Mechanisms for Evolving Hypervariability: The Case of Conopeptides

Abstract

Hypervariability is a prominent feature of large gene families that mediate interactions between organisms, such as venom-derived toxins or immunoglobulins. In order to study mechanisms for evolution of hypervariability, we examined an EST-generated assemblage of 170 distinct conopeptide sequences from the venoms of five species of marine Conus snails. These sequences were assigned to eight gene families, defined by conserved elements in the signal domain and untranslated regions. Order-of-magnitude differences were observed in the expression levels of individual conopeptides, with five to seven transcripts typically comprising over 50% of the sequenced clones in a given species. The conopeptide precursor alignments revealed four striking features peculiar to the mature peptide domain: (1) an accelerated rate of nucleotide substitution, (2) a bias for transversions over transitions in nucleotide substitutions, (3) a position-specific conservation of cysteine codons within the hypervariable region, and (4) a preponderance of nonsynonymous substitutions over synonymous substitutions. We propose that the first three observations argue for a mutator mechanism targeted to mature domains in conopeptide genes, combining a protective activity specific for cysteine codons and a mutagenic polymerase that exhibits transversion bias, such as DNA polymerase V. The high D:(n)/D:(s) ratio is consistent with positive or diversifying selection, and further analyses by intraspecific/interspecific gene tree contingency tests weakly support recent diversifying selection in the evolution of conopeptides. Since only the most highly expressed transcripts segregate in gene trees according to the feeding specificity of the species, diversifying selection might be acting primarily on these sequences. The combination of a targeted mutator mechanism to generate high variability with the subsequent action of diversifying selection on highly expressed variants might explain both the hypervariability of conopeptides and the large number of unique sequences per species.

ConusVenoms: A Rich Source of Novel Ion Channel-Targeted Peptides

“…The mechanisms that lead to the conservation of the signal sequences (a conservation that extends even to the third position of codons, making even silent mutations underrepresented in this region) juxtaposed with the hyperdivergence observed in the mature toxin region (149,193) remain a subject for speculation; a variety of mechanisms leading to the observed differences in the differential rate of divergence observed for the signal sequence region, the pro region, and the mature toxin region have been proposed (25,40,49,137,149).…”

Intraspecific variation of venom injected by fish-hunting Conussnails

“…Genes encoding Conus toxins have evolved by a mechanism of strong positive selection (Conticello et al, 2001;Duda and Palumbi, 2004Espiritu et al, 2001), and diversification of these peptide toxins may be responsible for success in the acquisition of new feeding behaviors and niche expansion leading to speciation within the genus. Although the biological relevance of these peptides is widely recognized, it is not known how the expression, maturation and delivery of these toxins are regulated.…”

A diverse family of novel peptide toxins from an unusual cone snail, Conus californicus

“…Thus, the variants detected in R11 appear to be more analogous to the differences between Cal12.1 and Cal12.2 members than to the modular differences within the Cal12.1 family. Variation in the Cal12.1 family is clearly different from that in Cal12.2, where it may represent allelic variation (Duda and Palumbi, 2000; or the diversity among paralogous members of a gene family that have been subject to gene duplication and rapid evolution (Duda and Palumbi, 1999;Conticello et al, 2001;Duda, 2008;Puillandre et al, 2010).…”

“…vermiforms (polychaetes or hemichordates), molluscs or fish, with many preying on specific taxa within these groups (Rockel et al, 1995). Interspecific competition within the genus is believed to have been an important evolutionary force leading to feeding-niche specialization and toxin diversification (Conticello et al, 2001;Duda et al, 2001;Duda and Palumbi, 1999;Espiritu et al, 2001). These ideas are primarily based on studies of Conus species from the Indo-Pacific region, an area with the greatest species diversity (Kohn, 1998).…”