Aneuploidy is responsible for many human genetic diseases, appears in most cancer cells and correlates with tumorigenicity. Clearly, in simple organisms, such as C. albicans
, studies of gene expression in aneuploid cells, in particular of genes residing on aneuploid chromosomes, may facilitate the understanding of the mechanisms operating in higher eukaryotes and are of wide interest. Studying the expression of genes on monosomic Ch5 in C. albicans
is also of special interest, as Ch5 monosomy is a means of survival under certain condition (see Introduction
Statistical analysis of the genome-wide transcriptome responses to Ch5b monosomy revealed that 125 of 5,542 non-Ch5 genes (2%) significantly changed their expression level with p-values less than 0.01. These changes, however, did not lead to a decrease of overall chromosome expression. In contrast to these chromosomes, the monosomic Ch5b exhibited a significant decrease of expression to approximately 83–85% of the level of two chromosomes, but not 50%, as might be expected. The lesser decrease resulted from various changes in expression for different genes: decrease for some genes and no change or even increase for some other genes. Specifically, 15% of genes were down regulated approximately twofold (0.2–0.6); 40% were expressed at various levels between a twofold decrease and no change (0.7–0.8); 40% were fully compensated to the level of the disomic strain (0.9–1.1) (among these genes a few were duplicated, see Results
); and 6% were up regulated above the disomic level up to twofold (1.2–2.1) with one peculiar gene, CAG1
, up regulated four-fold (3.9). Thus, multiple regulatory mechanisms, not only Ch5b monosomy, are acting upon Ch5b genes in different ways. Multiple mechanisms are also implied by the normal distribution of the expression ratios Sor55/3153A of Ch5b genes shown in . The generality of dosage compensation on Ch5 was confirmed with a limited number of genes on the alternative Ch5a.
We assume that, as estimated by a rigorous approach, a large number of fully compensated transcripts on monosomic Ch5, 40%, is important for maintaining cellular homeostasis. Because these transcripts represent a large portion of the Ch5 genes, which are scattered along Ch5, the regulatory system responsible for this dosage compensation can be considered to be robust, performing global regulation across the chromosome. (In this regard, see below for dosage compensation in Drosophila).
An equally large group, 40%, of transcripts whose amounts range between monosomic and disomic levels, could result from different events: i) partial compensation in order to match to the expression of the other slightly down regulated genes of the corresponding pathways; ii) failure to fully compensate due to an incomplete execution of compensatory mechanism(s). The group of genes that are expressed between monosomy and disomy needs further clarification.
A relatively small group of genes, 15%, that are down regulated twofold or more contrasts with the approximately three times larger group of fully compensated genes. According to the Candida Genome Database (CGD) (http://www.candidagenome.org
), many of the twofold down regulated genes are regulatory or metabolic and are implicated in either biosynthetic processes or translation, which is indicative of the overall decrease of metabolism of Sor55. Establishing more direct relevance of these genes to survival on sorbose medium needs further investigation.
While the twofold decrease could be explained by simple loss of DNA and represents a direct result of the monosomy, twofold and more up regulation of genes from another outstanding small group, 6%, could be due to interactions with other genes on various chromosomes representing an inverse affect of monosomy. A specific nature of these up regulated genes may be related to adaptation to sorbose; however this relationship at present remains obscure.
Surprisingly, there is a striking similarity between our data and some of the results with cancer cells. Platzer et al
analyzed four major amplifications of entire chromosomes or chromosome arms 7p, 8q, 13q, and 20q in liver metastases of colon cancer. Among more than 2,000 unique array targets within amplified chromosomes, only a small fraction, 3.8% of the genes, was up regulated twofold, two genes were up regulated five-fold, and, surprisingly, 7.7% of the genes were down regulated twofold, whereas the vast majority of the genes were expressed between twofold decrease and twofold increase suggesting that they are partially or fully compensated to the disomic level, despite the chromosomal amplifications. In the prostate tumor cell line, Phillips et al. 
identified multiple chromosomal rearrangements including duplications, amplifications, loss of entire chromosomes or chromosome arms, as well as non-reciprocal translocations. An overall significant association of approximately one half of down or up regulated genes with, respectively, DNA gain or loss was established. Although, changes in expression of the genes mapping within the aneuploid regions ranged from less than twofold to more than twofold, as compared to the disomic level, only a few genes were up regulated more that twofold on duplicated or amplified chromosomes. Also, there were cases of inversely regulated genes, 14% down regulated in regions of DNA gain and 9% up regulated in regions of DNA loss.
Similarly, Makarevitch et al
recently found selective dosage compensation on a chromosome acquiring triploid arm in plants: 40% of the genes were up regulared at a level that is expected for the trisomy, 1.5-fold; however, 60% exibited no changes, while a few genes were up regulated more than twofold compared to the disomic level.
Dosage compensation has been predominantly studied with heteromorphic sex chromosomes in species in which females possess two gene-rich large X chromosomes (XX), whereas males possess one X and one gene-poor small Y. Various mechanisms equalizing X genes with genes on autosomes and between males and females were uncovered in mammals, the fly Drosophila melanogaster
and the worm Caenorhabditis elegans
. For example, one X in female mammals is practically silent; while the active X is globally up regulated in both females and males. The latter is in contrast to the fly or the worm where the single X in males is up regulated, whereas in the XX hermaphrodite worm, both Xs are partially repressed 
. Dosage compensation for sex-chromosomes is thought to have evolved in order to prevent debilitating gene disbalance, as dramatically exemplified with various human diseases due to aneuploidy of sex-chromosomes, autosomes or portions of chromosomes 
. Surprisingly, recent studies with several species of birds having ZZ males and ZW females have challenged this idea 
. The dosage compensated and non-compensated genes occurred across Z in females, diminishing the overall Z expression to approximately 80% of the ZZ level in males.
Dosage compensation in the fly is currently well understood. The males-specific lethal (MSL) complex of proteins and non-coding RNAs binds to hundreds of sites along X in transcription-coupled fashion allowing a key component of MSL, a protein MOF, to acetylate histone H4 at lysine 16. The activity of MSL is thought to facilitate hyper-transcription by leading to more open chromatin structure. Furthermore, transcription-coupled methylation of histone H3 at lysine 36 enhances recruitment of MSL 
. On the other hand, in females dosage compensation is inhibited by the female-specific RNA-binding protein Sex lethal (SXL) 
In contrast to higher eukaryotes, dosage compensation at the transcriptional level has not been found in lower eukaryotes, such as the yeast Saccharomyces cerevisiae
. By studying large collection of laboratory strains, Hughes et al. 
identified twenty aneuploid strains, in which expression of nearly every gene on a trisomic or a monosomic chromosome was correspondingly altered. Torres et al
created a collection of haploid S. cerevisiae
strains that each bear an extra copy of one or more of chromosomes. An approximate doubling of gene expression along the entire length of duplicated disomic chromosomes was observed. Although no compensatory mechanisms at the level of transcription was revealed, the authors found that the amounts of many, but not all analyzed proteins, did not increase, thus, indicating the cell's attempt to restore its normal physiological state.
In this study, we demonstrated that in a lower eukaryote C. albicans, regulation by Ch5 monosomy is coupled with a widespread compensation of the gene dosage at a transcriptional level. Such coupling obviously diminishes detrimental consequences of aneuploidy, while allowing a decrease or increase of specific transcripts.