**2. Origin of the Hox gene cluster**

The Hox genes were discovered in 1915 by Calvin Bridges in a mutant *Drosophila melanogaster* named Bithorax, which showed a partial duplication of the thorax [4]. Years later, another mutation in the Hox genes was identified resulting in a mutant fly exhibiting legs instead of antenna named Antennapedia [5]. The Hox genes were then grouped into these two complexes (Bithorax and Antennapedia), which are located on chromosome 3 and play a key role in conferring the identity along the anteroposterior axis of the body. The role of these genes in establishing the anteroposterior axis is highly conserved in vertebrates [5, 6]; however, the Hox gene cluster has changed during its evolution, evidenced by different numbers of clusters between species (**Figure 1**). For example, whereas invertebrates typically possess a single cluster, vertebrates such as mice and humans possess four gene clusters coding for the three different axes: cervical, thoracic, and lumbosacral [2, 6]. Despite these differences, Hox genes have been identified in all species, which reflects the important role of these genes in the regulation of body structure [1, 7]. In humans, the 39 mammalian Hox genes are grouped into four chromosomal clusters named *HOXA*, *HOXB*, *HOXC*, and *HOXD*, located on chromosomes 7p14, 17q21, 12q13, and 2q31, respectively [8]. This large family encodes homeodomain transcription factors that share highly conserved DNA sequence formed by 183 bp called "homeobox," which encodes a polypeptide core of 61 amino acids formed by three alpha helices known as the homeodomain. Most homeodomains recognize highly conserved DNA elements that

**Figure 1.** The composition and evolutionary differences of the HOX gene cluster between *Drosophila melanogaster*, mouse, and *Homo sapiens*. The HOX gene clusters and their chromosomal location were compared between *Drosophila melanogaster*, mouse, and *Homo sapiens*. Genes were grouped according to the distribution of the three axes corresponding to the anteroposterior part of the body (cervical, thoracic, lumbosacral).

serve as a promoter for many genes (motif TAAT) being a T in the direction 5′ determinant for this coupling acknowledgment [9]. Hox transcription factors are well known for playing a key role during cell and tissue differentiation in developing embryos; however, other studies have shown that these homeotic genes also play a role in adult process such as hematopoiesis and embryo implantation by promoting neovasculogenesis and angiogenesis [10].
