For all the advantages that polyploidy can confer to an organism, there are also a great number of disadvantages, both observed and hypothesized. One of these disadvantages relates to the relative changes between the size of the genome and the volume of the cell. Cell volume is proportional to the amount of DNA in the cell nucleus. For example, doubling a cell's genome is expected to double the volume of space occupied by the chromosomes in the nucleus, but it causes only a 1.6-fold increase in the surface area of the nuclear envelope (Melaragno et al., 1993). This can disrupt the balance of factors that normally mediate interactions between the chromosomes and nuclear components, including envelope-bound proteins. The peripheral positioning of telomeric and centromeric heterochromatin may be disturbed as well, because there is less relative surface space on the nuclear envelope to accommodate this positioning (Fransz et al., 2002).

Polyploidy can also be problematic for the normal completion of mitosis and meiosis. For one, polyploidy increases the occurrence of spindle irregularities, which can lead to the chaotic segregation of chromatids and to the production of aneuploid cells in animals and yeast. Aneuploid cells, which have abnormal numbers of chromosomes, are more readily produced in meioses involving three or more sets of chromosomes than in diploid cells. Autopolyploids have the potential to form multiple arrangements of homologous chromosomes at meiotic metaphase I (Figure 2), which can result in abnormal segregation patterns, such as 3:1 or 2:1 plus one laggard. (Laggard chromosomes do not attach properly to the spindle apparatus and thus randomly segregate to daughter cells.) These abnormal segregation patterns cannot be resolved into balanced products, and random segregation of multiple chromosome types produces mostly aneuploid gametes (Figure 3). Chromosome pairing at meiosis I is more constrained in allopolyploids than in autopolyploids, but the stable maintenance of the two parental chromosomal complements also requires the formation of balanced gametes.

Another disadvantage of polyploidy includes potential changes in gene expression. It is generally assumed that an increase in the copy number of all chromosomes would affect all genes equally and should result in a uniform increase in gene expression. Possible exceptions would include genes that respond to regulating factors that do not change proportionally with ploidy. We now have experimental evidence for such exceptions in several systems. In one interesting example, investigators compared the mRNA levels per genome for 18 genes in 1X, 2X, 3X, and 4X maize. While expression of most genes increased with ploidy, some genes demonstrated unexpected deviations from expected expression levels. For example, sucrose synthase showed the expected proportional expression in 2X and 4X tissues, but its expression was three and six times higher, respectively, in 1X and 3X tissues. Two other genes showed similar, if less extreme, trends. Altogether, about 10% of these genes demonstrated sensitivity to odd-numbered ploidy (Guo et al., 1996).

Epigenetic instability can pose yet another challenge for polyploids. Epigenetics refers to changes in phenotype and gene expression that are not caused by changes in DNA sequence. According to the genomic shock hypothesis, disturbances in the genome, such as polyploidization, may lead to widespread changes in epigenetic regulation. Although there are few instances of documented epigenetic instability in autopolyploids, there are a couple of intriguing examples worth mentioning. In one case, transgene silencing occurred more frequently in Arabidopsis thaliana tetraploids than in A. thaliana diploids, suggesting an effect of ploidy on chromosome remodeling (Mittelsten Scheid et al., 1996). However, several factors cannot be ruled out in the observation of this phenomenon, including duplication of the strong 35S promoter from cauliflower mosaic virus in the transgene. In another case, the activation of a DNA transposon of the Spm/CACTA family was observed in autopolyploids. Unfortunately, the generality of this change could not be determined because multiple independent autopolyploids were not examined.

Conversely, extensive evidence for epigenetic remodeling is available in allopolyploids. Structural genomic changes, such as DNA methylation, and expression changes are reported to accompany the transition to alloploidy in several plant systems, including Arabidopsis and wheat (Shaked et al., 2001). The most detailed information is available for the model system Arabidopsis. For instance, in a cross of A. thaliana and A. arenosa, epigenetically regulated genes were identified by comparing transcripts from the autotetraploid parents to transcripts from the neoallopolyploid progeny. A. thaliana genes affected by epigenetic regulation were defined as those that responded to the transition from autopolyploidy to allopolyploidy. Altogether, between 2% and 2.5% of A. thaliana genes were estimated to have undergone regulatory changes during the transition to allopolyploidy. A more detailed microarray study that examined the regulation of 26,000 genes in Arabidopsis neoallopolyploids detected a transcriptome divergence between the progenitors of more than 15%, due to genes that were highly expressed in A. thaliana and not in A. arenosa or vice versa. Significantly, expression of approximately 5% of the genes diverged from the mid-parent value in two independently derived allotetraploids, consistent with nonadditive gene regulation after hybridization (Wang et al., 2006). Taken together, these results suggest that the instability syndrome of neoallopolyploids may be attributed primarily to regulatory divergence between the parental species, leading to genomic incompatibilities in the allopolyploid offspring.

Aneuploidy might also be a factor in epigenetic remodeling in neoallopolyploids, either by altering the dosage of factors that are encoded by chromosomes that have greater or fewer than the expected number of copies leading to changes in imprinted loci, or by exposing unpaired chromatin regions to epigenetic remodeling mechanisms. In the latter case, this susceptibility of meiotically unpaired DNA to silencing was first reported for the fungus Neurospora crassa, but it appears to be a general phenomenon. Therefore, some of the epigenetic instability that is observed in allopolyploids might result from aneuploidy.