Abstract
Genome introgressions drive evolution across the animal1, plant2 and fungal3 kingdoms. Introgressions initiate from archaic admixtures followed by repeated backcrossing to one parental species. However, how introgressions arise in reproductively isolated species, such as yeast4, has remained unclear. Here we identify a clonal descendant of the ancestral yeast hybrid that founded the extant Saccharomyces cerevisiae Alpechin lineage5, which carries abundant Saccharomyces paradoxus introgressions. We show that this clonal descendant, hereafter defined as a ‘living ancestor’, retained the ancestral genome structure of the first-generation hybrid with contiguous S. cerevisiae and S. paradoxus subgenomes. The ancestral first-generation hybrid underwent catastrophic genomic instability through more than a hundred mitotic recombination events, mainly manifesting as homozygous genome blocks generated by loss of heterozygosity. These homozygous sequence blocks rescue hybrid fertility by restoring meiotic recombination and are the direct origins of the introgressions present in the Alpechin lineage. We suggest a plausible route for introgression evolution through the reconstruction of extinct stages and propose that genome instability allows hybrids to overcome reproductive isolation and enables introgressions to emerge.
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Data availability
The genome sequences generated in this study are available at Sequence Read Archive (SRA), NCBI under the accession codes BioProject ID PRJNA594913, Biosample ID SAMN13540515–SAMN13540586. Re-analysed sequencing data are available as part of the project ERP014555 in the Sequence Read Archive. The phenotype data are available within the Supplementary Information files. All the strains generated in this work are freely available upon request. Source data are provided with this paper.
Code availability
Custom Bash and Perl scripts used in this study are available at: https://github.com/mdangiolo89/A-yeast-living-ancestor-reveals-the-origin-of-genomic-introgressions
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Acknowledgements
We thank A. Bergström, G. Fischer, B. Llorente, S. Mozzachiodi and L. Tattini for critical reading of the manuscript. This work was supported by Agence Nationale de la Recherche (ANR-11-LABX-0028-01, ANR-13-BSV6-0006-01, ANR-15-IDEX-01, ANR-16-CE12-0019 and ANR-18-CE12-0004) and the Swedish Research Council (2014-6547, 2014-4605 and 2018-03638). We thank the Institut Curie NGS platform for generating the sequence data. J.S. is a fellow of the University of Strasbourg Institute for Advanced Study and a member of the Institut Universitaire de France.
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M.D., M.D.C., J.X.Y., J.W. and G.L. designed the experiments; M.D., M.D.C. and J.X.Y. performed the genomic analyses; M.D., A.I. and A.L. performed and analysed sporulation efficiency, spore viability and LOH rates; S.S. and K.P. performed and analysed the growth phenotype data; B.B. performed and analysed the chronological life span; E.G., R.M., J.S., J.W. and G.L. contributed with resources and reagents; J.W. and G.L. conceived and supervised the project; M.D., J.W. and G.L. wrote the paper.
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Extended data figures and tables
Extended Data Fig. 1 Genome-wide distribution of LOH and introgressions.
a, Genotype maps of the genome of the living ancestor (top) and the 17 Alpechins. The DNA of the living ancestor is coloured to denote S. cerevisiae (blue) and S. paradoxus (red) DNA, respectively. The DNA of the Alpechins is coloured to denote the S. cerevisiae background (blue) and the interspersed introgressions that are homozygous (red) or heterozygous (grey) for S. paradoxus DNA. There is extensive overlap between the positions of S. paradoxus LOH in the living ancestor and introgressions in the Alpechins. b, Magnified view of chromosome II. Colours as in a. White circles indicate centromeres. Genomic coordinates are based on the S. cerevisiae DBVPG6765 genome assembly.
Extended Data Fig. 2 Alternative evolutionary models of the origins of the living ancestor and Alpechins.
The genome-wide overlap between LOH, introgressions and mutated sites within LOH regions with two copies of S. cerevisiae or S. paradoxus DNA allowed us to test the alternative models 1 (left) and 2 (right). See Supplementary Discussion 1 for details. Top boxes report the number of introgressions and LOH, partitioned into overlapping and non-overlapping events. Bottom boxes report the number of de novo point mutations in LOH blocks of the living ancestor. Left and right boxes show mutations in S. paradoxus and S. cerevisiae LOH blocks, respectively. Numbers around the top chromosome pair report the total number of de novo mutations, partitioned into those occurring on the S. cerevisiae and S. paradoxus haplotype, respectively. Numbers below the bottom chromosome pair report de novo mutations that are shared between the living ancestor and the Alpechins, again partitioned into those occurring on the S. cerevisiae and S. paradoxus haplotype, respectively. Haplotype phasing data are available only for the living ancestor. Patterns of overlap between S. paradoxus LOH/introgressions and shared de novo mutations between the living ancestor’s S. paradoxus LOH and the Alpechin strains are compatible with model 1. By contrast, the sequence of events in model 2 makes it incompatible with the observed data: the emergence of S. cerevisiae LOH and their de novo mutations after the hybridization between an Alpechin and a S. paradoxus implies that none of these de novo mutations should be present in any Alpechin strain. The presence of 20 mutations that are shared between the Alpechins and the living ancestor rules out model 2 in favour of model 1.
