You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: Dosage compensation can buffer copy-number variation in wild yeast}
Article:
Abstract:
Aneuploidy is linked to myriad diseases but also facilitates organismal evolution. It remains unclear how cells overcome the deleterious effects of aneuploidy until new phenotypes evolve. Although laboratory strains are extremely sensitive to aneuploidy, we show here that aneuploidy is common in wild yeast isolates, which show lower-than-expected expression at many amplified genes. We generated diploid strain panels in which cells carried two, three, or four copies of the affected chromosomes, to show that gene-dosage compensation functions at 10–30% of amplified genes. Genes subject to dosage compensation are under higher expression constraint in wild populations—but they show elevated rates of gene amplification, suggesting that copy-number variation is buffered at these genes. We find that aneuploidy provides a clear ecological advantage to oak strain YPS1009, by amplifying a causal gene that escapes dosage compensation. Our work presents a model in which dosage compensation buffers gene amplification through aneuploidy to provide a natural, but likely transient, route to rapid phenotypic evolution.
Introduction:
Susumu Ohno proposed over 40 years ago that gene duplication could provide a major force in the evolution of new gene functions, by relaxing constraint on gene sequences and allowing one or both gene copies to evolve( Ohno, 1970). The genomic era has largely borne out that hypothesis, and many studies have characterized the outcomes of whole and partial genome amplification( Jaillon et al., 2009). The immediate consequence of duplication is assumed to be increased expression of the affected genes, and in some cases the increased expression provides a selective advantage( e. g., Sandegren and Andersson, 2009; Chang et al., 2013; Edi et al., 2014). Over longer periods, the relaxed constraint afforded by functional redundancy allows one or both gene copies to evolve( Ohno, 1970), driving sub- and neo-functionalization( Lynch and Force, 2000; Lynch et al., 2001), expression divergence( Gu et al., 2004, 2005; Li et al., 2005; Wang et al., 2012), and network rewiring( Presser et al., 2008; Freschi et al., 2011; De Smet and Van de Peer, 2012). Whole and partial chromosome amplification through aneuploidy is frequently observed in laboratory evolution studies and in drug-resistant fungal pathogens( Hughes et al., 2000; Dunham et al., 2002; Selmecki et al., 2006; Pavelka et al., 2010; Yona et al., 2012; Ni et al., 2013), suggesting that aneuploidy is a rapid route to phenotypic evolution. However, aneuploidy comes with a fitness cost, most famously in cases of human aneuploidies such as Down syndrome( DS)( Antonarakis et al., 2004). The reasons for aneuploidy toxicity are not entirely clear but may be due to increased expression from genes that are toxic when overexpressed( Siegel and Amon, 2012). Several studies have used Saccharomyces cerevisiae as a model for aneuploidy syndromes, since laboratory strains are extremely sensitive to chromosomal amplification. Laboratory strains with forced aneuploidy are extremely slow growing, regardless of the chromosome amplified( Torres et al., 2007; Pavelka et al., 2010). Transcriptomic and proteomic studies in these strains reported proportionately higher expression from virtually all amplified genes( Torres et al., 2007; Pavelka et al., 2010; Torres et al., 2010; Sheltzer et al., 2012), with a handful of exceptions recently identified at the protein level( Dephoure et al., 2014). The apparent lack of dosage compensation is consistent with another study by Springer et al.( 2010), which found that expression at hemizygous genes is not up-regulated to compensate for reduced gene copy. While these studies have generated important results on aneuploidy intolerance in these particular strains, one caveat is that they were all done in laboratory strains, which have lost many features inherent in wild strains( Kvitek et al., 2008; Lewis et al., 2010; Lewis and Gasch, 2012). A remaining question is the extent to which aneuploidy occurs in nature and contributes to phenotypic variation in the wild. Here, we report that chromosomal amplification is common in non-laboratory yeast strains, which are inherently tolerant of aneuploidy and display an active mode of gene-dosage compensation at the transcript level, for specific classes of amplified genes. Strikingly, genes subject to dosage compensation are buffered against copy-number variation( CNV) and thus show elevated rates of gene amplification in natural isolates. Our results raise new implications for the role of aneuploidy in phenotypic evolution and the mechanisms cells use to tolerate it.
