We rename them ZEB1 and ZEB2 to distinguish them from genes belonging to the distantly related Zfhx gene family. In a few cases, it is useful to erect an intermediate rank between these levels, and for this we use the term subclass. It is currently unclear if this gene family is derived from one or more genes in the common ancestor of bilaterians [18]. We designate them CUX2P1 and CUX2P2 because they are clearly retrotransposed pseudogenes of CUX2. Mamm Genome. Google Scholar. Harada R, Brub G, Tamplin OJ, Denis-Larose C, Nepveu A: DNA-binding specificity of the cut repeats from the human cut-like protein. Finally, we have identified the Drosophila ortholog, IP09201. The alternative view, argued by Hart et al [36], is that this locus is a functional gene, and should be named NANOG2. Perhaps the most interesting case, however, is found on the tip of the long arm of chromosome 9, where there is a concentration of homeobox genes from disparate gene classes. For the rank of gene family, we use a specific evolutionary-based definition based on common practice in the field of comparative genomics and developmental biology. The Class I homeobox genes (HOX in human, Hox in mouse) are a transcription factor family, involved in embryo development containing a sequence of 183 nucleotides (homeobox) encoding a protein alpha helix-domain structure of 61 aminoacids (homeodomain); the homeodomain recognizes and binds a specific nucleotide sequence on DNA. These include genes lost from human, as well genes known to have undergone unusually rapid evolution in Drosophila. Most of the 50 genes in the PRD class have been adequately named previously. Cite this article. Chen S, Saiyin H, Zeng X, Xi J, Liu X, Li X, Yu L: Isolation and functional analysis of human HMBOX1, a homeobox containing protein with transcriptional repressor activity. CUX1 [Entrez Gene ID: 1523] and CUX2 [Entrez Gene ID: 23316]. Classes and/or families are color coded as shown in the key. This is done by gradients of mRNAs and proteins encoded by the mother's genes and placed in the egg by her. Its lack of annotation may reflect the fact that it is located within an intron of an unrelated and well characterized gene, STAU2. The pseudogene shares 86% identity with VENTX mRNA (after masking of an Alu element in the parental mRNA sequence), lacks intronic sequence, and has remnants of a 3' poly(A) tail. Genes that have taken on non-Hox-like functions are shown in brown and discussed in the text. These genes were previously known as CUTL1 and CUTL2 respectively. 2003, 255: 128-137. Pseudogenes undergo mutational decay and would eventually become unrecognizable, but in practice ambiguous cases were not encountered. PubMed NKX2-2 and NKX2-8 are collectively orthologous to Drosophila vnd and amphioxus AmphiNk2-2 [31, 32]; these comprise a second gene family: Nk2.2. Fourth, the LEUTX gene is located close to the PRD-class genes TPRX1, CRX, DPRX and DUXA on the distal end of the long arm of chromosome 19 (Figure 4). 2000, 16: 75-83. 2015; 225 (6):353-7. We designate this previously unnamed gene NKX2-6 on the basis of clear orthology to mouse Nkx2-6, inferred from sequence identity and synteny, although nomenclature revision for the entire Nk4 gene family should be discussed (see above). Mutations in human Hox genes can cause genetic disorders. 1989, 5: 164-166. PBX2P1 [Entrez Gene ID: 5088]. These include genes very tightly linked to the Hox clusters, notably the Evx-family genes (on chromosomes 2 and 7), Dlx-family genes (on chromosomes 2 and 17), and Meox-family genes (on chromosomes 2 and 17). 10.1080/10635150390235520. We have also identified a total of three CUT-class pseudogenes in the human genome (Tables 1 and 4); we have named all of these (CUX2P1, CUX2P2 and SATB1P1). Curr Biol. 2000, 97: 8904-8909. Nk2.1 and Nk2.2 gene families. Hox genes, a subset of homeobox genes, are a group of related genes that specify regions of the body plan of an embryo along the head-tail axis of animals. 10.1093/nar/gkh435. The genes NKX2-1 (formerly TITF1), NKX2-4, NKX2-2 and NKX2-8 divide into two distinct gene families each with an invertebrate ortholog, not a single Nk2 gene family. Dearden PK, Wilson MJ, Sablan L, Osborne PW, Havler M, McNaughton E, Kimura K, Milshina NV, Hasselmann M, Gempe T, et al: Patterns of conservation and change in honey bee developmental genes. SATB1P1 is a short partial integrant derived from part of the 3' untranslated region of SATB1 mRNA; it does not encompass the homeobox. There is one exception: the human Lmo gene family encodes LIM domains that have been grouped by sequence similarity and domain arrangement with the LIM domains of the LIM homeobox gene class [59]. 