
NCC emanating from the fourth rhombomere normally populate the second or hyoid arch and form the stapes, styloid bone, and lesser horn of the hyoid bone.
However, at this level of the anteroposteior axis its expression is restricted to the neurectoderm; thus, the NCC of the first pharyngeal arch do not express any Hox gene. In contrast, Hoxa-2 is expressed in the NCC of the second pharyngeal arch. In the Hoxa-2 null fetuses the NCC-derived skeleton of the second pharyngeal arch is selectively lacking e.
In the place of second arch skeletal elements, an ectopic caudal set of first arch skeletal elements is present, mostly as a mirror image of its orthotopic counterpart. This ectopic set comprises: 1 within the middle ear region, a supernumerary incus, malleus, truncated Meckel's cartilage, and tympanic bone Fig.
These data from skeletal analysis, combined with gene expression data, indicate that disruption of the Hoxa-2 gene results in a homeotic transformation of second to first pharyngeal arch identity. Such a transformation reveals that the morphogenetic program of the NCC derived from the first two rhombomeres corresponds to a ground or default skeletogenic patterning program GPP which is common to mesenchymal NCC of at least the first and second pharyngeal arches, and does not require Hox gene expression.
In wild-type mice, the GPP is respecified by Hoxa-2, which, like Drosophila homeotic genes, acts as a selector gene to yield the second arch-specific morphogenetic program. Interestingly, an atavistic skeletal structure corresponding to the reptilian upper jaw or pterygoquadrate cartilage is developed from the second arch of Hoxa-2 mutants Fig. Additional inactivation studies also supported important roles of Hox genes in patterning hindbrain and pharyngeal arches.
For instance, targeted inactivation of Hoxa-3 leads to hypoparathyroidism and thymic and thyroid hypoplasia Interestingly, these defects are also observed in the Di George syndrome which, however, is not due to a Hox gene mutation [See Daw et al. Defects of rhombomeres 4 and 5, cranial nerve and inner ear abnormalities were found in Hoxa-1 null mutants 44 , 45 , and selective facial nerve motor nucleus deficiencies were observed in Hoxb-1 and Hoxb-2 knockout mice 46 — Features of these phenotypes, such as paralysis of facial muscles, resemble those of Bell's palsy and Moebius syndromes in humans.
As already pointed out, Hox genes are not expressed in the neurectoderm anterior to rhombomere 2 and thus cannot participate in the development of the anterior hindbrain, midbrain, or forebrain i. Likewise, Hox gene expression is lacking in the non overtly -segmented paraxial mesoderm which gives rise to craniofacial striated muscles, and is also absent in the NCC of the first pharyngeal arch and frontonasal mass which form most of the skull bones as well as the mesenchymal component of the teeth.
In flies, the control of head specification is dependent on homeobox gene not present within a cluster including the orthodenticle odt and empty spiracles ems genes.
Drosophila sequences were used to identify vertebrate homologues, and this approach led to the cloning of the Emx-1 and Emx-2 genes related to ems, and of the Otx-1 and Otx-2 genes related to odt reviewed in Ref. In the mouse, the two Emx and the two Otx genes are expressed in discrete, overlapping regions of the developing forebrain and midbrain, which often coincide with anatomical landmarks, and loss-of-function studies have shown that they play an important role in the patterning of these structures 50 — Therefore, both the sequence conservation and the related expression patterns of the two gene families suggests that cephalization was established in a primitive ancestor of both flies and humans.
De novo mutations in the human EMX2 gene have been reported in patients with schizencephaly, an extremely rare congenital disorder characterized by a full-thickness cleft within the cerebral cortex; eventually, large portions of the cerebral hemispheres may be lacking, resulting in an holohemispheric cleft filled with cerebrospinal fluid.
The phenotype of these patients suggests a requirement of the EMX2 protein for the correct formation of the cerebral cortex Interestingly, Otx-1 null mice show spontaneous epileptic behavior associated with subtle brain abnormalities, suggesting that mutations in the human OTX1 gene might be responsible for some cases of epilepsy associated with cortical dysgenesis The Engrailed homeobox genes En-1 and En-2 are both expressed in a domain spanning the first rhombomere and the midbrain.
Targeted gene disruption experiments have shown that En-1 has a critical role in the specification of its entire region of expression, whereas En-2 function is restricted to cerebellar foliation. However, the En-1 null phenotype, agenesis of the tectum and cerebellum, is completely rescued by insertion of the En-2 cDNA into the En-1 locus, suggesting that the distinct phenotypes of the En-1 and En-2 mutations reflect differences in the temporal expressions of the corresponding proteins, rather than differences in their biochemical activity The Pax family consists of nine unlinked genes; for example, each human PAX gene is located on a different chromosome reviewed in Ref.
