molecular evolution of spectrin repeats
TRANSCRIPT
Molecular evolutionof spectrin repeatsSir,In their BioEssays article entitled ‘‘Evolution of the SpectrinRepeat,’’ Pascaul et al.(1) describe the results of phylogenetic treebuilding for the repetitive protein unit found within the humanrepresentatives of the cytoskeletal proteins a-actinin, a-spectrin,and b-spectrin. Their results corroborate the previously proposedblock duplications for these proteins identified using dot plots(2)
and lend further support to the model, which proposed a commonorigin for these proteins along with dystrophin from an a-actinin-like ancestor.(2,3) What warrants discussion, and is the purpose ofthis letter, concerns the significance of identifying such blockduplications.
In two contemporaneous papers, we show that the use ofsuch trees can successfully be extended to the analysis of all thecompleted a- and b-spectrin sequences, including the novelb-spectrin isoform bHeavy-spectrin (bH).(4,5) Our analysis also de-tected traces of block duplications that are similar in location andscope to the other analyses,(1,2) and we were also able to detect asingle duplication event that extended the b-spectrin repeat arrayby 13 units to the 30 seen in bH. Furthermore, our analysis of thebH Src Homology 3 domain shows that is most closely related tothat found in a-spectrin lending further credence to the commonorigins of a- and b-spectrin. We also proposed that a- andb-spectrin originated through DNA rearrangement; however, wesuggest that this event was a single unequal exchange betweenthe homodimeric spectrin ancestor and a pleckstrin homology(PH) domain containing protein. This parsimonious modelachieves the same results as the ‘‘promoter insertion’’ model ofPascual et al., but it also explains the origin of the C-terminal PHdomain that all b-spectrin genes encode.
Rather than limiting such analyses to attempts to try and piecetogether the exact sequence of events leading to the currentstructure of such repeat arrays, we feel that the identified blockduplications should be seen as an example of the types ofmechanism at work during the evolution of tandem arrays ofprotein motifs. These mechanisms—unequal crossing over andgene conversion—are essentially driven by DNA identity, as theyrequire misalignment during meiosis. Given that such mecha-nisms were operational in these tandem arrays, they would haveled to the phenomenon known as concerted evolution, (6) wherebythe arrays would tend to stay relatively homogeneous with theoccasional sweep-through of variants. Accordingly, we wouldexpect that successive rounds of homogenization would oftenerase the evidence for the earliest duplications leaving only tracesof the most recent events. Furthermore, while there is substantialheterogeneity between repeat lengths today, the dystrophinarrays are thought to have had a 109-amino acid progenitor, whilethe spectrin arrays are based on 106 amino acids and such
array-wide differences could easily arise through the mechanismsdiscussed above.
Two observations indicate that there has been no inter-repeatsequence exchange since the split leading to the divergence ofthe arthropod and vertebrate lineages. First, any given repeat in amodern spectrin is more similar to the corresponding repeat inother spectrins than it is to the other repeats of the spectrin inwhich it resides. Second, three different statistical proceduresdesigned to detect the presence of recombination or geneconversion (by looking for the appearance of several new muta-tions simultaneously into a localized sequence block) failed toprovide evidence for such events.(4) However, given the evidencefor earlier concerted evolution during the origins of the a-actinin/spectrin/dystrophin superfamily, we must propose that theseproteins have undergone two phases in their evolution. The firstphase was dominated by DNA identity between repeats leadingto array expansion and concerted evolution, while the secondphase is characterized by stable structures with no sequenceexchange between repeats. This begs the question: why did thearray became stable? Stability would come very rapidly if thehomogenizing effects of concerted evolution were decreased byDNA divergence that in turn would allow further divergence, in asnowball effect. We suggest two models that might have initiatedthis process. First, any selective pressure constraining the lengthof the array (i.e., actin cross-linking distance) would preventunequal exchanges from participating in the homogenizing ef-fects of concerted evolution. Second, specialization of individualrepeats (e.g., ankyrin binding) would also initiate the transition. Inaddition, the process of random mutations and drift would alwaystend to make repeats more dissimilar.
As there are many many proteins that contain tandemlyarrayed motifs, such a two-phase model for the evolution ofthe spectrin repeats probably applies to them as well. At-tempts to identify all the duplication events leading to theexpansion of an array are doomed to fail and we must becontent with tracing relatively recent events.
References1 Pascaul J, Castresana J, Saraste M (1997) Evolution of the spectrinrepeat. BioEssays 19:811–817.2 Byers TJ, Brandin E, Lue RA, Winograd E, Branton D (1992) Thecomplete sequence of Drosophila beta-spectrin reveals supra-motifs compris-ing eight 106-residue segments. Proc Natl Acad Sci USA 89:6187–6191.3 Dubreuil RR, et al. (1989) The complete sequence of Drosophilaalpha-spectrin: Conservation of structural domains between alpha-spectrinsand alpha-actinin. J Cell Biol 109:2197–205.4 Muse SV, Clark AG, Thomas GH (1997) Comparisons of the nucleo-tide substitution process among repetitive segments of the a- and b-spectringenes. J Mol Evol 44:492–500.5 Thomas GH, et al . (1997) Intragenic duplication and divergence in thespectrin superfamily of proteins. Mol Biol Evol 14:1285–1295.6 Zimmer EA, Martin SL, Beverley SM, Kan YW, Wilson AC (1980)Rapid duplication and loss of genes coding for the a-chains of hemoglobin.Proc Natl Acad Sci USA 77:2158–2162.
Dr. Graham ThomasDepartments of Biology and Biochemistry/Molecular BiologyThe Pennsylvania State University208 Mueller LaboratoryUniversity Park, PA 16820
Correspondence
600 BioEssays 20.7 BioEssays 20:600, r 1998 John Wiley & Sons, Inc.