124 Similar genes in the separate clusters are considered paralogs . Our new nomenclature (ZEB2P1) reflects the origin of this locus. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. We designate this previously unnamed gene LEUTX (leucine twenty homeobox) to reflect the presence of a leucine residue at the otherwise highly conserved homeodomain position 20; other PRD-class homeodomains have a phenylalanine at this position (Additional file 6). Google Scholar. The SIX domain is a DNA-binding domain of approximately 115 amino acids; both the SIX domain and the homeodomain are required for DNA binding [68]. Topologies that separate the gene families are also only weakly supported, so it is most parsimonious to assume that the class is actually monophyletic but the constituent genes underwent rapid sequence divergence following their initial duplications. NKX6-3 [Entrez Gene ID: 157848] is the third of three human members of the Nk6 gene family. Circulation Res. Each clearly aligns to the mRNA sequence of POU5F1 but with sequence alterations, indicating origin by retrotransposition. We review phenotypes, inheritance and molecular genetics of human HOX disorders. Not all of these loci possess a homeobox because for completeness we include all sequences derived from homeobox-containing genes. 1997, 7: 331-337. This definition has been made explicitly in previous work [2, 6] but is actually a principle that has been in widespread, but rather inconsistent, use for over a decade [15]. 10.1016/S0168-9525(99)01883-1. The accumulation on the distal half of the long arm of chromosome 10 is particularly striking, comprising eleven ANTP-class genes from 10 gene families. Detailed relationships between different gene families should not be inferred from this tree. This gene was previously known as CHX10; we rename it VSX2 to better reflect its paralogous relationship to VSX1. Chromosomal distribution of human homeobox genes. Dev Biol. Also, secondary structure prediction did not predict the expected organisation of alpha helices. Only genes encoding both LIM domains and homeodomains are included in our LIM homeobox gene count. 2005, 390: 263-271. Over the coding region, there are just two nucleotide substitutions (both nonsynonymous); one of these results in an unusual change within the homeodomain (arginine to cysteine at position 18). Chromosomal position does not shed light on the issue, as its location at 7q35 is close to both ANTP- and PRD-class genes (Figure 4). 1994, 144: 213-219. We suggest that this style, and most of these gene family names, can be used in other bilaterian genomes. 10.1006/dbio.1997.8626. ZEB1 [Entrez Gene ID: 6935] and ZEB2 [Entrez Gene ID: 9839]. Using the aforementioned criteria, we recognize 102 homeobox gene families in the human genome (Table 1). Google Scholar, Akam ME, Holland PWH, Ingham PW, Wray G: The evolution of developmental mechanisms. Caubit X, Cor N, Boned A, Kerridge S, Djabali M, Fasano L: Vertebrate orthologues of the Drosophila region-specific patterning gene teashirt. The fact that they are not included in the total count, therefore, is likely to have limited bearing on understanding the diversity and normal function of human homeobox genes. We place LEUTX in the PRD class for four reasons. 2002, 110: 725-735. statement and PWHH and HAFB drafted the manuscript. 1996, 93: 10858-10863. Further information on this gene may allow this tentative classification to be revisited. 1999, 399: 772-776. The three horizontal lines indicate the positions of the three alpha-helices. BMC Genom. Dev Genes Evol. 10.1007/s004270050243. 10.1046/j.1525-142X.2003.03052.x. Changes in these genes can have a profound impact on morphology. Holland PWH, Takahashi T: The evolution of homeobox genes: implications for the study of brain development. 