Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad Autónoma de Barcelona, Barcelona, Spain
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Abstract |
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Key Words: Histone H1 simplicity slippage tandem repeats length mutations
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Introduction |
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H1 has multiple isoforms. The sequences of some 100 H1 subtypes from plants, invertebrates, and vertebrates are available (Sullivan et al. 2002). Often more than one H1 subtype is expressed in a given species. The H1 complement has been best characterized in mammals, where six somatic subtypes, a germ linespecific subtype and an oocyte-specific subtype have been identified (Panyim and Chalkley 1969; Bucci, Brock, and Meistrich 1982; Lennox 1984; Tanaka et al. 2001). The subtypes differ in extent of phosphorylation and in turnover rate (Lennox, Oshima, and Cohen 1982; Langan 1982). In vitro evidence supports the idea that the subtypes differ in their ability to condense chromatin (Liao and Cole 1981; Kadake and Rao 1995; Talasz et al. 1998). In vertebrates, the subtypes differ widely in evolutionary stability, suggesting that each subtype may have acquired a unique function (Lennox 1984; Ponte et al. 1998).
H1 histones from metazoa have a characteristic three-domain structure: the central domain is globular and contains a winged helix motif, while the N-terminal and C-terminal domains are highly basic and have little or no structure in solution. However, both terminal domains acquire a substantial proportion of secondary structure upon interaction with the DNA (Vila et al. 2000, 2001a, 2001b, 2002). The terminal domains have different evolutionary properties than the globular domain. Globular domains are much more evolutionarily stable and have basically evolved by nucleotide substitution. Terminal domains are, in general, more variable and have evolved by insertion/deletion, in addition to nucleotide substitution. The composition of the H1 terminal domains is dominated by the amino acids Lys, Ala, and Pro. These residues are often arranged in simple repeats, such as KPK, AKP, SPKK, PKKA, and AAKK (Suzuki 1989; Churchill and Travers 1991). The low complexity of the H1 terminal domains suggests that the DNA coding for the terminal domains could also be simple. Simple DNA is formed by the clustering of a number of interspersed short and often imperfect repeats (Tautz, Trick, and Dover 1986; Hancock 1996). Simple sequences are easily misaligned during DNA replication, recombination, and repair and are prone to short insertions and deletions (Levinson and Gutman 1987). Slippage has been shown to act on both coding (Eickbush and Burke 1986; Djian and Green 1989; Treiter, Pfeifle, and Tauz 1989; Paulsson et al. 1990; Costa et al. 1991) and noncoding sequences (Hancock and Dover 1988; Hoelzel, Hancock, and Dover 1991; Ponte et al. 1996). We have studied the length variation and the complexity of the amino acid and nucleotide coding sequences of available H1 subtypes, including those of some protists and eubacteria, which lack a winged helix motif, and found evidence for the involvement of slippage in their evolution. The analysis of a large sample of subtypes has shown that although the majority of H1 subtypes have N-terminal and C-terminal domains of low complexity, the N-terminal and C-terminal domains of a few subtypes are only marginally simple and approach the complexity of common globular proteins. A third class of subtypes contains tandem repeats. The coexistence of these three kinds of subtypes suggests that ancestral terminal domains could have originated in the amplification of short sequence motifs, which would then have evolved by point mutation and further slippage.
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Materials and Methods |
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Briefly, clustered nucleotide motifs of three and four nucleotides were searched within a window of ±32 nucleotides. The algorithm assigns a simplicity score (SS) to individual nucleotides, which is a measure of the abundance of trinucleotide and tetranucleotide motifs starting to the right of each nucleotide inside the window. A score of 1 is assigned for each trinucleotide repeat and a score of 3 is assigned for each tetranucleotide repeat. Overall simplicity factors (SF) are calculated by summing all scores and dividing the sum by the number of nucleotides. Relative simplicity factors (RSF) are obtained by dividing the overall simplicity factors of the test sequences by the mean of the corresponding SF for 10 random sequences of the same composition and length as the test sequence. Randomization was carried out independently in three reading frames. No significant difference in RSF values was observed when position-independent randomization was carried out (Hancock and Armstrong 1994). The RSF of sequences showing the same amount of motif clustering as the random sequences should be close to 1 and significantly greater for simple sequences. The standard deviation of the 10 random sequences allows the analysis of the statistical significance of the RSF. Two confidence levels are returned by the program: 99 % (P < 0.01) and 95 % (P < 0.05). In addition, the program identifies simplicity scores associated with individual motifs that are significantly higher (10 times greater) than could be expected by chance.