Discussion:
Our results provide new insight into a long-standing conundrum: how do cells tolerate duplication of toxic genes long enough for new phenotypes to evolve? Our results show that up to 40% of amplified genes in naturally aneuploid strains show lower-than-expected expression. The reduced expression is in part due to heritable polymorphisms that down-regulate expression from amplified genes, some of which may have been selected for during the adaptation to aneuploidy. But reduced expression of other amplified genes—up to 30–36% in some strains—appears to be actively regulated in proportion to increased gene dosage. The prevalence of the dosage compensation found here is likely true for other species and may explain the lack of expression increase previously noted for amplified autosomal genes in Drosophila( Zhang et al., 2010; Zhou et al., 2011) and humans( Antonarakis et al., 2004; Schuster-Bockler et al., 2010; Wang et al., 2011; Woodwark and Bateman, 2011). The clear enrichment of specific functional classes—including genes encoding RP and mitochondrial proteins—points to specific targeted processes. While we did not find overwhelming support for the balance hypothesis, dosage compensated genes include several multi-subunit protein complexes and pathways. In the case of RP genes, dosage compensation most likely occurs via feedback to modulate mRNA abundance( Figure 7). Feedback is known to occur for several RP genes, including excess, unassembled L32 that binds a stem loop structure in its own transcript and inhibits intron splicing, perhaps triggering mRNA degradation( Dabeva and Warner, 1987; Vilardell and Warner, 1997). Our results imply that feedback pertains more broadly to other RP genes, including RPL15A( Figure 7A)—notably, this transcript lacks an intron and thus must utilize a mechanism distinct from RPL32. The mechanism of dosage compensation at nuclear-encoded mitochondrial genes is less clear; however, several mitochondrial proteins are known to regulate translation or stability of other transcripts in shared pathways. For example, unassembled Cox1 protein can suppress translation of the COX1 transcript( Van Loon et al., 1983; Mick et al., 2011), while several TCA-cycle enzymes double as RNA-binding proteins that report on TCA activity( Elzinga et al., 1993; de Jong et al., 2000). A mode of dosage compensation that functions at the level of transcript abundance may provide an additional level of regulation to control protein stoichiometry. Natural isolates are generally tolerant to aneuploidy, whether or not they have had time to adapt to the extra chromosome. We did observe a common expression response in different aneuploid strains, including the up-regulation of oxidoreductases and the down-regulation of genes involved in mitochondrial translation and respiration. Interestingly, these trends are also seen in DS cells, which are extremely sensitive to reactive-oxygen species( ROS), and perhaps consequently, down-regulate mitochondrial respiration that in turn limits ROS production( Helguera et al., 2013). We found no defect in respiratory capacity in naturally aneuploid yeast, and so the implications of this response in yeast are not clear. Human patients display significant variability in their sensitivity to DS, suggesting genetic effects on DS pathologies( Roper and Reeves, 2006; Prandini et al., 2007). Our results also implicate strain-specific responses to Chr 8 amplification, in particular in the genes subject to dosage compensation vs heritably reduced expression. While some of the Class 2a genes could be mis-classified, these results raise the possibility of natural genetic variation in dosage compensation. While the expression of dosage-compensated genes is controlled in proportion to gene copy, many genes escape dosage compensation in response to aneuploidy and can contribute significantly to phenotypic variation. Whole and partial chromosome amplification is common in laboratory selection experiments( Dunham et al., 2002; Gresham et al., 2008; Yona et al., 2012) and is particularly prevalent in laboratory mutants that have an extreme fitness defect( Hughes et al., 2000; Koszul et al., 2004; Rancati et al., 2008). Yet the Saccharomycotina karyotype is extremely stable, holding at eight or sixteen chromosomes in most pre- and post-genome duplication species, respectively. This suggests that aneuploidy may serve as a transient intermediate, one that can be readily generated—and readily lost—depending on the selective pressures. Yona et al.( 2012) showed that selection for increased stress tolerance in the laboratory produced aneuploid strains that eventually gave way to other solutions even when the selective pressure persisted. Our results show that aneuploidy is frequent and tolerated in nature and may provide an important route toward natural genetic variation.
Evolution is driven by changes to the genes and other genetic information found in the DNA of an organism . These changes might , for example , alter the physical characteristics of the organism , or change how efficiently crucial tasks are carried out inside cells . Whatever the change , if it makes it easier for the organism to survive and reproduce , it is more likely to be passed on to future generations . DNA is organized inside cells in structures called chromosomes . Most of the cells in animals , plants , and fungi contain two copies of each chromosome . However , sometimes mistakes happen during cell division and extra copies of a chromosome—and hence the genes contained within it—may end up in a cell . These extra copies of genes might help to speed up the rate at which a species evolves , as the ‘spare’ copies are free to adapt to new roles . However , having extra copies of genes can also often be harmful , and in humans can cause genetic disorders such as Down syndrome . In the laboratory , chromosomes are commonly studied in a species of yeast called Saccharomyces cerevisiae . This species consists of several groups—or strains—that are genetically distinct from each other . Over the years , breeding the yeast for experiments has created laboratory strains that have lost some of the characteristics seen in wild strains . Earlier studies suggested that these cells fail to grow properly if they contain extra copies of chromosomes . Now , Hose et al . have studied nearly 50 wild strains of Saccharomyces cerevisiae . In these , extra copies of chromosomes are commonplace , and seemingly have no detrimental effect on growth . Instead , Hose et al . found that cells with too many copies of a gene use many of those genes less often than would be expected . This process is known as ‘dosage compensation’ . This dosage compensation has not been observed in laboratory strains , in part because the extra gene copies make them sickly and hard to study . Together , the results provide examples of how dosage compensation could help new traits to evolve in a species by reducing the negative effects of duplicated genes . This knowledge may have broad application , from suggesting methods to alleviate human disorders to implicating new ways to engineer useful traits in yeast and other microbes .