Effect of the Major Repeat Sequence on Chromosome Loss in Candida albicans

Abstract

The major repeat sequence (MRS) is found at least once on all but one chromosome in Candida albicans, but as yet it has no known relation to the phenotype. The MRS affects karyotypic variation by serving as a hot spot for chromosome translocation and by expanding and contracting internal repeats, thereby changing chromosome length. Thus, MRSs on different chromosomes and those on chromosome homologues can differ in size. We proposed that the MRS's unique repeat structure and, more specifically, the size of the MRS could also affect karyotypic variation by altering the frequency of mitotic nondisjunction. Subsequent analysis shows that both natural and artificially induced differences in the size of the chromosome 5 MRS can affect chromosome segregation. Strains with chromosome 5 homologues that differ in the size of the naturally occurring MRSs show a preferential loss of the homologue with the larger MRS on sorbose, indicating that a larger MRS leads to a higher risk of mitotic nondisjunction for that homologue. While deletion of an MRS has no deleterious effect on the deletion chromosome under normal growth conditions and leads to no obvious phenotype, strains that have the MRS deleted from one chromosome 5 homologue preferentially lose the homologue with the MRS remaining. This effect on chromosome segregation is the first demonstration of a phenotype associated with the MRS.

Effect of the Major Repeat Sequence on Mitotic Recombination in Candida albicans

“…The MRS remains a tantalizing structure within the genome of C. albicans; it has interesting connections to essential functions and chromosome dynamics and yet seems to be dispensable to chromosome 3 (naturally) and chromosome 5 (deleted in Lephart et al 2005). We have now shown that the MRS on chromosome 5 does not enhance mitotic recombination under standard in vitro growth conditions and rather may slightly inhibit mitotic recombination.…”

“…The loss of a recombinant chromosome would introduce a partial hemizygosity for two separate chromosomes and thus potentially a new phenotype unattainable by the loss of a nonrecombinant homolog. Interestingly, the size of an MRS has also been shown to affect the frequency of chromosome nondisjunction (Lephart et al 2005); thus this repeated sequence may be involved in the regulation of both translocation and nondisjunction.…”

“…Its structure is complex: one end is a 6-kb sequence called RB2, the central part has multiple repeats of a 2-kb sequence called RPS, and centromere proximal is a different 8-kb sequence called HOK (Chibana et al 1994;Chindamporn et al 1998). Earlier studies showed that the size of the MRS on a given homolog of chromosome 5 in C. albicans was inversely correlated with the frequency of appearance of that homolog among cells that acquired the ability to grow on sorbose as a sole carbon source (Lephart et al 2005). The MRS also has a well-documented history of association with genome rearrangements and translocations in numerous clinical isolates (Chu et al 1993;Lockhart et al 1995;Chibana et al 2000;Iwaguchi et al 2000Iwaguchi et al , 2001.…”

Evolution inCandida albicansPopulations During a Single Passage Through a Mouse Host

“…However, the genome and population processes underlying observed variation in host populations is not well understood. Appreciable rates of mitotic recombination estimated at specific genome regions (Lephart et al 2005;Lephart and Magee 2006) and in repetitive regions (Zhang et al 2003) have been evaluated primarily from in vitro cultures. Chromosomal variation as well as point mutations accumulate rapidly in populations evolving resistance to azole antifungal drugs (Selmecki et al 2006;Coste et al 2007), and in a few cases, the evolution of a pathogen within the same individual has been studied over the time course of antifungal drug treatment (Lopez-Ribot et al 1998;Marr et al 1998;Coste et al 2007;Selmecki et al 2008).…”

Noise-Driven Heterogeneity in the Rate of Genetic-Variant Generation as a Basis for Evolvability

“…Clinical studies reveal the accumulation of variations in host-associated populations, but rates of mitotic recombination at specific genome regions have been evaluated primarily from in vitro studies (Lephart et al 2005). High chromosomal instability in C. albicans has already been observed during growth in rich medium (Rustchenko 2007), but LOH is also widespread in natural isolates (Diogo et al 2009).…”