24 Altmetric Metrics Abstract Background The homeobox genes are a large and diverse group of genes, many of which play important roles in the embryonic development of animals. There is confusion as to whether this should be split into two gene families, because invertebrate homologs generally group with PAX6 in phylogenetic analyses and not as an outgroup to the two genes as might be expected. Pax2/5/8 gene family. The finished human genome sequence (build 35.1) was subjected to a series of tBLASTn searches [85, 86] using known homeodomain sequences from the ANTP, PRD, LIM, POU, HNF, SINE, TALE, CUT, PROS and ZF classes. Gabrils J, Beckers M-C, Ding H, De Vriese A, Plaisance S, van der Maarel SM, Padberg GW, Frants RR, Hewitt JE, Collen D, et al: Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. IHGSC: Initial sequencing and analysis of the human genome. It has been proposed that the ancestor of these two genes arose by retrotransposition of TGIF2 mRNA [84]. We identified 300 homeobox loci in the euchromatic regions of the human genome, and divide these into 235 probable functional genes and 65 probable pseudogenes. 10.1016/S0959-437X(97)80146-3. Increasingly, homeobox genes are being compared between genomes in an attempt to understand the evolution of animal development. As previously discussed, most members of this gene family are intronless and are probably derived by retrotransposition of an mRNA transcript from a functional intron-containing Dux gene (or duplication of such an integrant). 10.1242/dev.00977. Dev Dynam. The LIM and ZF classes are not recovered as two distinct monophyletic groups, a result also found by neighbor-joining analysis (Additional file 5). Bootstrap values supporting internal nodes with over 70% are shown. Plouhinec J-L, Sauka-Spengler T, Germot A, Le Mentec C, Cabana T, Harrison G, Pieau C, Sire J-Y, Vron G, Mazan S: The mammalian Crx genes are highly divergent representatives of the Otx5 gene family, a gnathostome orthology class of orthodenticle-related homeogenes involved in the differentiation of retinal photoreceptors and circadian entrainment. The HOX genes are an interesting case as their precise number in the most recent common ancestor of bilaterians is unknown due to lack of phylogenetic resolution between 'central' genes [20]. Ryan JF, Burton PM, Mazza ME, Kwong GK, Mullikin JC, Finnerty JR: The cnidarian-bilaterian ancestor possessed at least 56 homeoboxes: evidence from the starlet sea anemone, Nematostella vectensis. Curr Biol. Pseudogenes were recognized as those genomic regions with similarity to non-repetitive DNA sequences of the parent gene, even if aligning to only part of the locus. 2000, 22: 616-626. We have identified a total of seven CUT-class homeobox genes in the human genome (Tables 1 and 4). VENTX [Entrez Gene ID: 27287] is the only functional member of the Ventx gene family in the human genome. 2005, 15: R12-R13. Nucleic Acids Res. Thus, we stick with convention for this set of genes. Genome Biol. Bertolino E, Reimund B, Wildt-Perinic D, Clerc RG: A novel homeobox protein which recognizes a TGT core and functionally interferes with a retinoid-responsive motif. 2002, 33: 285-294. Thus, in both instances, reliable indicators of non-functionality were sought in order to assign pseudogene status, notably frameshift mutations, premature stop codons and non-synonymous substitutions at otherwise conserved sites in the original coding region. TGIF2P4 is a short partial integrant derived from part of the 3' untranslated region of TGIF2 mRNA. NANOGP8 [Entrez Gene ID: 388112]. VENTXP7 [Entrez Gene ID: 391518]. Holland, P.W., Booth, H.A.F. Shin CH, Liu Z-P, Passier R, Zhang C-L, Wang D-Z, Harris TM, Yamagishi H, Richardson JA, Childs G, Olson EN: Modulation of cardiac growth and development by HOP, an unusual homeodomain protein. No arbitrary E-value cut-off was selected, but instead each list of hits was analyzed manually until true homeodomain sequences ceased to be detected. Guidebook to the Homeobox Genes. GSC2 [Entrez Gene ID: 2928] is the second of two human members of the Gsc gene family. Cell. As noted earlier, phylogenetic analyses of homeodomains does not recover the ZF class as a monophyletic group (Figure 3; Additional files 1, 2 and 5). Phylogenetic analyses of homeodomains place it basally in a clade with the POU class (Figure 3; Additional files 1 and 5), or within the POU class (Additional file 2), suggesting that the HDX protein either diverged before the POU-specific domain became associated with the homeodomain or lost the POU-specific domain during evolution. Pewzner-Jung Y, Ben-Dor S, Futerman AH: When do Lasses (longevity assurance genes) become CerS (ceramide synthases)? Article Some of the copies are 100% identical to the previously reported DUX4 sequence over the homeobox regions, others have single nucleotide polymorphisms, some have critical sequence mutations, and others have just a single homeobox. The PBX2P1 sequence aligns to the mRNA of PBX2 but has a frameshift mutation in the coding region. 