Abstract
During adaptation to host environments, many microorganisms alter their cell surface. One mechanism for doing so is variation in the number of amino acid repeats in cell surface proteins encoded by hypermutable DNA tandem repeats. In the yeast Candida albicans, an opportunistic human pathogen, the gene SSR1 encodes a GPI-anchored cell wall protein with a structural role. It contains two regions consisting of tandem repeats, almost exclusively encoding the amino acid pair Ser-Ala. As expected, the repeat regions make SSR1 highly mutable. New SSR1 alleles arose with a frequency of 1.11×10−4 per cell division in serially propagated cells. We also observed a large number (25) of SSR1 alleles with different repeat lengths in a survey of 131 isolates from a global strain collection. C. albicans is diploid, and combinations of these allele generated 41 different SSR1 genotypes. In both repeat regions, nonsynonymous mutations were largely restricted to one particular repeat unit. Two very similar allele combinations were largely restricted to one clade, clade 1. Each combination was present in ~30% of 49 infection-causing clade 1 strains, but one was rare (2%), the other absent in 46 infection-causing strains representing the remainder of the species (P < 0.00018 and 0.00004; Fisher’s exact test). These results indicate that both repeat regions are under selection and that amino acid repeat length polymorphisms generate Ssr1 protein variants most suitable for specific genetic backgrounds. One of these two allele combinations was 5.51 times more frequent, the other 1.75 times less frequent in 49 clade 1 strains that caused disease than in 36 commensal clade 1 strains (P = 0.0105; Chi2 test). This indicates that insertion and deletion of repeats not only generates clade-optimized Ssr1p variants, but may also assist in short-term adaptation when C. albicans makes the transition from commensal to pathogen.
Highlights
Bacterial and eukaryotic pathogens use the high frequency of insertions and deletions in tandem repeat (TR) DNA in so–called contingency genes to rapidly and transiently adapt to specific host niches or to avoid the host’s immune response by altering expression or the amino acid sequences of the encoded proteins [1,2]
To expand the search for C. albicans contingency genes we investigated the TR-ORF of a surface protein-encoding gene, SSR1, encoding a GPI-anchored cell wall protein, that plays a role in cell wall stability [21]
The set of strains used in this study represents a collection of 131 isolates, including 86 clade 1 isolates from 6 countries plus 46 isolates from the remainder of the species [18,22,23,24,25] (S1 Table; permission for use of these C. albicans isolates had been granted by the Massey University Human Ethics Committee; the table lists an additional strain, the laboratory strain Sc5314, but this was not used in our analyses)
Summary
Bacterial and eukaryotic pathogens use the high frequency of insertions and deletions in tandem repeat (TR) DNA in so–called contingency genes to rapidly and transiently adapt to specific host niches or to avoid the host’s immune response by altering expression or the amino acid sequences of the encoded proteins [1,2]. For SSR1heterozygous C. albicans strains, the repeat unit sizes were inferred by generating PCR products containing both repeat regions as well as individual regions (Table 1, Fig 1).
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