Fermentation innovation through complex hybridization of wild and domesticated yeasts


The most common fermented beverage, lager beer, is produced by interspecies hybrids of the brewing yeast Saccharomyces cerevisiae and its wild relative S. eubayanus. Lager-brewing yeasts are not the only example of hybrid vigour or heterosis in yeasts, but the full breadth of interspecies hybrids associated with human fermentations has received less attention. Here we present a comprehensive genomic analysis of 122 Saccharomyces hybrids and introgressed strains. These strains arose from hybridization events between two to four species. Hybrids with S. cerevisiae contributions originated from three lineages of domesticated S. cerevisiae, including the major wine-making lineage and two distinct brewing lineages. In contrast, the undomesticated parents of these interspecies hybrids were all from wild Holarctic or European lineages. Most hybrids have inherited a mitochondrial genome from a parent other than S. cerevisiae, which recent functional studies suggest could confer adaptation to colder temperatures. A subset of hybrids associated with crisp flavour profiles, including both lineages of lager-brewing yeasts, have inherited inactivated S. cerevisiae alleles of critical phenolic off-flavour genes and/or lost functional copies from the wild parent through multiple genetic mechanisms. These complex hybrids shed light on the convergent and divergent evolutionary trajectories of interspecies hybrids and their impact on innovation in lager brewing and other diverse fermentation industries.

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Fig. 1: Summary of genomic contributions and isolation environments for interspecies hybrids.
Fig. 2: Population and phylogenomic analyses of S. cerevisiae, S. kudriavzevii, S. uvarum, S. eubayanus and their hybrid subgenomes.
Fig. 3: Mitochondrial genome inheritance in interspecies hybrids.
Fig. 4: Hybrid inheritance and functionality of genes responsible for 4VG production.
Fig. 5: Summary of hybrids and origin of lager traits.

Data availability

References and accession numbers for the published data used can be found in Supplementary Dataset 16. Short-read data (newly published here) are available through the NCBI SRA database under the BioProject accession number PRJNA522928. Assembled genomes published here are available under GenBank BioProject PRJNA522928.

Code availability

Custom R and Python scripts used for this publication can be found on GitHub (https://github.com/qlangdon/hybrid-ferment-invent).


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We thank K.J. Verstrepen for coordinating publication with their study; A.B. Hulfachor and M. Bontrager for preparing a subset of Illumina libraries; the University of Wisconsin Biotechnology Center DNA Sequencing Facility for providing Illumina sequencing facilities and services; M.-A. Lachance, A. Kinart, D.T. Doering, R. Thiel and D. Carey for strains; and M. Langdon, A.B. Hulfachor and K. Sylvester for collecting fermentation samples and/or isolating strains. This material is based upon work supported by the National Science Foundation (grant nos. DEB-1253634 to C.T.H. and DGE-1256259 (Graduate Research Fellowship to Q.K.L.), the USDA National Institute of Food and Agriculture Hatch Project (nos. 1003258 and 1020204 to C.T.H.) and in part by the DOE Great Lakes Bioenergy Research Center (DOE BER Office of Science nos. DE-SC0018409 and DE-FC02-07ER64494). Q.K.L. was also supported by the Predoctoral Training Program in Genetics, funded by the National Institutes of Health (grant no. 5T32GM007133). D.P. is a Marie Sklodowska-Curie fellow of the European Union’s Horizon 2020 research and innovation programme (grant no. 747775). E.P.B. was supported by a Louis and Elsa Thomsen Wisconsin Distinguished Graduate Fellowship. U.B. is funded by Horizon 2020 MSCA-ITN grant no. 764364. D.L. was supported by CONICET (grant no. PIP 392), FONCyT (grant no. PICT 3677) and Universidad Nacional del Comahue (grant no. B199). C.T.H. is a Pew Scholar in the Biomedical Sciences, Vilas Faculty Early Career Investigator and H.I. Romnes Faculty Fellow, supported by the Pew Charitable Trusts, Vilas Trust Estate and Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation, respectively.

Author information

Q.K.L. performed most analyses with assistance from D.A.O. D.P. and Q.K.L. performed mitochondrial genome analyses and drafted text. E.P.B. and Q.K.L. analysed genes of functional interest and drafted text. Q.K.L., E.P.B. and D.A.O. sequenced genomes. H.-V.N., U.B., P.G. and J.P.S. contributed key strains to study design. Q.K.L., D.P., E.P.B., D.L. and C.T.H. designed the study. Q.K.L. and C.T.H. wrote the manuscript with editorial input from all coauthors.

Correspondence to Chris Todd Hittinger.

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Supplementary information

Supplementary Information

Supplementary text and Supplementary Figs. 1–15.

Reporting Summary

Supplementary Dataset 1

All hybrids and their parent contributions.

Supplementary Dataset 2

PCA analyses. Percent explained by each principal component included in column headers.

Supplementary Dataset 3

Newick formatted file of the S. kudriavzevii phylogeny with major hybrids.

Supplementary Dataset 4

Newick formatted file of the S. kudriavzevii phylogeny with minor hybrids.

Supplementary Dataset 5

Newick formatted file of the S. eubayanus phylogeny with major hybrids.

Supplementary Dataset 6

Newick formatted file of the S. eubayanus phylogeny with minor hybrids.

Supplementary Dataset 7

Newick formatted file of the S. uvarum phylogeny with major hybrids.

Supplementary Dataset 8

Newick formatted file of the S. uvarum phylogeny with minor hybrids.

Supplementary Dataset 9

Newick formatted file of the S. cerevisiae phylogeny with all strains analysed.

Supplementary Dataset 10

Newick formatted file of the S. cerevisiae phylogeny of just the Ale/Beer1 clade.

Supplementary Dataset 11

Results of Fisher’s exact test and Bonferroni correction of mitochondrially localized genes. mtInteracting = nuclear-encoded but mitochondrially localized gene.

Supplementary Dataset 12

Summary of number of 1:1:1:1 orthologues present in each subgenome.

Supplementary Dataset 13

GO term results of genes found in novel regions of the de novo assembled genomes.

Supplementary Dataset 14

Brewing relevant gene summaries. 30“-“ Indicates when HybPiper failed to recover and assemble genes for this group or that these assemblies failed our length and coverage cutoffs.

Supplementary Dataset 15

Metadata for all strains newly sequenced in this study. The “New hybrid” column denotes hybrid genome sequences that are newly published in this study.

Supplementary Dataset 16

Published data accession information.

Supplementary Dataset 17

Haplotype key for mitochondrial genomes, PAD1 and FDC1. Dataset A only includes strains where 15S rRNA could be assembled, while Dataset B has 15S rRNA removed.

Supplementary Dataset 18

Regions used for minor contribution analyses.

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Langdon, Q.K., Peris, D., Baker, E.P. et al. Fermentation innovation through complex hybridization of wild and domesticated yeasts. Nat Ecol Evol 3, 1576–1586 (2019). https://doi.org/10.1038/s41559-019-0998-8

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