1996, 79: 920-929. These genes were previously known as ZFHX1A and ZFHX1B respectively. Figure 1. Felsenstein J: PHYLIP: Phylogeny Inference Package (version 3.2). The former name of PBXP1 did not indicate its transcript of origin. We designate this previously undescribed sequence OTX2P1 because it is clearly a retrotransposed pseudogene of OTX2. )[92], with a JTT model of amino acid substitution and 1000 bootstrap resamplings. 10.1093/hmg/7.11.1681. Thus, CRX could be considered the true OTX3 gene [44]. Rao E, Weiss B, Fukami M, RumpAndreas , Niesler B, Mertz A, Muroya K, Binder G, Kirsch S, Winkelmann M, et al: Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. The mouse version of the gene was first identified first and named Hop (homeodomain only protein) because the encoded protein is just 73 amino acids long, with 61 of these making up the homeodomain [41, 42]. First, several genes and pseudogenes possess more than one homeobox sequence, notably members of the Dux (double homeobox), Zfhx and Zhx/Homez gene families. This gene family is also known as Pax group II; it contains PAX2, PAX5 and PAX8, clearly derived from a single ancestral gene [45]. Beckers M-C, Gabrils J, van der Maarel S, De Vriese A, Frants RR, Collen D, Belayew A: Active genes in junk DNA? CAS We designate this previously unnamed gene POU5F2 on the basis of clear orthology to the mouse Sprm1 gene, which has been assigned the second member of the Pou5 gene family [63]. Almost every gene found in one species so far has been found in a closely related form in the other. NKX1-1 [Entrez Gene ID: 54729] and NKX1-2 [Entrez Gene ID: 390010] are the only two members of the Nk1 gene family in the human genome. Therefore, they do not belong to the Nk2.1 or Nk2.2 gene families, but belong to a separate Nk4 gene family. Bayarsaihan D, Enkhmandakh B, Makeyev A, Greally JM, Leckman JF, Ruddle FH: Homez, a homeobox leucine zipper gene specific to the vertebrate lineage. [http://www.compbio.dundee.ac.uk/Software/JPred/jpred.html], Ensembl Genome Browser. Pollard SL, Holland PWH: Evidence for 14 homeobox gene clusters in human genome ancestry. This is perhaps not surprising as trees that encompass many homeobox genes can only be built with a short sequence alignment (the homeodomain); under these conditions, phylogenetic trees can only be used as a guide to possible classification, not the absolute truth. Arbitrarily rooted phylogenetic tree of human ANTP-class homeodomains constructed using the maximum likelihood method. 1995, 6: 280-292. The Drosophila Hox complex, HOM-C, is highlighted. This gene family falls close to the division between the ANTP and PRD classes in both maximum likelihood and neighbor-joining phylogenetic analyses (Additional files 1 and 2). These are the IRX domain, MKX domains, the MEIS domain, the PBC domain and TGIF domains [2, 7173]. This is not a tight gene cluster, but it is compatible with ancestry by extensive tandem gene duplication followed by dispersal. 2005, 22: 2386-2394. 10.1073/pnas.97.16.8904. Hox genes are clustered in the genome. The symbol PRRXL1 is misleading because it infers membership of the Prrx gene family, containing PRRX1 and PRRX2 in the human genome. 10.1159/000093328. While the gene family definition described above is generally workable for homeobox genes, by necessity there are some exceptions. Accordingly, we also replace the VENTX1 symbol with VENTXP7 (see below). These four sequences were unannotated prior to this study. Hopx gene family. 10.1073/pnas.93.20.10858. Thus, we recognize a total of 31 gene families in the PRD class (Table 1). The human PROX1 gene is well characterized; we have identified and named its paralog, PROX2. Nucleic Acids Res. McGinnis S, Madden TL: BLAST: at the core of a powerful and diverse set of sequence analysis tools. Phylogenetic analyses confirm previous suggestions [67] that HMBOX1 is more distantly related to HNF1A and HNF1B (Figure 3; Additional files 1, 2 and 5). 