For the analysis of protein sequences, a window of ±10 amino acid residues was used. For the generation of the protein simplicity profiles, a weight of 1 point was accorded to repeats of a single amino acid and a weight of 2 points to repeats of two amino acids. For the detection of motifs of two to four amino acids, a score of 1 was assigned to the repeat to be detected and a score of 0 was assigned to the rest. To test whether short motifs showed significant clustering, 100 random sequences of the same composition and length were generated by random shuffling. The number of random sequences was higher in the analysis of nucleotide sequences than in the analysis of nucleotide sequences to take into consideration the high degree of variation when randomizing relatively short sequences that may have 20 different amino acids (instead of four nucleotides) at each position. Only those motifs which reached a score at least ten times higher than the averaged random sequences were considered. Tandem repeats were searched with the program DNASTAR.
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Results |
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The complexity of the structural domains was independently analyzed in a sample of subtypes from plants, including Chlorophyta and Streptophyta, fungi, invertebrates, and vertebrates (table 2). When sequences were divided into 5', central, and 3' regions, corresponding, respectively, to the N-terminal, globular, and C-terminal domains, it was apparent that in most cases the sequences encoding the globular domain were not simple. In contrast, the terminal domains were as a rule significantly simple, in particular the C-terminal domain. For subtypes of average simplicity, the effect was clear enough to allow fairly precise identification of the limit between the globular and C-terminal domains merely from inspection of the simplicity profiles (fig. 2). However, this was not possible in subtypes of low simplicity, such as those of Drosophila and vertebrate H1t subtypes, whose C-terminal domains did not reach a high enough simplicity. The limit between the N-terminal and globular domains was often not so neat, although the N-terminal domain generally contained a large peak of simplicity.
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The simplicity profiles of the protein sequences were analogous to those of the nucleotide sequences: they reflected the lower sequence complexity of the N-terminal and C-terminal domains compared with the globular domain. Moreover, in general, they permitted definition of the limits of the domains as in the corresponding profiles of the nucleotide sequences (fig. 2). Significant di-amino, tri-amino, and tetra-amino acid motifs were found in the terminal domains. As for nucleotide sequences, significant motifs were exclusive of the terminal domains. Most motifs were combinations of the three most abundant amino acids in the sequences, Lys, Ala, and Pro, as KK, KA, KP, KPK, KKA, AAK, PKKA, AKKP, and KKAK. It is remarkable that each different motif was present only in a subset of the sample sequences. This reflects the variety of simple sequence patterns displayed by the terminal domains.
Tandem Repeats in H1 Subtypes
The above analysis does not distinguish between cryptic simplicity and simplicity arising from tandem repeats. A specific search for tandem repeats showed that repeats of short amino acid motifs longer than duplications were infrequent in H1 subtypes. However, a small subset of subtypes contained significantly longer tandem repeats, which often represented a large fraction of the domain (fig. 3). A subtype from the fly Chironomus dorsalis contained nine copies of the consensus sequence KPAAKKPAA. The repeat was composed of two related shorter sequences, one containing a Lys residue and the other containing a Lys-Lys doublet. This tandem repeat represented about the 79% of the C-terminal domain. Motifs of six amino acids repeated seven times were present in tomato and wheat subtypes (41% and 31% of the C-terminus, respectively). In the sea urchin Strongylocentrotus purpuratus, a motif of seven amino acids was repeated 10 times (59% of the C-terminus). A tandem repeat with consensus (KPKAA)5 was found in mammalian somatic subtypes. In H1b, it incorporated a single Ala/Val substitution in one of the motifs; in H1c, H1d, and H1e, it was shorter and more extensively modified; and it was absent in H1a (Parseghian et al. 1994). Among the one-domain subtypes of Protists, an Euplotes crasus subtype had a short (KKSAT)3 tandem repeat.
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Even more remarkable were some of the tandem repeats of the H1 homologues of eubacteria. One of the subtypes of Bordetella pertussis contained 29 copies of the consensus sequence KKAVA, representing 79% of the entire protein. In Pseudomonas aeruginosa, a tandem of 40 copies of the consensus motif KPAA was present, representing 49% of the protein. In Escherichia coli, a repeat of the consensus (AAAEKAAADKAAAE)6 was present, but it was extensively modified by insertion/deletion. The other eubacterial H1s listed in table 1 did not contain tandem repeats.
The comparison of the simplicity profiles of the nucleotide and amino acid sequences shows that the overall simplicity of the proteins correlates with the simplicity of the DNA. In tandem repeats, the repeats in the protein always correlated with repeats in the DNA. This is not always the case in other proteins. Recent studies of polyglutamine-encoding regions show that a large proportion are encoded by near-random mixtures of codons (Albà, Santibáñez-Koref, and Hancock 1999a, 1999b; Albà, Laskowski, and Hancock 2001).
