Molecular evolution of the homeodomain family of transcription factors.

The homeodomain family of transcription factors plays a fundamental role in a diverse set of functions that include body plan specification, pattern formation and cell fate determination during metazoan development. Members of this family are characterized by a helix-turn-helix DNA-binding motif known as the homeodomain. Homeodomain proteins regulate various cellular processes by specifically binding to the transcriptional control region of a target gene. These proteins have been conserved across a diverse range of species, from yeast to human. A number of inherited human disorders are caused by mutations in homeodomain-containing proteins. In this study, we present an evolutionary classification of 129 human homeodomain proteins. Phylogenetic analysis of these proteins, whose sequences were aligned based on the three-dimensional structure of the homeodomain, was performed using a distance matrix approach. The homeodomain proteins segregate into six distinct classes, and this classification is consistent with the known functional and structural characteristics of these proteins. An ancestral sequence signature that accurately describes the unique sequence characteristics of each of these classes has been derived. The phylogenetic analysis, coupled with the chromosomal localization of these genes, provides powerful clues as to how each of these classes arose from the ancestral homeodomain.

[1]  Kurt Wüthrich,et al.  Homeodomain-DNA recognition , 1994, Cell.

[2]  M. Cleary,et al.  Structure of a HoxB1–Pbx1 Heterodimer Bound to DNA Role of the Hexapeptide and a Fourth Homeodomain Helix in Complex Formation , 1999, Cell.

[3]  R. Mazzarella,et al.  Pathological consequences of sequence duplications in the human genome. , 1998, Genome research.

[4]  I. Hanson,et al.  Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly , 1994, Nature Genetics.

[5]  M. Scott,et al.  Structural relationships among genes that control development: sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[6]  A. Sidow,et al.  A molecular evolutionary framework for eukaryotic model organisms , 1994, Current Biology.

[7]  J. Seidman,et al.  Congenital heart disease caused by mutations in the transcription factor NKX2-5. , 1998, Science.

[8]  M. O. Dayhoff,et al.  Atlas of protein sequence and structure , 1965 .

[9]  D. Landsman,et al.  Threading analysis of prospero-type homeodomains. , 1999, In silico biology.

[10]  Dr. Susumu Ohno.  Evolution by Gene Duplication , 1970, Springer Berlin Heidelberg.

[11]  Sarah E. Ades,et al.  Engrailed (Gln50-->Lys) homeodomain-DNA complex at 1.9 A resolution: structural basis for enhanced affinity and altered specificity. , 1997, Structure.

[12]  Y. Kurosawa,et al.  The HOX complex neighbored by the EVX gene, as well as two other homeobox‐containing genes, the GBX‐class and the EN‐class, are located on the same chromosomes 2 and 7 in humans , 1993, FEBS letters.

[13]  M. Capecchi,et al.  Axial homeosis and appendicular skeleton defects in mice with a targeted disruption of hoxd-11. , 1994, Development.

[14]  E. Jabs,et al.  A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis , 1993, Cell.

[15]  M. Nirenberg,et al.  Interactions of the vnd/NK-2 homeodomain with DNA by nuclear magnetic resonance spectroscopy: basis of binding specificity. , 1997, Biochemistry.

[16]  K. Weiss,et al.  Genomic analysis of a new mammalian distal-less gene: Dlx7. , 1996, Genomics.

[17]  E. Zackai,et al.  Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination , 2000, Nature Genetics.

[18]  C. Pabo,et al.  Crystallization and preliminary X-ray diffraction studies of the engrailed homeodomain and of an engrailed homeodomain/DNA complex. , 1990, Biochemical and biophysical research communications.

[19]  W. J. Gehring,et al.  The structure of the Antennapedia homeodomain determined by NMR spectroscopy in solution: Comparison with prokaryotic repressors , 1989, Cell.

[20]  W. J. Ouweneel.  Developmental genetics of homoeosis. , 1976, Advances in genetics.