1990, 4: 372-379. Article Peter WH Holland. Leutx gene family. These additional residues are inserted at a different position compared to the TALE class, being between the second and third alpha helices (Additional file 6). We do not include probable pseudogenes on these ideograms, because most of these have originated by reverse transcription of mRNA and secondary integration into the genome, and hence give no insight into ancestral locations of genes. Bootstrap values supporting gene family designations are shown. There is more consensus in classification at a lower level, just above the level of the gene, where very similar genes are grouped into gene families. Nat Genet. 1. they're small 2. easy to keep 3. have short life cycles what do all homeobox genes contain? The structure of the four murine Hox complexes and the co-ordinate expression patterns of Hox genes have been elucidated for almost a decade. Additional file 1: Maximum likelihood phylogenetic tree of all human plus selected protostome and cnidarian homeodomains for identification of gene families. This gene was previously known as GSCL; we rename it GSC2 to remove the inadvertent implication that it is not a true gene, and also to reflect the clear orthology to chick Gsc2 as inferred by phylogenetic analysis and synteny. 2002, 46: 115-123. Therefore, we revise the gene symbol from HOP to HOPX (HOP homeobox) in accordance with homeobox gene nomenclature convention. This fourth observation leads us to hypothesize that this gene family arose by tandem duplication and extensive divergence during mammalian evolution. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. All organisms have Hox genes. Each gene family has two human members and dates to a single ancestral gene in the most recent common ancestor of bilaterians [60]. To ensure that every pseudogene was detected, including truncated or decayed versions lacking the homeobox, the full mRNA sequence of each gene was deduced and used in a BLASTn search of the human genome sequence [85, 86]. We have identified a previously undescribed pseudogene from the Otx gene family (OTX2P1), and argue that the majority of Dux-family sequences are pseudogenes. We have updated these as follows. They encode transcription factors that are selectively expressed in the reproductive tract; in humans this gene cluster is mainly expressed in male and female germ cells ( 12-15 ). open access Highlights Germline mutations in 10 Hox genes have been found to cause human disorders. There is an Alu element (AluSx subfamily) insertion, a Made1 (Mariner derived element 1) insertion, and a 1182-nucleotide deletion in OTX2P1 compared to OTX2. The PROS domain is a DNA-binding domain of approximately 100 amino acids [77]. Homeodomain sequences derived from pseudogenes are excluded. The POU-specific domain is a DNA-binding domain of approximately 75 amino acids; the POU-specific domain and the homeodomain are collectively known as the bipartite POU domain [61]. One other gene could conceivably be included in the ANTP class, but is excluded from our survey. Using exhaustive database screening, followed by manual examination of sequences, we identified 300 homeobox loci in the human genome. 2006, 7: R64-10.1186/gb-2006-7-7-r64. Second, the HOPX homeodomain possesses the same combination of residues that are invariably conserved across human PRD-class homeodomains (Additional file 6). Springer Nature. Therefore, these are exceptions to the rule defining gene families as dating to the base of the Bilateria. Google Scholar. J Biol Chem. Phylogenetic analyses of homeodomains divide the SIX class into three gene families (Figure 3; Additional files 1, 2 and 5), consistent with previous studies [68, 69]. Introduction How many legs does a fruit fly have? Yes, humans have Hox genes. This gene was previously known as OG9X with SEBOX as the alternative symbol; we favor SEBOX because the OG prefix was originally used for several unrelated homeobox genes. 2000, 10: 1059-1062. The LIM domain is a protein-protein interaction domain of approximately 55 amino acids comprising two specialised cysteine-rich zinc fingers in tandem [59]. Wada H, Holland PWH, Sato S, Yamamoto H, Satoh N: Neural tube is partially dorsalized by overexpression of HrPax-37: the ascidian homologue of Pax-3 and Pax-7. This should not be taken as a precise figure due to copy number polymorphism and the possibility of additional copies existing in currently unsequenced heterochromatic regions. We favor placement in the PRD class for three reasons. The steps that Hox genes undergo to regulate vvI1+2 can inform how Hox genes regulate other DNA, not just in fruit flies but beyond including in vertebrates, such as mammals, and even humans. 