Laboratory for Systems Biology

Leuven, Belgium

Laboratory for Systems Biology

Leuven, Belgium
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News Article | October 11, 2016

From small craft breweries to mass bottle fillers like Anheuser-Busch InBev, few would argue that the market for the most widely consumed alcoholic beverage in the world is—well, overflowing with growth potential. Research and Markets projects the global beer market to be valued at $318 billion by 2020, though similar projections fluctuate based on the emphasis given to increasingly popular microbreweries opening shop and fine-tuning their craft. Whatever data you use, it’s safe to say there’s been significant movement in this hoppy corner of the food and beverage space—and its taking biotechnology along for the ride. All of the main ingredients in beer help contribute to its flavor in some way: grains form the malt that determines how dark and heavily bodied a beer is, water can impact the minerality and even indicate the region in which the beer was produced and hops produce pounced bitter or floral undertones. But it’s the final step, in which yeast spurs fermentation, that is perhaps the most important and impactful—for both the beer consumer and scientists. Two research teams from White Labs (California) and a Belgian genetics laboratory have collaborated to map out yeasts’ genealogy, creating the first genetic family tree for brewing yeasts. The research team has already sequenced the DNA of more than 240 strains of brewing yeast from around the world, enabling them to tell how closely related two yeasts are. For example, is Brewery A’s yeast closer to the yeast used in Brewery B or Brewery C? Do Brewery A and Brewery C use yeasts derived from the same strain? Many breweries today simply reuse the same strain of yeast or rotate between two or three, but few experiment further with this aspect of brewing. Kevin Verstrepen, leader of the Belgian lab, wants to change that. “People come to the lab and they think ‘you’re working on beer,’ but it’s a product like any other. We try to make it better and more efficient, and yeast is really the key for us,” Verstrepen told Laboratory Equipment. “Yes, we do this work for flavor, but also to improve fermentation so brewers can make beers faster, or so a smaller brewer can make more beer.” Verstrepen’s lab—a joint venture of the Flaunders Institute for Biotechnology and the University of Leuven, Belgium—is extremely well known in the brewing industry. The lab offers a collection of more than 10,000 different yeast strains, including hundreds of industrial yeasts suitable for beer production (ale and lager), wine making, ethanol production and food fermentation. Because yeast is a sexual microbe and the sexual cycle is very short, crossing two yeasts in an attempt to reach one that will better suit the consumers’ liking only takes a week or so. Each of the 10,000+ strains are carefully characterized in Verstrepen’s lab, enabling researchers to select yeasts with specific characteristics—such as aroma production, fermentation efficiency, flocculation, etc. Of course, Verstrepen and his team are still limited by the natural boundaries of biology when it comes to yeast breeding. That’s why he advocates the genetic modification of the fungi, which he says can open new doors. Identifying what genes create particular flavors (like banana or apple) and over-activating them can increase the flavor profile of a brew by hundreds of times. While some craft brewers have shown interest in the potential of using genetically modified yeasts to create the perfect beer pre-conception, Verstrepen said he hasn’t given them the yeast just yet, as he first wants to be sure they would follow the appropriate legal procedures. Genetically modified foodstuffs, after all, aren’t always exactly welcomed by the public. Interested breweries are by far the exception, not the norm. “While I don’t think genetically modifying yeast is unsafe, bigger brewers are certainly not open to it, and that’s because many consumers are afraid of it,” Verstrepen said. “For a lot of companies, it’s all about tradition and natural products. We miss out on some opportunities, like making cheaper beer or doing it in a more sustainable way that’s better for the planet. I understand that consumers and producers have to be on the same page, so it’s definitely a balance issue.” Verstrepen’s lab describes its work as “combining theory and experiment to investigate how biological systems work.” Genetics, genomics and systems biology are used to unravel biological questions and improve industrial fermentation processes. The lab comprises three separate groups—the CMPG Laboratory for Genetics and Genomics, the Laboratory of Industrial Fermentation and the Laboratory for Systems Biology. The focus throughout the groups is on “rapid evolution”—or the idea that some properties of living organisms evolve and diverge at a much higher pace than other traits. Much of this work is conducted using the common brewer’s yeast S. cerevisiae as a model for more complex eukaryotes. Their research shows that the mechanisms underlying hyper-evolveable properties often lie at the border between genetics and epigenetics. The technologies developed for basic research into biological mechanisms and principles are then transferred to related research for industrial applications. “This research is good for brewers, it’s good for the environment and it’s good for humans, too. This yeast research is interesting for beers, but there are also implications for other areas, such as biofuels. In fact, half of my lab is using yeast cells as a model to unravel the basic mechanisms of cancer.” Much like beer, the key to biofuel and other bio-based products lies in yeasts. Yeasts can use a wide range of carbon and energy sources, ranging from cellulosic (6-carbon) and hemicellulosic (5-carbon) sugars to methanol, glycerol and acetic acid. To help boost the use of a wider range of yeasts and to explore the use of genes and pathways encoded in their genomes, a team led by researchers at the U.S. Department of Energy Joint Genome Institute (DOE JGI) conducted a comparative genomic analysis of 29 yeasts, including 16 whose genomes were newly sequenced and annotated. According to the DOE JGI, sequencing less-known yeasts and characterizing their metabolic pathways helps fill in knowledge gaps regarding the fungal enzymes that can help convert a wide range of sugars into biofuel. The well-known yeast S. cerevisiae, for example, ferments glucose, but not other sugars found in plant biopolymers. One of the newly sequenced yeasts is Pachysolus tannophilus, which can ferment xylose, otherwise known as wood sugar, as it is derived from hemicellulose, which along with cellulose, is one of the main constituents of woody biomass. It is only distantly related to well-studied xylose fermenters such as Scheffersomyces stipitis—another yeast sequenced by the DOE JGI. “We might think of yeasts as simple unicellular, creatures similar to each other, but in fact their genetic diversity is like the difference between human and invertebrate sea squirt,” said DOE JGI’s Robert Riley in a press release. “We sequenced these diverse genomes to discover and facilitate the next generation of biotechnological workhorse yeasts for producing the fuels and products we use in daily life.”

