Quantitative Genetics of Hybrid Yeasts: overcoming sterility and biotechnological exploitation of diversity

Lead Research Organisation: University of Leicester
Department Name: Genetics


Selection for improved characteristics of crops and animals over the millennia of modern human history has benefited from the ability to breed. Artificial selection for such improvement through selective breeding feeds the world as well as gives us the wide variety of dog breeds, faster race horses, etc. Without the ability to breed there is limited variation on which to base improvements. Many plants, including various crops of great importance such as wheat, originated from the hybridization of two or more closely related species. These initially were sterile and dead ends in terms of evolution but overcame their sterility by duplicating their genomes. Variation could still be limited in these as the fertile derivatives may have occurred only once in history resulting in variation being fixed at that point and accumulated over time via mutations. A lot of effort goes into crop improvement by introgressing chromosomes from parental species of the hybrids to bring in new variation. In animals it is more difficult to overcome sterility and so working animals such as mules can only really be improved by breeding in the horse and donkey parents and hoping for improved characteristics in each new mules created by mating the two parents. This is a hit or miss approach and not very efficient.

In fermentation uses with yeast there are hybrids that are used, the most famous being the lager yeast Saccharomyces carlsbergensis. There are also some used in the wine industry and others are found in nature. These are sterile hybrids which preclude improvement by breeding. In this project we overcome the sterility barrier by duplicating the genomes of several new and existing hybrids, first to determine the genetics of particular characteristics, like why does lager yeast ferment better at cold temperatures, and then to create new diverse hybrids with improved or even new characteristics. We will generate a large number of new hybrids and explore their characteristics, isolating useful strains for use in brewing and wine making as well as industrial production strains. We will also learn about the biology of hybrids and how their two genomes interact. Finally we will answer the question 'Can mules evolve?'

Technical Summary

Yeast hybrids are important in many industrial situations including various fermentations used to produce alcoholic beverages. These and other production strains have been improved upon over the decades by relying on mutations and selection. A much greater potential for improvement would be available if these strains were amenable to genetics and breeding. We will apply several mating/fusion techniques to create tetraploids out of existing hybrids and new hybrids created in the lab from extant species in the group. These will then be assessed for basic phenotypes and new genetically variable hybrids will be generated by putting the tetraploids through meiosis. Rather than being sterile the 4n hybrids will generate 2n diploid hybrids similar to the original sterile hybrid created but with new genetic combinations from the input parental strains of each species going into the hybrid. This will make the progeny amenable to the latest QTL analysis techniques in yeast using next generation sequencing on pools of selected individuals. The result will be first the generation of new hybrids with new characteristics, some will have improvements of desired traits. The analysis of these will provide the determination of why these new hybrids are improved. Finally some will be taken through fermentation processes with all the inherent stresses to determine whether the improved strains are still fit for fermentation purposes. Any useful strains will be protected by safe storage in the national culture collection (NCYC). Ultimately we will produce new hybrids to order for various fermentation and industrial purposes.

Planned Impact

Who will benefit from this research?

The opening up of hybrids to genetic analysis and breeding solves an age old problem and is of great potential benefit to several groups, primarily the fermentation industries producing alcoholic beverages but also to the biotech industries producing flavours and other high value compounds as well as those producing platform chemicals for new compound development, biofuels, bespoke compounds from engineered pathways, new enzymes, etc. Beyond the biotech and fermentation industries the methods could be beneficial to agriculture providing a means to bring in more genetic variation to hybrid crops that already have undergone tetraploidization. This research will also reach public and educational communities, such as agricultural and winery colleges (i.e. Plumpton College, East Sussex, UK), delivering awareness in new cutting-edge technologies, such as next generation sequencing and large-scale quantitative trait analysis, and specifically promoting UK basic science in the yeast physiology and evolution community.

How will they benefit from this research?

Immediate benefits will arise from the generation of new hybrid strains with improved properties, which will come along with the knowledge of the underlying genetics providing the improvement. Some beneficiaries will be able to utilize these immediately while other can use the approach on their production strains for improvement or can take the genetic knowledge to help engineer improvements in their strains.

What will be done to ensure that they have the opportunity to benefit from this research?

In addition to the traditional routes of publication and academic seminars, the results of this project will be communicated to target groups through the communications offices of the Universities of Leicester, Manchester and Nottingham and the BBSRC media office. Various activities of the PI, CoIs and Industrial Partner involve a wide range of industrial contacts including the Industrial Platform of the LACE programme under BSBEC, the Industrial members of the EU Cost Action Network on Bioflavours from Yeast, and attendance at conferences concentrating on applied aspects of yeast fermentation such as the ISSY in October 2014 and the Yeast in Bioeconomy in November 2013 where relevant outputs and methodologies will be disseminated. We will engage college students by publishing scientific articles in the "Biological Science Review" (http://www.bsr.manchester.ac.uk/) and by meeting them face-to-face in the 'Meet the Scientists' days, organized by Nowgen, a centre for genetics in healthcare, in Manchester.