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Discussion |
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The sequences encoding the terminal domains show, in general, high or very high levels of sequence simplicity. This contrasts with the globular domain, the complexity of which is that proper to common globular proteins. In H1 subtypes, simplicity at the protein level is correlated with simplicity at the nucleotide level. A number of lines of evidence associate high levels of sequence simplicity with the occurrence of DNA slippage, which results in short insertions/deletions (Levinson and Gutman 1987; Schlotterer and Tautz 1992). It thus seems likely that DNA slippage has played a major role in the evolution of H1 terminal domains. Other DNA amplification mechanisms, such as unequal crossing-over, may also have operated in the evolution of H1 terminal domains, especially in the case of long duplications.
The simplicity of the terminal domains is, in general, of the cryptic type, that is, it does not basically arise from tandem repeats but reflects the clustering of different repeated motifs interspersed with each other and with unrepeated motifs. Tandem repetitions of short sequences longer than duplications are indeed infrequent in H1 subtypes. However, tandem repeats, which in some cases amount to a large proportion of the C-terminal domain, were found in some subtypes, mainly from invertebrates and plants, and also in the H1-like proteins from eubacteria.
It has been suggested that cryptic simplicity may be the remnant of ancestral tandem repeats that were eroded by point mutations and slippage (Hancock 1993). The H1 subtypes containing tandem repeats are thus of great interest, as they suggest that the C-terminal domains could have originated through the amplification of short sequence motifs that would have accumulated by DNA slippage and then evolved by point mutation and further slippage. Some subtypes, such as those of Drosophila and mammalian H1t, would have been modified to such an extent as to no longer retain a significant degree of simplicity. H1 subtypes can thus be classified in three groups, according to the complexity of the C-terminal domain: (1) those containing tandem repetitions, (2) those having a high level of sequence simplicity, but without long tandem repetitions, comprising, among others, the mammalian subtypes, and (3) those with low or very low sequence simplicity.
Clear examples of how the DNA amplification mechanisms have been involved in the genesis of the H1 terminal domains are the H1-like protein from the sperm of the bivalve Ensis minor (Bandiera et al. 1995) and the eubacterial H1-like proteins from Bordetella pertussis (Scarlato et al. 1995) and Pseudomonas aeruginosa (Kato, Misra, and Chakrabarty 1990). In E. minor, and in contrast to typical H1s, the tandem repeats are in the N-terminal domain, which is constituted by a series of 17 almost identical repeats of 12 amino acid residues. As in other tandem repeats, the repeats in the protein are correlated with the repeats in the DNA. Each repeat contains two related half-repeats, reminiscent of the hierarchical organization of human satellites. In B. pertussis, 79% of the protein is formed by 29 copies of the consensus motif KKAVA, whereas in P. aeruginosa, 40 copies of the consensus motif KPAA constitute 49% of the protein.
The H1 family of subtypes shows different degrees of simple sequence incorporation in the different lineages. Subtypes with significantly different sequence complexity were found in the same lineages and even in the same species. This suggests that sequence complexity may be related to subtype functional differentiation. The subtypes with long tandem repeats were basically circumscribed to plants, invertebrates, and eubacteria. In order to extend the knowledge on the functionality and evolutionary history of tandem repeats, it would be useful to obtain close homologues of tandem-containing subtypes as well as to explore the presence of polymorphisms (Albà, Santibáñez-Koref, and Hancock 1999b; Nishizawa and Nishizawa 1999; Pizzi and Frontali 2001).
Kasinsky et al. (2001) proposed on the basis of composition and sequence comparisons of H1 proteins from bacteria, protists, fungi, plants, and animals that H1-related histones originated in eubacteria long before the addition of the globular domain. The analysis of the complexity of eubacterial H1s, showing that these subtypes are significantly simple and that some even contain tandem repeats, supports this conclusion in that it shows additional common properties besides composition end sequence similarity between eubacterial H1s and the C-terminus of H1s with tripartite structure. Eubacteria even show a striking example of the efficacy of the mechanisms of insertion/deletion in conditions that probably are of low selective presure: the B. pertussis homologue, BpH1, which is encoded by a dispensable gene, varies in size in different strains from 182 to 206 amino acids. The variability is due to the insertion or deletion of DNA modules (Scarlato et al. 1995).
The sequences of the N-terminal and C-terminal domains of most subtypes would still appear to be good substrates for slippage-based mutational mechanisms, which may produce gap mutations with much higher frequency than nucleotide substitutions. However, insertions/deletions that might allow the fast evolution of protein variants and their functional differentiation may be hard to tolerate once functions have become fixed.
Recent evidence showing that H1 may be involved in the activation or repression of specific genes and that some of these effects can be attributed to the terminal domains, places the sequence variation and complexity of H1 subtypes in a wider context that goes beyond chromatin condensation.
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Acknowledgements |
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Footnotes |
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Claudia Kappen, Associate Editor
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