Pax3, 4, 6, and 7 encode, in addition to the characteristic paired domain a amino acid DNA binding domain , a full-length homeodomain. In mouse embryos, Pax genes are widely expressed in the CNS and, as with the Otx, Emx, and En genes, their domains of expression in the brain suggest a role in its regionalization.
Pax6 is also expressed in the optic vesicle a prosencephalic derivative and in the presumptive lens. Heterozygotic mutations in PAX6 have been reported in families with eye defects such as: 1 aniridia, a panocular disorder in which the development of the iris, cornea lens, and retina are disturbed; 2 Peters' anomaly, a defect of the anterior chamber of the eye with corneal malformations and attachment of the lens to the central aspect of the cornea; and 3 isolated foveal hypoplasia [ e.
It is noteworthy that mutations in PAX6 involve the inactivation or complete deletion of the PAX6 gene; hence, their autosomal dominant nature is not due to the presence of a dominantnegative mutant protein that could interfere with the function of the normal protein or related proteins, as appears to be the case for HOXA13, HOXD13, and PIT1 mutations see below. Instead, it must reflect haploinsufficiency, a condition in which the amount of protein produced from a single functional allele is not sufficient to control the expression of downstream genes.
In this respect, it is noteworthy that a putative case of PAX6 homozygous mutation resulted in anophthalmia and severe brain defects The patterning of the first pharyngeal arch is partially reflected by the number, size, and shape of the teeth.
Expression of Msx-1 and 2 in the mouse fetus and the phenotype displayed by Msx-1 null mice anodontia, i. These and other homeobox genes such as Distal-less 1 and 2 Dlxl, Dlx2 and Goosecoid Gsc , are expressed in restricted overlapping fields in the developing mandible.
Interestingly, it was recently demonstrated that selective tooth agenesis i. MSX1 is not, however, linked to the more common human hypodontia, agenesis of the lateral incisors and second premolars [for a review, see Thesleff and Nieminen 60 and references therein]. Mutation analysis in families with Rieger's syndrome an autosomal-dominant disorder characterized by hypodontia, abnormalities of the anterior chamber of the eye, and a protuberant ombilicus has led to the identification of a novel homeobox gene, RIEG, whose mutations are responsible for the abnormalities observed in the Rieger syndrome Mutations in the homeobox of the human MSX2 gene have been associated with a rare form of craniosynostosis, called the Boston type.
It is, however, noteworthy that more frequent craniosynostotic syndromes i. Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes are caused by point mutations in fibroblast growth factor receptor genes reviewed in Ref. Mutations in the gene encoding Pit-1 have been identified in patients with combined pituitary hormone deficiency, in which there is no production of growth hormone, prolactin, and TSH, resulting in mental retardation and growth deficiency [for a review, see Rhodes et al.
The mutant Pit-1 can still bind to its DNA-binding site in target genes, but unlike the normal transcription factor, it does not activate transcription and, moreover, it prevents the normal protein from binding to DNA. These findings account for the dominant nature of the disease.
Mutations in the POU3F4 gene cause deafness with fixation of the stapes, which represents the most frequent X-linked form of hearing impairment The homeobox gene mutations causing human birth defects are summarized in Table 1.
The demonstration of cell lineage-specific patterns of Hox gene activation in human and murine leukemic cell lines supports the hypothesis that Hox gene expression can regulate normal hematopoietic differentiation reviewed in Ref.
Notably, expression of all HoxA cluster members was reported predominantly within cells of myelomonocytic origin. Very recently, two groups have reported the involvement of HOXA9 in the t 7;11 p15;p15 chromosomal translocation, a rare but recurrent chromosomal rearrangement associated with AML. Hoxa-9 and Hoxa-7 have also recently been shown to be activated by proviral integration in a mouse model of myeloid leukemia The induction of leukemogenesis was strongly correlated with the simultaneous proviral insertion into the Pbx related Meis gene, a finding that is particularly interesting given that Hox proteins appear to cooperatively bind DNA with Pbx proteins see below.
Pbx-1 is a divergent homeobox gene that was identified as the chromosome 1 partner of the t 1;19 translocation in human preB-cell ALL. The t 1;19 results in the fusion of a portion of PBX1 including the homeodomain, with a truncated EA2 protein. Pbx-1, as well as the E2A-Pbx-1 fusion, cooperatively bind DNA in vitro with several other Hox proteins, thus further suggesting that the oncogenic effects of Pbx proteins involve the formation of Pbx-Hox heterodimers [see references in Nakamura et al.