[21]  R. Kaptein,et al.  Solution structure of the POU-specific DNA-binding domain of Oct-1 , 1993, Nature.

[22]  F. Beemer,et al.  MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans , 2000, Nature Genetics.

[23]  N. Saitou,et al.  The neighbor-joining method: a new method for reconstructing phylogenetic trees. , 1987, Molecular biology and evolution.

[24]  M. D'Esposito,et al.  Cloning and characterization of two members of the vertebrate Dlx gene family. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[25]  D. Mortlock,et al.  Mutation of HOXA13 in hand-foot-genital syndrome , 1997, Nature Genetics.

[26]  Peter W. H. Holland,et al.  Ancient origin of the Hox gene cluster , 2001, Nature Reviews Genetics.

[27]  E. Eichler,et al.  Structure of chromosomal duplicons and their role in mediating human genomic disorders. , 2000, Genome research.

[28]  G. Wagner,et al.  Phylogenetic reconstruction of vertebrate Hox cluster duplications. , 1997, Molecular biology and evolution.

[29]  Juli D. Klemm,et al.  Crystal structure of the Oct-1 POU domain bound to an octamer site: DNA recognition with tethered DNA-binding modules , 1994, Cell.

[30]  D. Duboule,et al.  The structural and functional organization of the murine HOX gene family resembles that of Drosophila homeotic genes. , 1989, The EMBO journal.

[31]  R. Maas,et al.  Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation , 2000, Nature Genetics.

[32]  E. Bertolino,et al.  Expression of a novel murine homeobox gene in the developing cerebellar external granular layer during its proliferation , 1996, Developmental dynamics : an official publication of the American Association of Anatomists.

[33]  P. Scambler,et al.  Deletions in HOXD13 segregate with an identical, novel foot malformation in two unrelated families. , 1998, American journal of human genetics.

[34]  G. Lyons,et al.  Vertebrate homologs of tinman and bagpipe: roles of the homeobox genes in cardiovascular development. , 1998, Developmental genetics.

[35]  B. Mosinger,et al.  Specification of Pituitary Cell Lineages by the LIM Homeobox Gene Lhx3 , 1996, Science.

[36]  E. Zackai,et al.  Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly , 1999, Nature Genetics.

[37]  E. Eichler,et al.  Masquerading repeats: paralogous pitfalls of the human genome. , 1998, Genome research.

[38]  P. Holland,et al.  Evidence for 14 homeobox gene clusters in human genome ancestry , 2000, Current Biology.

[39]  D. Duboule.  Guidebook to the homeobox genes , 1994 .

[40]  T. Ceska,et al.  The X‐ray structure of an atypical homeodomain present in the rat liver transcription factor LFB1/HNF1 and implications for DNA binding. , 1993, The EMBO journal.

[41]  Y. Zou,et al.  Functional Analyses of Three Csx/Nkx-2.5 Mutations That Cause Human Congenital Heart Disease* , 2000, The Journal of Biological Chemistry.

[42]  Cynthia Wolberger,et al.  Crystal structure of a MAT alpha 2 homeodomain-operator complex suggests a general model for homeodomain-DNA interactions. , 1991, Cell.

[43]  M. Capecchi,et al.  Absence of radius and ulna in mice lacking hoxa-11 andhoxd-11 , 1995, Nature.

[44]  W. J. Gehring,et al.  A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes , 1984, Nature.

[45]  A. Grüters,et al.  Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency , 2000, Nature Genetics.

[46]  W. Gehring,et al.  Homeodomain proteins. , 1994, Annual review of biochemistry.

[47]  R. Breitling,et al.  Origin of the paired domain , 2000, Development Genes and Evolution.

[48]  G J Barton,et al.  ALSCRIPT: a tool to format multiple sequence alignments. , 1993, Protein engineering.

[49]  J. Hurst,et al.  Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification , 2000, Nature Genetics.

