Homeobox genes are a group of genes that regulate development in multicellular organisms; this includes cell differentiation and morphogenesis. They were first discovered in the fruit fly Drosophila, and since their discovery examples have been found in all multicellular organisms from fungi to vertebrate animals. Some homeobox genes have been linked to congenital abnormalities and diseases.
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The common motif in homeobox genes is typically a 180 base pair DNA sequence which encodes a 60 amino acid homeodomain. This becomes the DNA binding motif of larger homeoproteins, which act as transcriptional regulators; either upregulating or downregulating specific target genes.
How many homeobox genes are there in the human genome?
The draft human genome, which became available in 2001, has been used to estimate the number of homeobox genes in the human genome; Venter et al. identified 160 homeobox genes, which in turn had 178 varying homeobox sequences. On the other hand, the IHGSC team estimated that the human genome had 267 homeobox genes.
It is important to note, however, that both of these estimates were made using the draft human genome, therefore it is possible that some homeobox genes could have been missed, or that some pseudogenes have been characterized as genes.
In vertebrates, homeobox genes are broadly divided into two subfamilies; Hox genes or class I homeobox genes, which cluster, and other divergent homeobox genes that are scattered across the genome.
The Greek word “homeo” means “alike”, and the Drosophila homeotic (HOM) genes were named as mutations within the HOM genes that can lead to a body segment resembling a different body segment. Hox genes in mammals are named because of their similarity to “homeotic complex” genes in Drosophila. Human Hox genes can be grouped into four clusters; HoxA genes on chromosome 7, HoxB genes on chromosome 17, HoxC genes on chromosome 12 and HoxD genes on chromosome 2. Each Hox gene cluster has between 9 and 11 individual genes.
Studies have shown that mutations in Hox genes can lead to defects in the morphologies of multicellular organisms. There is evidence to suggest that these Hox genes mutations actually play a role in evolution, as they lead to morphological differences, which in turn lead to bigger changes in the body of these organisms.
How do Hox genes affect development?
The earliest stage of embryo development when Hox genes can be detected is during gastrulation when the germ layers are formed and specified into a body plan. The ability to target and modify specific genes and the availability of transgenic mice have allowed for the function of Hox genes to be studied.
One example is the role of HoxD13 during limb development in mice; when this Hox gene is disrupted, it results in the metacarpal and metatarsal bones being truncated, phalanges can either be shorted or missing and a supernumerary digit rudiment is formed in the forelimb. Interestingly, synpolydactyly in humans has been linked to a mutation in HoxD13; here, a poly-Alanine stretch is inserted into the N-terminus region of the HoxD13 product, and this results in limb abnormalities which are more severe than those seen in transgenic mice.
Do homeobox genes play a role in cancer?
Studies using cell lines derived from leukemia have shown that they have specific Hox gene expression patterns; for example, HoxA genes seem to be expressed in the myelomonocytic lineage of blood cells. This means that there is a possibility that Hox genes are involved in the normal differentiation of blood cells.
Studies have shown that a rare chromosomal rearrangement (translocation) seen in acute myeloid leukemia (AML) involves HoxA9. This translocation leads to the production of a chimeric product, comprised of NUP98 and HoxA9, which may promote the development of AML.
Another HoxA gene, HoxA11, has been shown to be involved in another chromosomal translocation that leads to rare T cell acute lymphoblastic leukemia. In this instance, HoxA11 is overexpressed as the translocation has brought it in close proximity to the T cell receptor gene promoters.
Two other homeobox genes, PAX3 and PAX7, have been linked to certain cases of rhabdomyosarcomas, again linked to chromosomal translocation. It is possible that there other cases of cancers driven by changes in the way homeobox genes are expressed that are yet to be discovered.
Mark, M. et al. (1997) Homeobox Genes in Embryogenesis and Pathogenesis. Pediatric Research https://www.nature.com/articles/pr19972506
Holland, P. W. H. et al. (2007) Classification and nomenclature of all human homeobox genes. BMC Biology https://bmcbiol.biomedcentral.com/articles/10.1186/1741-7007-5-47
Solnica-Krezel, L. and Sepich, D. S. (2012) Gastrulation: Making and Shaping Germ Layers. Annual Review of Cell and Developmental Biology www.annualreviews.org/doi/full/10.1146/annurev-cellbio-092910-154043
Pearson, J. C. et al. (2005) Modulating Hox gene functions during animal body patterning. Nature Reviews Genetics https://www.nature.com/articles/nrg1726