MBE Advance Access originally published online on September 23, 2008
Molecular Biology and Evolution 2008 25(12):2513-2516; doi:10.1093/molbev/msn212
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Letters |
Regulation Dynamics of WGD Genes during Yeast Metabolic Oscillation
* Division of Nutritional Sciences, Cornell University
Department of Molecular Biology and Genetics, Cornell University
E-mail: zg27{at}cornell.edu.
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Abstract |
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Saccharomyces cerevisiae and its close relatives are characterized by their propensity to ferment even in the presence of oxygen. It was hypothesized that whole-genome duplication (WGD) led to the development of this efficient fermentative lifestyle (WGD–fermentation hypothesis, Piskur 2001
. In this study, we found that a significantly higher proportion of WGD genes than non-WGD genes are dynamically regulated during metabolic oscillation in response to oxygen change. The same data set also shows that the WGD genes, as compared with the smaller scale duplicate genes, are enriched with pairs where both copies have cyclic expression during the metabolic oscillation (either with the same or different phases). These results provide new evidences for the WGD–fermentation hypothesis and new insights into the relationship between the genome duplication and the evolution of new lifestyles in eukaryotic organisms.
Key Words: WGD • yeast • metabolic cycling genes • WGD–fermentation hypothesis
Gene duplication, as a primary source of materials for evolutionary novelties, had long been thought to play an important role in the adaptation of organisms to their environments (Ohno 1970; Lynch and Conery 2000, Zhang 2003). Models that aim to explain the retention of duplicate genes include subfunctionalization (Hughes 1994; Force et al. 1999), neofunctionalization (Ohno 1970), and selection for high dosage (Kondrashov et al. 2002; Withers et al. 2006). Baker's yeast Saccharomyces cerevisiae and its close relatives owe their competitiveness to a combination of several properties including fast growth with or without oxygen, efficient glucose repression of respiration genes, and good ability to produce and consume ethanol (Piskur et al. 2006). It was proposed that the whole-genome duplication (WGD) that occurred about 100 MYA in this lineage (Wolfe and Shields 1997; Dietrich et al. 2004; Dujon et al. 2004; Kellis et al. 2004) might have provided the basis for specialization of a number of duplicate genes, enabling their optimal functions in either aerobic or anaerobic conditions, and thus providing a competitive advantage for the "new" Saccharomyces group (Piskur 2001).
This "WGD–fermentation hypothesis" is supported by various observations. A recent study indicates that the ability to grow anaerobically on minimal media and the presence of a Crabtree effect are strongly associated with yeasts possessing the WGD (Merico et al. 2007). Another study found a general trend for higher rates of ethanol production in post-WGD yeasts than in non-WGD yeasts (Blank et al. 2005). There are also evidences indicating that many retained WGD genes could contribute to yeast's ability to ferment glucose anaerobically (Wolfe 2004) and that glycolytic flux was increased as an outcome of WGD (Conant and Wolfe 2007). These studies are inspiring; nevertheless, it remains unclear how the WGD genes are regulated between aerobic and anaerobic metabolisms, an issue that is central to the WGD–fermentation hypothesis.
Based on this hypothesis, we would expect an enrichment of WGD genes underlying the physiological response of S. cerevisiae to oxygen change. A recent work investigating genome-wide expression during a robust metabolic oscillation in budding yeast provides an opportunity to test our prediction (Tu et al. 2005). During the metabolic oscillation, many parameters—such as respiration rate, ethanol production, and dissolved oxygen concentration in the media—change periodically, so each cycle could be characterized by a respiratory phase followed by an ethanol fermentative phase (Satroutdinov et al. 1992). The genes that exhibit periodic expression patterns during the metabolic oscillation should be closely related to the physiological regulation between aerobic and anaerobic metabolisms. Using this data set, we are able to show that WGD genes tend to have more dynamic regulation than non-WGD genes during the oscillation, which could provide new evidences for the WGD–fermentation hypothesis.
The genes exhibiting periodic expression patterns during the metabolic oscillation are called metabolic cycling genes (Tu et al. 2005). We compared 1,044 WGD and 5,165 non-WGD genes to test whether WGD genes were more likely to have cycling expression pattern than the other genes in the genome. As a result, 703 WGD and 2,796 non-WGD genes were identified as metabolic cycling genes (table 1). The proportion of metabolic cycling genes was significantly higher for the WGD genes than that for the non-WGD genes (P = 1.4x10–15, Fisher's exact test). Ribosomal protein (RP) genes are commonly retained after WGD (110 out of 137 RPs are WGD genes), and most of them cycle during the metabolic oscillation. On the other hand, spurious genes do not cycle because they are functionless. To exclude the possibility that the result above was caused by these genes, we removed them from the data set and redid the analysis; the result remained the same (P = 8.5x10–7, table 1).
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All metabolic cycling genes can be classified into three supergene clusters: Ox (oxidative), R/B (reductive/building), and R/C (reductive/charging) (Tu et al. 2005
). Each of these superclusters comprises genes that are periodically expressed and peak within a certain window of the yeast metabolic cycle. There are four possible expression profiles for duplicate gene pairs during the metabolic oscillation (fig. 1). The expression profile where two copies cycle in the same supercluster (fig. 1A) suggests that dosage effect might be important for keeping both genes working together in the same condition. Indeed, most of the RP duplicates have this expression pattern. The expression profile where two copies cycle in different superclusters (fig. 1B) may indicate subfunctionalization, neofunctionalization, or a combination of the two events (He and Zhang 2005) in which case two duplicate genes have divergent functions in aerobic and anaerobic metabolic conditions. The regulation divergence could facilitate the functional optimization of duplicate genes in individual condition. Both these expression profiles could provide competitive advantage for organisms during adaptation to the new fermentative lifestyle. On the other hand, the duplicate gene pairs with expression profiles where only one duplicate copy cycles (fig. 1C) or where both copies do not cycle (fig. 1D) might be functionally less relevant to the evolution of efficient fermentation. The names of gene pairs with each regulation pattern are listed in supplementary table 1 (Supplementary Material online).