Professional development for staff working on the project

The project will offer opportunities for the PDRAs to acquire additional skill sets. These will include training in quantitative trait analysis and NGS informatics as well as communication skills through scientific conferences and public engagement events. By attending the BBSRC Media courses, the PDRAs will achieve a better understanding on how to communicate science to the public and explain research strategies to policy makers and general communities.


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Description We have successfully taken a sterile hybrid from the wine industry and made it fertile - now allowing for genetic analysis and manipulation.

We have generated all the parental species strains to go into our new hybrid production and will concentrate first on brewing related hybrids.
Exploitation Route The techniques will be applicable to hybrid crops in the future.

For the yeast hybrid outcomes there will eventually be improved brewing traits with the potential for bespoke yeast hybrids for specific purposes.
Sectors Agriculture, Food and Drink,Creative Economy,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL http://www2.le.ac.uk/colleges/medbiopsych/research/gact/projects
Description Discussions with brewers and wine makers. More recently this has led to the founding of a startup company - Phenotypeca - which will exploit the genetic diversity of yeasts including hybrids to generate and develop new strains for a variety of industrial purposes. Although mostly a therapeutic company, Phenotypeca has been working with food companies to make synthetic components of various products.
First Year Of Impact 2019
Sector Agriculture, Food and Drink,Creative Economy,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

Description H2020-MSCA-ITN-2017: 764927 - YEASTDOC
Amount € 3,094,944 (EUR)
Funding ID 764927-YEASTDOC 
Organisation European Commission H2020 
Sector Public
Country Belgium
Start 08/2017 
End 09/2022
Description Phenotypeca research contract to develop new yeasts 
Organisation Phenotypeca
Country United Kingdom 
Sector Private 
PI Contribution New startup company (started 12/2018) to develop new production yeast strains for the biopharma and biotech industries. It is my science that the collaboration is based on and currently my University lab is subcontracted to initiate the strain development.
Collaborator Contribution Phenotypeca has obtained an Innovate UK grant and has lab and office space along with partners with analytical and fermentation tools. They are providing high throughput analytics and assessment of strains as well as a variety of expression vectors (proprietary) for different partners.
Impact New collaboration so outputs are still to come. The spinout itself is an output as seen in another section.
Start Year 2019
Company Name Phenotypeca Ltd 
Description Phenotypeca provides novel biologics production strains of the regulatory friendly baker's yeast, Saccharomyces cerevisiae for the manufacture of biologicals. We offer world leading yeast technology to rapidly provide cost-effective production strains optimised for specific biotechnology processes. This is achieved by harnessing the natural diversity in up to a billion different yeast cells to identify those with the ideal phenotypes and performance characteristics for industrial process conditions. Working with our customers we aim to improve access to life-saving medicines and promote sustainable manufacturing. With baker's yeast now fully established for the safe and economic production of FDA approved biologics, such as insulins and vaccines, our technology is ideal for taking bioprocesses to the next level. 
Year Established 2018 
Impact As a recent startup there is limited impact at the moment. There are 6 salaried employees, one full time research scientist, a scientific officer, a research director, business director and tech support. An Innovate UK award for proof of principle was awarded in January 2020 which subcontracts some work to the University lab in Leicester.
Website https://phenotypeca.com/
Description FEMS 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussion in yeast for biotechnology session with a mixed audience resulting in longer term interactions on developing yeast and hybrids for industrial uses.
Year(s) Of Engagement Activity 2015
Description ICY15 Invited talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk in scientific session relevant to Yeats hybrids.
Year(s) Of Engagement Activity 2021
URL https://fems-microbiology.org/opportunities/15th-international-congress-on-yeasts-icy15/
Description Invited Speaker at Cold Spring Harbor Meeting on Yeast History 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Over 200 yeast biologists/geneticists from academia and industry from around the world attend the special Cold Spring Harbor meeting on Yeast History. The main outcome was to reintroduce the classical and sometimes forgotten areas of yeast biology to the younger generations which will benefit science and research approaches.
Year(s) Of Engagement Activity 2019
URL https://meetings.cshl.edu/meetings.aspx?meet=biohist&year=19
Description Keynote at Benelux annual yeast meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Several Universities and Industries attended and interest in future collaborations was expressed.
Year(s) Of Engagement Activity 2018
URL https://www.yeasterday.nl
Description Plenary speaker at ISSY33 in Cork 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact New collaborations starting with potential of future benefit.
Year(s) Of Engagement Activity 2017