A natural (evolutionary) classification is provided for 242 basic helix-loop-helix (bHLH) motifcontaining proteins. Phylogenetic analyses of amino acid sequences describe the patterns of evolutionary change within the motif and delimit evolutionary lineages. These evolutionary lineages represent well known functional groups of proteins and can be further arranged into five groups based on binding to DNA at the hexanucleotide E-box, the amino acid patterns in other components of the motif, and the presence͞ absence of a leucine zipper. The hypothesized ancestral amino acid sequence for the bHLH transcription factor family is given together with the ancestral sequences of the subgroups. It is suggested that bHLH proteins containing a leucine zipper are not a natural, monophyletic group.Transcription factors belonging to the helix-loop-helix family are important regulatory components in transcriptional networks of many developmental pathways (1-3). They are involved in regulation of neurogenesis, myogenesis, cell proliferation and differentiation, cell lineage determination, sex determination, and other essential processes in organisms ranging from yeast to mammals.Helix-loop-helix proteins are characterized by common possession of highly conserved bipartite domains for DNA binding and protein-protein interaction (1-2). A motif of mainly basic residues permits helix-loop-helix proteins to bind to a consensus hexanucleotide E-box (CANNTG) (4). A second motif of primarily hydrophobic residues referred to as the helix-loop-helix domain allows these proteins to interact and to form homoand͞or heterodimers (2). The dimerization motif contains about 50 amino acids and produces two amphipathic ␣-helices separated by a loop of variable length. Additionally, some basic helix-loop-helix (bHLH) proteins contain a leucine zipper (LZ) dimerization motif characterized by heptad repeats of leucines that occur immediately C-terminal to the bHLH motif.The bHLH motif was first identified in murine transcription factors E12 and E47 (1). Subsequent descriptions of numerous new bHLH proteins have made it increasingly difficult to understand their interrelationships, and a natural classification scheme is badly needed to bring order to this large and important group of proteins. A ''natural'' classification is an evolutionary one based on rules of descent and uses sequence data and information about function and is predictive with regard to new information. Herein, we provide an evolutionary classification of the bHLH motif based on 242 distinct amino acid sequences. The final phylogenetic analyses described here are based on a subset of 122 divergent sequences. The selection of a subset of 122 sequences was based primarily on extent of sequence similarity (sequences that were very similar were culled). The bHLH sequences were aligned using the Clustal-W algorithm (5) and were improved by eye. Only the bHLH motif was used in these analyses because the flanking sequences for proteins from independent clades are either nonhomologo...
How 'complex' or composite morphological structures like the mammalian craniomandibular region arise during development and how they are altered during evolution are two major unresolved questions in biology. Herein, we have described a model for the development and evolution of complex morphological structures. The model assumes that natural selection acts upon an array of phenotypes generated by variation in a variety of underlying genetic and epigenetic controlling factors. Selection refines the integration of the various morphogenetic components during ontogeny in order to produce a functioning structure and to adapt the organisms to differing patterns of environmental heterogeneity. The model was applied to the development and evolution of the mammalian mandible (which is used as a paradigm of complex morphological structures). The embryology of the mandible was examined in detail in order to identify the fundamental developmental units which are necessary to assemble the final morphological structure. The model is quite general since equivalent units exist for the development of many other biological structures. This model could be applied to many other developing morphological structures as well as other groups of organisms. For example, it can be applied to cell parameters during Drosophila development (Atchley, 1987). The model as discussed in this paper assumes that morphological changes in the mandible result from evolutionary changes in its underlying developmental units. The developmental units relate to characteristics of cellular condensations which are produced from the differentiation of embryonic neural crest cells. The developmental units include: the number of stem cells in preskeletal condensations (n), the time of initiation of condensation formation (t), the fraction of cells that is mitotically active within a condensation (f), the rate of division of these cells (r), and their rate of cell death (d). These units and their derivative structures are discussed in terms of types of tissue differentiation (chondrogenesis, osteogenesis, primary/secondary osteogenesis, intramembranous/endochondral ossification) and growth properties of major morphological regions of the mandible. Variation in these five units provides the developmental basis for ontogenetic and phylogenetic modification of mandibular morphology. We have discussed how these developmental units are influenced by (a) the cell lineage from which they arise, (b) epithelial-mesenchymal (inductive tissue) interactions, (c) regulation of cell differentiation, and (d) extrinsic factors such as muscles, teeth and hormones. Evidence was provided that variation in mandibular morphology is heritable, subject to modification by natural selection, and that divergence among different genetic stocks has apparently occurred through changes in these developmental units and their derivative structures.(ABSTRACT TRUNCATED AT 400 WORDS)
Biological sequences are composed of long strings of alphabetic letters rather than arrays of numerical values. Lack of a natural underlying metric for comparing such alphabetic data significantly inhibits sophisticated statistical analyses of sequences, modeling structural and functional aspects of proteins, and related problems. Herein, we use multivariate statistical analyses on almost 500 amino acid attributes to produce a small set of highly interpretable numeric patterns of amino acid variability. These high-dimensional attribute data are summarized by five multidimensional patterns of attribute covariation that reflect polarity, secondary structure, molecular volume, codon diversity, and electrostatic charge. Numerical scores for each amino acid then transform amino acid sequences for statistical analyses. Relationships between transformed data and amino acid substitution matrices show significant associations for polarity and codon diversity scores. Transformed alphabetic data are used in analysis of variance and discriminant analysis to study DNA binding in the basic helix-loop-helix proteins. The transformed scores offer a general solution for analyzing a wide variety of sequence analysis problems.basic helix-loop-helix ͉ molecular evolution ͉ multivariate statistics ͉ amino acid attributes ͉ factor analysis
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