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After comparing the expression profiles for 522 WGD duplicate pairs (Byrne and Wolfe 2005
) and 1,477 smaller scale duplicate (SSD) ones (Guan et al. 2007), we found a significantly higher proportion of the WGD duplicate genes than the SSD ones with patterns A and B (P 
0.0001 Fisher's exact test), whereas the gene pairs with the other two expression patterns show opposite trends (fig. 2), suggesting that dosage effect and functional specialization related with aerobic and anaerobic metabolisms might be important in keeping both duplicate genes after WGD. The results provide evidence that WGD event contributed to the fermentative lifestyle because of more WGD genes, rather than SSD genes, are preferentially retained with the selective function of increasing the organism's ability to regulate its metabolism in response to oxygen change.
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It has been reported that WGD genes have unique functional distributions when compared with the rest of the genome (Guan et al. 2007
). Using the new data set, we confirmed the previous results (Davis and Petrov 2005; Blomme et al. 2006) that genes belonging to Gene Ontology (GO) classes such as "structural molecule," "transcription regulator," "enzyme regulator," and "signal transducer" were preferentially retained after WGD. WGD genes are more likely to keep metabolic cycling in GO classes such as "ase activity," "binding," and "transcription regulator," which do not necessarily overlap with biased WGD gene retention in the genome (supplementary table 2, Supplementary Material online). Furthermore, within the same functional group, such as ase activity, the fact that WGD genes are more likely to cycle than non-WGD genes indicates that the increased oscillation of WGD genes observed in this study is not totally due to their functional biases but was part of metabolic adaptation to a new lifestyle.
We have to emphasize that WGD might not be necessary for all the adaptive properties in a fermentative lifestyle. Some pre-WGD yeast species are also capable of facultative fermentation; yet, none of them are comparable to S. cerevisiae. The fission yeast, Schizosaccharomyces pombe, which diverged from the ancestor of S. cerevisiae much earlier than the WGD, can conduct efficient aerobic fermentation. It can also consume ethanol but not as its sole carbon source (de Jong-Gubbels et al. 1996) owing to the absence of a complete glyoxylate cycle. Kluyveromyces lactis, which is a poor producer of ethanol, can efficiently consume ethanol as its only carbon source. Therefore, it seems that these adaptive properties are unevenly developed among different yeast lineages.
On the other hand, the WGD event is also not sufficient for fermentative lifestyle development. Soil yeast Kluyveromyces polysporus cannot carry out efficient fermentation although the organism experienced WGD during its evolution (Fekete et al. 2007). It was recently reported that K. polysporus and S. cerevisiae diverged very soon after the WGD and that the following gene loss in these two clades proceeded completely independently (Scannell et al. 2007). Increased availability of fruit sugars at the end of the Cretaceous period might have provided a selective pressure for the development of fermentative ability (Wolfe and Shields 1997; Thomson et al. 2005), and the WGD happened to coincide with that event, thus providing a possible cause for the evolution of the efficient fermentation in Saccharomyces lineage. However, soil yeast K. polysporus, due to its unique living environment, might not be influenced much by the abundant fruit sugars, thus evolving in a totally different direction.
It remains unclear whether there were other molecular events that initiated the evolution of efficient fermentation in the ancestor of S. cerevisiae after its divergence from K. polysporus. Nevertheless, in accordance with previous observations, our results indicate that the WGD event could have led to a unique combination of adaptive properties related with efficient fermentation in S. cerevisiae and its closest relatives, thus providing new insights into the relationship between the WGD and the evolution of new lifestyles in eukaryotic organisms.
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Materials and Methods |
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Expression data during the metabolic oscillation were taken from Tu et al. (2005)
. The 554 WGD pairs were from Byrne and Wolfe (2005). The 1,636 SSD pairs were derived from all the yeast's duplicate genes that are not associated with WGD (Guan et al. 2007). Only gene pairs with both copies having microarray gene expression data (Tu et al. 2005) were retained in our analysis (522 and 1,477 for WGD and SSD, respectively). The genes that are not included in the reannotated gene list from Wood et al. (2001) were regarded as spurious genes. There are four possible expression profiles for duplicate gene pairs: if both members of a gene pair cycled during the metabolic oscillation, then the gene pair was classified as pattern A if two genes were in the same supercluster (Ox-oxidative, R/B-reductive/building, and R/C-reductive/charging) and pattern B if they were in different superclusters. If only one cycled, then the pair was classified as pattern C, and if neither cycled, it belongs to pattern D. For gene pairs in pattern B, they could have out-of-phase cycles with various degrees, depending on what superclusters two genes belong to.
GO categories were downloaded from GO database (OBO-Edit version 1.002, http://www.geneontology.org/ontology/function.ontology) at March 2007. The categories in supplementary table 2 (Supplementary Material online) are at the GO level under "Molecular_Function."
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Supplementary Material |
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Supplementary tables 1 and 2 are available at Molecular Biology and Evolution online (http://www.mbe.oxfordjournals.org/).
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Acknowledgements |
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TOPAbstractMaterials and MethodsSupplementary MaterialAcknowledgementsReferences |
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The authors thank Benjamin P. Tu and Yuanfang Guan for providing the data, Huifeng Jiang for discussion, and David Pinney for reading the manuscript. Comments from editor and reviewers are appreciated. The study was supported by the faculty startup funds from Cornell University awarded to Z.G.
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Footnotes |
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Kenneth Wolfe, Associate Editor
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