HOX11 is another example of divergent homeobox gene originally isolated from a human leukemia. MLL, does not possess a homeodomain; it is mentioned here because of its homology to the Drosophila trithorax gene, a regulator of the expression of HOM-C genes during embryogenesis. Loss-of-function data support a functional conservation in mammals, thus suggesting that MLL may act in hematopoietic malignancies by altering Hox genes expression [see Yu et al.
As to solid tumors, only PAX3 and PAX7 have been so far involved in some forms of rhabdomyosarcoma characterized by t 2;13 q35;q14 and t 1;13 q36;q14 chromosomal translocations, respectively reviewed in Ref. The homeobox gene mutations involved in tumorigenesis are summarized in Table 2. The study of mouse homeobox genes mutations have clearly established the fundamental role of their products in patterning and organogenesis. It is likely that, in humans, mutations in such important genes are responsible for some of the early cases of spontaneous abortion and that, in the future, an increasing number of congenital malformation syndromes will be correlated with Hox gene mutations.
It is also noteworthy that environmental factors such as retinoids [ e. Gehring WJ A history of the homeobox. Oxford University Press, Oxford, pp 3— Google Scholar. Mech Dev 55 : 91— Development , Suppl. Nearly every animal that's been tested has homeobox sequences in its DNA, suggesting that Hox genes arose very early in the animal family tree.
Genetic sequences maintained over evolutionary time are thought to be especially important to the basic development of even distantly related organisms. The presence of homeotic gene sequences in animals as different as jellyfish, insects, and mammals suggests that these genes have a crucial function in many, and perhaps all, animals. Scientists have studied the genes' DNA sequences, functions, and organization to learn about evolutionary relationships.
Hox genes have revelaed many clues about the evolution of the animal family tree. The similarities among Hox genes, especially in the shared homeobox sequence, suggest that they all arose from a single ancestral gene that was duplicated multiple times. After each duplication event, the genes gradually changed, taking on slightly different jobs. This process is known to evolutionary biologists as "duplication and divergence.
The first duplications happened a very long time ago. An animal that lived about a billion years ago, the ancestor to all animals, had at least 4 Hox genes. By million years ago, in the ancestor to all modern animals that have bilateral symmetry, the number grew to at least 7. We know this because animals descended from this ancestor have homologues of these genes.
Additional duplication events happened in some branches of the animal family tree. In insects, for example, a gene near the right end of the cluster was duplicated. In vertebrates, the entire Hox cluster was duplicated—three times in mammals and up to 8 times in some types of fish.
The duplicate genes were then free to take on new functions, often leading to more-complex body structures. Like other genes, Hox genes are more similar in closely related species and less similar in more distantly related species. By comparing sequence similarity, scientists can determine when in evolutionary history certain duplication events happened, and where some Hox genes were lost along the way additional gains and losses have happened within individual species in each group.
Illustraiton based on information from Pascual-Anaya et al , Carroll et al , and Garcia-Fernandez Hox genes code for proteins that attach to molecular switches on DNA, turning other genes on and off. The DNA-binding piece of a Hox protein is called the homeodomain, and it's encoded by the homeobox. The homeodomains in different Hox proteins are similar but not identical—they bind to different DNA sequences. So different Hox proteins regulate different sets of genes, and combinations of Hox proteins working together to regulate still other sets of genes.
As regulators of other genes, Hox proteins are very powerful. A single Hox protein can regulate the activity of many genes. And sets of genes work together to carry out "programs" during embryonic development—programs for building a leg or an antenna, for example—much like computer programs carry out specific tasks.
A large amount of animal diversity is built on two simple ideas: bodies made up of repeating units or segments , and genetic programs for building structures. Just within arthropods shown on the right , variations on this theme have given rise to an enormous diversity of body types. Once a program exists for building a structure, it can be reused elsewhere simply by shifting Hox gene expression. A genetic change that leads to a change in body shape might allow an organism to capture food more effectively or avoid predators, giving it a reproductive advantage.
Its genes may be preferentially passed along to the next generation, thus influencing the course of evolution. In vertebrates animals that have backbones , the entire Hox cluster has been duplicated multiple times. Mice and other mammals have four Hox clusters.
All four are similar, but each is different. Similar genes in different clusters are called paralogs. Most paralogs have partially overlapping functions, so figuring out how Hox genes function in vertebrates a challenge: the effects of changing a single gene are often hidden by functioning genes in the same paralogous group.
But changing the function of multiple genes in the group can have dramatic effects. The photos on the left, provided by Mario Capecchi's research group at the University of Utah, show mouse forelegs. Inactivating one paralog or the other has subtle effects middle two images.
But inactivating both makes a dramatically different limb right. This experiment and others have shown that Hox genes in mice work much the same way as they do in fruit flies. While mice and other vertebrates are not as obviously segmented as arthropods, certain regions of their bodies actually are.
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