Hypervariability generated by natural selection in an extracellular complement-inhibiting protein of serotype M1 strains of group AStreptococcus

Abstract

In many countries, M1 strains of the human pathogenic bacterium group A Streptococcus are the most common serotype recovered from patients with invasive disease episodes. Strains of this serotype express an extracellular protein that inhibits complement [streptococcal inhibitor of complement (Sic)] and is therefore believed to be a virulence factor. Comparative sequence analysis of the 915-bp sic gene in 165 M1 organisms recovered from diverse localities and infection types identified 62 alleles. Inasmuch as multilocus enzyme electrophoresis and pulsed-field gel electrophoresis previously showed that most M1 organisms represent a distinct streptococcal clone, the extent of sic gene polymorphism was unexpected. The level of polymorphism greatly exceeds that recorded for all other genes examined in serotype M1 strains. All insertions and deletions are in frame, and virtually all nucleotide substitutions alter the amino acid sequence of the Sic protein. These molecular features indicate that structural change in Sic is mediated by natural selection. Study of 70 strains recovered from two temporally distinct epidemics of streptococcal infections in the former East Germany found little sharing of Sic variants among strains recovered in the different time periods. Taken together, the data indicate that sic is a uniquely variable gene and provide insight into a potential molecular mechanism contributing to f luctuations in streptococcal disease frequency and severity.

Comparative Sequencing of the Serine-Aspartate Repeat-Encoding Region of the Clumping Factor B Gene ( clfB ) for Resolution within Clonal Groups of Staphylococcus aureus

“…Furthermore, because clfB typing was useful in discriminating among the collection of strains representing the breadth of diversity in S. aureus, clfB typing may also be used by bacterial population geneticists for interrogating large clonal groups of strains for previously undetected or newly emerging strain subclusters. Markers with similar utility have been successfully employed for other bacterial species, such as group A Streptococcus species (45).…”

Evolutionary History of hrgA , Which Replaces the Restriction Gene hpy IIIR in the hpy III Locus of Helicobacter pylori

“…For example, for hpyIIIM, the overall Ka is 0.04, the overall Ks is 0.18, and the Ka/Ks ratio is 0.24, values which are typical for H. pylori and suggest selection for a conserved amino acid sequence (1). However, for hrgA, a higher Ka/Ks ratio (0.74, based on a Ka value of 0.17 and a Ks value of 0.23) suggests that there is selective pressure for variation, which would be consistent with a role in virulence (16). When the Ka and Ks of hrgA were compared by using a window of 30 amino acids, a region (amino acid residues 50 to 90) ( Fig.…”

Group A Streptococcus: allelic variation, population genetics, and host-pathogen interactions

“…This gene is present in M1 strains but occurs very rarely in other GAS organisms. Analysis of allelic variation in the sic gene in 1,673 M1 GAS isolates obtained from comprehensive, population-based surveillance studies of invasive disease discovered a strikingly high level of diversity among organisms that are otherwise very closely related genetically ( Figure 2) (6,10,11). Hence, M1 epidemic waves are composed of an array of subclones characterized by Sic variants that are rapidly selected in human populations.…”

“…Conventional wisdom and published data led to the concept that most M1 epidemic waves are mono-or oligoclonal. Recent analysis of allelic variation in the sic virulence gene has proven otherwise (6,10,11) (Figure 2).…”

“…One common theme revealed by large-scale analysis of virulence gene variation is that several mechanisms have contributed to generating allelic diversity in natural populations of GAS, including point mutations, slipped-strand mispairing, and assortive recombination (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”