Jansen A.,Laboratory for Systems Biology | Jansen A.,Catholic University of Leuven | Van Der Zande E.,Laboratory for Systems Biology | Van Der Zande E.,Catholic University of Leuven | And 5 more authors.
Nucleic Acids Research | Year: 2012

The positions of nucleosomes across the genome influence several cellular processes, including gene transcription. However, our understanding of the factors dictating where nucleosomes are located and how this affects gene regulation is still limited. Here, we perform an extensive in vivo study to investigate the influence of the neighboring chromatin structure on local nucleosome positioning and gene expression. Using truncated versions of the Saccharomyces cerevisiae URA3 gene, we show that nucleosome positions in the URA3 promoter are at least partly determined by the local DNA sequence, with so-called 'antinucleosomal elements' like poly(dA:dT) tracts being key determinants of nucleosome positions. In addition, we show that changes in the nucleosome positions in the URA3 promoter strongly affect the promoter activity. Most interestingly, in addition to demonstrating the effect of the local DNA sequence, our study provides novel in vivo evidence that nucleosome positions are also affected by the position of neighboring nucleosomes. Nucleosome structure may therefore be an important selective force for conservation of gene order on a chromosome, because relocating a gene to another genomic position (where the positions of neighboring nucleosomes are different from the original locus) can have dramatic consequences for the gene's nucleosome structure and thus its expression. © 2012 The Author(s).

Pougach K.,Catholic University of Leuven | Pougach K.,Laboratory for Systems Biology | Voet A.,RIKEN | Kondrashov F.A.,Center for Genomic Regulation | And 15 more authors.
Nature Communications | Year: 2014

The emergence of new genes throughout evolution requires rewiring and extension of regulatory networks. However, the molecular details of how the transcriptional regulation of new gene copies evolves remain largely unexplored. Here we show how duplication of a transcription factor gene allowed the emergence of two independent regulatory circuits. Interestingly, the ancestral transcription factor was promiscuous and could bind different motifs in its target promoters. After duplication, one paralogue evolved increased binding specificity so that it only binds one type of motif, whereas the other copy evolved a decreased activity so that it only activates promoters that contain multiple binding sites. Interestingly, only a few mutations in both the DNA-binding domains and in the promoter binding sites were required to gradually disentangle the two networks. These results reveal how duplication of a promiscuous transcription factor followed by concerted cis and trans mutations allows expansion of a regulatory network. © 2014 Macmillan Publishers Limited. All rights reserved.