[50]  M. Nirenberg,et al.  Structural basis of an embryonically lethal single Ala --> Thr mutation in the vnd/NK-2 homeodomain. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[51]  A. Baldini,et al.  Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome , 1998, Nature Genetics.

[52]  A. Laughon,et al.  DNA binding specificity of homeodomains. , 1991, Biochemistry.

[53]  C Kappen,et al.  Two steps in the evolution of Antennapedia-class vertebrate homeobox genes. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[54]  E. Lewis.  A gene complex controlling segmentation in Drosophila , 1978, Nature.

[55]  C Kappen,et al.  Analysis of a complete homeobox gene repertoire: implications for the evolution of diversity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[56]  M. King,et al.  Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans. , 1998, Science.

[57]  E. G. Strauss,et al.  RNA viruses: genome structure and evolution , 1991, Current Biology.

[58]  N. M. Brooke,et al.  The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster , 1998, Nature.

[59]  M. Martindale,et al.  Combined-method phylogenetic analysis of Hox and ParaHox genes of the metazoa. , 2000, The Journal of experimental zoology.

[60]  M. D'Esposito,et al.  Isolation and mapping of EVX1, a human homeobox gene homologous to even-skipped, localized at the 5' end of HOX1 locus on chromosome 7. , 1991, Nucleic acids research.

[61]  Carl O. Pabo,et al.  Crystal structure of an engrailed homeodomain-DNA complex at 2.8 Å resolution: A framework for understanding homeodomain-DNA interactions , 1990, Cell.

[62]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[63]  P. Scambler,et al.  Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. , 2000, American journal of human genetics.

[64]  K. Wüthrich,et al.  Nuclear magnetic resonance solution structure of the fushi tarazu homeodomain from Drosophila and comparison with the Antennapedia homeodomain. , 1994, Journal of molecular biology.

[65]  R. Maas,et al.  Pax6 and the genetic control of early eye development. , 2000, Results and problems in cell differentiation.

[66]  M. Scott.  A rational nomenclature for vertebrate homeobox (HOX) genes. , 1993, Nucleic acids research.

[67]  Long T. Nguyen,et al.  Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation , 2000, Nature Genetics.

[68]  S. Izumo,et al.  The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. , 1999, Development.

[69]  M. Ferguson,et al.  Epithelial-mesenchymal interactions are required for msx 1 and msx 2 gene expression in the developing murine molar tooth. , 1993, Development.

[70]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[71]  M Bitner-Glindzicz,et al.  Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4 , 1995, Science.

[72]  P. Traber,et al.  Cdx1 and cdx2 expression during intestinal development. , 2000, Gastroenterology.

[73]  R. Bodmer.  The gene tinman is required for specification of the heart and visceral muscles in Drosophila. , 1993, Development.

[74]  D. Bowden,et al.  Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome. , 1998, Human molecular genetics.

[75]  M. D'Esposito,et al.  EVX2, a human homeobox gene homologous to the even-skipped segmentation gene, is localized at the 5' end of HOX4 locus on chromosome 2. , 1991, Genomics.

[76]  T R Bürglin,et al.  Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. , 1997, Nucleic acids research.

[77]  J. Rubenstein,et al.  Role of the Dlx homeobox genes in proximodistal patterning of the branchial arches: mutations of Dlx-1, Dlx-2, and Dlx-1 and -2 alter morphogenesis of proximal skeletal and soft tissue structures derived from the first and second arches. , 1997, Developmental biology.

[78]  A. Sidow.  Gen(om)e duplications in the evolution of early vertebrates. , 1996, Current opinion in genetics & development.

[79]  D. Davidson,et al.  The function and evolution of Msx genes: pointers and paradoxes. , 1995, Trends in genetics : TIG.

[80]  P. Gruss,et al.  Disruption of the murine homeobox gene Cdx1 affects axial skeletal identities by altering the mesodermal expression domains of Hox genes , 1995, Cell.

[81]  R. Maas,et al.  Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development , 1994, Nature Genetics.