2003, 100: 10358-10363. It is intriguing, but probably coincidental, that the MSX2P1 pseudogene has integrated at 17q23.2, close to several ANTP-class genes (HOXB cluster, MEOX1, DLX3 and DLX4). We draw attention here to newly defined gene families and cases that could cause confusion. Phillips K, Luisi B: The virtuoso of versatility: POU proteins that flex to fit. 10.1007/s00335-005-0138-4. the homeodomain The NKL (NK-Like or NK-Linked) genes are more dispersed, but there is a concentration on the NKL or MetaHox paralogon (2p/8p, 4p, 5q and 10q) (Figure 4). The IRX4P1 sequence is a partial integrant derived from a region of the IRX4 mRNA around the stop codon; it lacks the homeobox. CAS Proc Natl Acad Sci USA. 2006, 16: 1376-1384. MacLean JA, Chen MA, Wayne CM, Bruce SR, Rao M, Meistrich ML, Macleod C, Wilkinson MF: Rhox: a new homeobox gene cluster. The figures exclude the repetitive DUX1 to DUX5 homeobox sequences of which we identified 35 probable pseudogenes, with many more expected in heterochromatic regions. As previously discussed, the subclasses are largely consistent with the chromosomal positions of genes [26, 27]. Rhox gene family. 10.1016/S0925-4773(99)00318-4. POU5F2 [Entrez Gene ID: 134187]. Unfortunately, the OTX3 symbol was formerly used erroneously for a gene in a different family, now called DMBX1, thus complicating its future use. We have also identified a total of eight POU-class pseudogenes in the human genome (Tables 1 and 4); we have named six of these (POU5F1P2, POU5F1P4 to POU5F1P8), and revised the nomenclature of one other (POU5F1P3). 10.1126/science.1058040. The POU-like domain, as its name indicates, is weakly similar in sequence to the POU-specific domain [64]; more importantly, it has nearly the same three-dimensional structure and mode of DNA binding as the POU-specific domain [65]. We designate this previously unannotated sequence IRX4P1 because it is clearly a retrotransposed pseudogene of IRX4. The HOP gene symbol is not ideal as it is also used for unrelated genes, including hopscotch in Drosophila and hop-sterile in mouse. POU5F1P2 and POU5F1P6 have frameshift mutations in the homeobox. Homeobox genes are characterized by the possession of a particular DNA sequence, the homeobox, which encodes a recognizable although very variable protein domain, the homeodomain [1, 2]. For the entire set of homeobox genes, we use the term superclass. The number of homeobox sequences is also different from the number of loci because several genes contain multiple homeobox motifs. These include a large number of ANTP-class genes on the distal end of the long arm of chromosome 10, and a combination of LIM-, ANTP-, PRD- and TALE-class genes on the distal end of the long arm of chromosome 9. Terms and Conditions, 2002, 110: 713-723. PROS-class genes encode a highly divergent homeodomain with three extra amino acids. Proc Natl Acad Sci USA. A gene class contains one or more gene families, which in turn will contain one or more genes. 1993, 3: 487-491. Nature. POU5F1P2 [GeneID: 100009665], POU5F1P3 (formerly POUF51L) [GeneID: 5461], POU5F1P4 [GeneID: 100009666], POU5F1P5 [GeneID: 100009667], POU5F1P6 [GeneID: 100009668], POU5F1P7 [GeneID: 100009669] and POU5F1P8 [GeneID: 100009670]. Nam and Nei [11] found 230 homeobox genes, containing 257 homeobox sequences. In previous studies, the PRD class has been subdivided in several different ways, often based on identify of the amino acid at residue 50 in the homeodomain, for example S50, K50 and Q50. Your privacy choices/Manage cookies we use in the preference centre. 10.1093/nar/29.15.3258. Monophyly of the CUT class is not recovered in this tree, but is by maximum likelihood analysis (Figure 3). The pseudogene shares 83% identity with VENTX mRNA (after masking of an Alu element in the parental mRNA sequence), lacks intronic sequence, and has remnants of a 3' poly(A) tail. Hox genes and atavisms. The homeodomains encoded by the human HNF1A and HNF1B genes are atypical in possessing 21 extra amino acid residues between the second and third alpha helices (Additional file 6). There are six widely recognized gene families within the POU class (Pou1 to Pou6), and nomenclature revisions approximately 10 years ago clarified which genes belong to which gene family [62]. The total number of homeobox sequences in the human genome is higher than 300 for two reasons.