Voordeckers K.,Laboratory for Systems Biology | Voordeckers K.,Catholic University of Leuven | De Maeyer D.,Catholic University of Leuven | van der Zande E.,Laboratory for Systems Biology | And 11 more authors.
Molecular Microbiology | Year: 2012

When grown on solid substrates, different microorganisms often form colonies with very specific morphologies. Whereas the pioneers of microbiology often used colony morphology to discriminate between species and strains, the phenomenon has not received much attention recently. In this study, we use a genome-wide assay in the model yeast Saccharomyces cerevisiae to identify all genes that affect colony morphology. We show that several major signalling cascades, including the MAPK, TORC, SNF1 and RIM101 pathways play a role, indicating that morphological changes are a reaction to changing environments. Other genes that affect colony morphology are involved in protein sorting and epigenetic regulation. Interestingly, the screen reveals only few genes that are likely to play a direct role in establishing colony morphology, with one notable example being FLO11, a gene encoding a cell-surface adhesin that has already been implicated in colony morphology, biofilm formation, and invasive and pseudohyphal growth. Using a series of modified promoters for fine-tuning FLO11 expression, we confirm the central role of Flo11 and show that differences in FLO11 expression result in distinct colony morphologies. Together, our results provide a first comprehensive look at the complex genetic network that underlies the diversity in the morphologies of yeast colonies. © 2012 Blackwell Publishing Ltd.

Gemayel R.,Laboratory for Systems Biology | Gemayel R.,Catholic University of Leuven | Cho J.,Laboratory for Systems Biology | Cho J.,Catholic University of Leuven | And 4 more authors.
Genes | Year: 2012

Copy Number Variations (CNVs) and Single Nucleotide Polymorphisms (SNPs) have been the major focus of most large-scale comparative genomics studies to date. Here, we discuss a third, largely ignored, type of genetic variation, namely changes in tandem repeat number. Historically, tandem repeats have been designated as non functional "junk" DNA, mostly as a result of their highly unstable nature. With the exception of tandem repeats involved in human neurodegenerative diseases, repeat variation was often believed to be neutral with no phenotypic consequences. Recent studies, however, have shown that as many as 10% to 20% of coding and regulatory sequences in eukaryotes contain an unstable repeat tract. Contrary to initial suggestions, tandem repeat variation can have useful phenotypic consequences. Examples include rapid variation in microbial cell surface, tuning of internal molecular clocks in flies and the dynamic morphological plasticity in mammals. As such, tandem repeats can be useful functional elements that facilitate evolvability and rapid adaptation. © 2012 by the authors; licensee MDPI, Basel, Switzerland.

Steensels J.,Catholic University of Leuven | Steensels J.,Laboratory for Systems Biology | Snoek T.,Catholic University of Leuven | Snoek T.,Laboratory for Systems Biology | And 8 more authors.
FEMS Microbiology Reviews | Year: 2014

Yeasts have been used for thousands of years to make fermented foods and beverages, such as beer, wine, sake, and bread. However, the choice for a particular yeast strain or species for a specific industrial application is often based on historical, rather than scientific grounds. Moreover, new biotechnological yeast applications, such as the production of second-generation biofuels, confront yeast with environments and challenges that differ from those encountered in traditional food fermentations. Together, this implies that there are interesting opportunities to isolate or generate yeast variants that perform better than the currently used strains. Here, we discuss the different strategies of strain selection and improvement available for both conventional and nonconventional yeasts. Exploiting the existing natural diversity and using techniques such as mutagenesis, protoplast fusion, breeding, genome shuffling and directed evolution to generate artificial diversity, or the use of genetic modification strategies to alter traits in a more targeted way, have led to the selection of superior industrial yeasts. Furthermore, recent technological advances allowed the development of high-throughput techniques, such as 'global transcription machinery engineering' (gTME), to induce genetic variation, providing a new source of yeast genetic diversity. Whereas yeasts have been used for thousands of years in human food production, there still are many opportunities to isolate or generate superior variants, using various techniques such as breeding, genome shuffling, protoplast fusion, directed evolution, or novel genetic modification strategies like global transcriptional engineering. © 2014 The Authors. FEMS Microbiology Reviews published by John Wiley & Sons Ltd on behalf of Federation of European Microbiological Societies..

Steensels J.,Catholic University of Leuven | Steensels J.,Laboratory for Systems Biology | Meersman E.,Catholic University of Leuven | Meersman E.,Laboratory for Systems Biology | And 6 more authors.
Applied and Environmental Microbiology | Year: 2014

The concentrations and relative ratios of various aroma compounds produced by fermenting yeast cells are essential for the sensory quality of many fermented foods, including beer, bread, wine, and sake. Since the production of these aroma-active compounds varies highly among different yeast strains, careful selection of variants with optimal aromatic profiles is of crucial importance for a high-quality end product. This study evaluates the production of different aroma-active compounds in 301 different Saccharomyces cerevisiae, Saccharomyces paradoxus, and Saccharomyces pastorianus yeast strains. Our results show that the production of key aroma compounds like isoamyl acetate and ethyl acetate varies by an order of magnitude between natural yeasts, with the concentrations of some compounds showing significant positive correlation, whereas others vary independently. Targeted hybridization of some of the best aroma-producing strains yielded 46 intraspecific hybrids, of which some show a distinct heterosis (hybrid vigor) effect and produce up to 45% more isoamyl acetate than the best parental strains while retaining their overall fermentation performance. Together, our results demonstrate the potential of large-scale outbreeding to obtain superior industrial yeasts that are directly applicable for commercial use. © 2014, American Society for Microbiology.

Gemayel R.,Laboratory for Systems Biology | Gemayel R.,Catholic University of Leuven | Vinces M.D.,Laboratory for Systems Biology | Vinces M.D.,Catholic University of Leuven | And 3 more authors.
Annual Review of Genetics | Year: 2010

Genotype-to-phenotype mapping commonly focuses on two major classes of mutations: single nucleotide polymorphisms (SNPs) and copy number variation (CNV). Here, we discuss an underestimated third class of genotypic variation: changes in microsatellite and minisatellite repeats. Such tandem repeats (TRs) are ubiquitous, unstable genomic elements that have historically been designated as nonfunctional "junk DNA" and are therefore mostly ignored in comparative genomics. However, as many as 10 to 20 of eukaryotic genes and promoters contain an unstable repeat tract. Mutations in these repeats often have fascinating phenotypic consequences. For example, changes in unstable repeats located in or near human genes can lead to neurodegenerative diseases such as Huntington disease. Apart from their role in disease, variable repeats also confer useful phenotypic variability, including cell surface variability, plasticity in skeletal morphology, and tuning of the circadian rhythm. As such, TRs combine characteristics of genetic and epigenetic changes that may facilitate organismal evolvability. © 2010 by Annual Reviews. All rights reserved.

Steensels J.,Catholic University of Leuven | Steensels J.,Laboratory for Systems Biology | Verstrepen K.J.,Catholic University of Leuven | Verstrepen K.J.,Laboratory for Systems Biology
Annual Review of Microbiology | Year: 2014

Yeasts are the main driving force behind several industrial food fermentation processes, including the production of beer, wine, sake, bread, and chocolate. Historically, these processes developed from uncontrolled, spontaneous fermentation reactions that rely on a complex mixture of microbes present in the environment. Because such spontaneous processes are generally inconsistent and inefficient and often lead to the formation of off-flavors, most of today's industrial production utilizes defined starter cultures, often consisting of a specific domesticated strain of Saccharomyces cerevisiae, S. bayanus, or S. pastorianus. Although this practice greatly improved process consistency, efficiency, and overall quality, it also limited the sensorial complexity of the end product. In this review, we discuss how Saccharomyces yeasts were domesticated to become the main workhorse of food fermentations, and we investigate the potential and selection of nonconventional yeasts that are often found in spontaneous fermentations, such as Brettanomyces, Hanseniaspora, and Pichia spp. Copyright © 2014 by Annual Reviews. All rights reserved.

Jansen A.,Laboratory for Systems Biology | Jansen A.,Catholic University of Leuven | Jansen A.,Human Genome Laboratory | Gemayel R.,Laboratory for Systems Biology | And 3 more authors.
Genome Dynamics | Year: 2012

Tandem repeats are intrinsically highly variable sequences since repeat units are often lost or gained during replication or following unequal recombination events. Because of their low complexity and their instability, these repeats, which are also called satellite repeats, are often considered to be useless 'junk' DNA. However, recent findings show that tandem repeats are frequently found within promoters of stress-induced genes and within the coding regions of genes encoding cell-surface and regulatory proteins. Interestingly, frequent changes in these repeats often confer phenotypic variability. Examples include variation in the microbial cell surface, rapid tuning of internal molecular clocks in flies, and enhanced morphological plasticity in mammals. This suggests that instead of being useless junk DNA, some variable tandem repeats are useful functional elements that confer 'evolvability', facilitating swift evolution and rapid adaptation to changing environments. Since changes in repeats are frequent and reversible, repeats provide a unique type of mutation that bridges the gap between rare genetic mutations, such as single nucleotide polymorphisms, and highly unstable but reversible epigenetic inheritance. Copyright © 2012 S. Karger AG, Basel.

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