Extended Data Fig. 3 Genome structure of the living ancestor.
Each coloured bar represents a chromosome, with dark tones representing S. paradoxus DNA and light tones representing S. cerevisiae DNA. Dark blocks within S. cerevisiae chromosomes represent S. paradoxus LOH, and light blocks within S. paradoxus chromosomes represent S. cerevisiae LOH. White circles indicate centromeres and numbers (from 1 to 5) annotate the recombination breakpoints of the gross chromosomal rearrangements listed in the top-right box. Subgenome assignment for rearranged chromosomes is based on centromere flanking sequences. Genomic coordinates of S. cerevisiae and S. paradoxus chromosomes are based on the genome assemblies of DBVPG6765 and CBS432 strains, respectively. We cannot confidently say whether intrinsic (genetic) or extrinsic (environmentally induced) genome instability explain the astounding genome instability signature, nor we can say whether it emerged from a single event or accumulated gradually.
Extended Data Fig. 4 LOH size distribution.
a, Histograms of LOH sizes in the living ancestor. Left, the size histogram of S. cerevisiae LOH events (two copies of S. cerevisiae DNA retained and loss of the S. paradoxus DNA copy). Bin width is 4 kb. Right, the size histogram of the S. paradoxus LOHs (two copies of S. paradoxus DNA retained and loss of the S. cerevisiae DNA copy). Dark and light colours respectively indicate terminal and interstitial LOH events. Insets show magnified views of the x axis up to 30 kb. Bin width is 2.5 kb. b, Size histograms of new LOH events in the mutation accumulation lines. Bin width is 15 kb. Insets show magnified views of the x axis up to 30 kb. Bin width is 2 kb. Panel order and colour codes are as in a.
Extended Data Fig. 5 Genome-wide genotype of the living ancestor gametes.
a, We used the genome sequences of 25 living ancestor haploid gametes to infer their recombination landscape. Red and blue colours represent S. paradoxus and S. cerevisiae DNA, respectively. The top part shows the living ancestor. Grey segments represent heterozygous regions for which both S. paradoxus and S. cerevisiae DNA is present and correspond to duplicated regions derived from segregation of rearranged chromosomes or aneuploidies. Aneuploidies were all gain-of-copies, with chromosome III particularly prone to duplicate (7 out of 25 gametes), consistent with the presence of a single LOH block encompassing the centromere, where crossovers are rare69. Chromosomes with intra-homologue and inter-homologue gross chromosomal rearrangements are indicated by an asterisk and a plus sign, respectively. Genomic coordinates are based on the S. cerevisiae DBVPG6765 genome assembly. b, Percentage of the genome bearing S. cerevisiae or S. paradoxus DNA in the 25 living ancestor gametes. Colours as in a. c, The number of observed S. cerevisiae (blue) and S. paradoxus (red) haplotype blocks in three living ancestor gametes. These blocks derive from the combination of meiotic recombination events and pre-existing LOH. As comparison, we calculated the theoretical number of haplotype blocks expected from a single meiosis, considering only the number of crossovers, in an experimental S. cerevisiae–S. paradoxus F1 hybrid (data from ref. 13, brown bar), and in the living ancestor if LOH were not present (green bar). We estimated the number of expected haplotypes (y) as y = 16(x + 1), in which x represents the number of crossovers per chromosome. d, Size distribution of S. paradoxus haplotype blocks in three living ancestor gametes (top) and of introgression blocks in three Alpechins (bottom).
Extended Data Fig. 6 Living ancestor clonal evolution.
a, Genome-wide genotype maps of the living ancestor and its diploid clones derived by mutation accumulation line protocol (MAL) through 120 single-cell bottlenecks and return-to-growth clones derived by inducing and then aborting meiosis. Grey represents heterozygous DNA, red represents LOH blocks with two S. paradoxus DNA copies, and blue represents LOH blocks with two S. cerevisiae DNA copies. Green arrows indicate new LOH recombination events, purple arrows indicate chromosome homogenization by loss and re-synthesis events. Genomic coordinates are based on the S. cerevisiae DBVPG6765 genome assembly. b, c, Sporulation efficiency (at day 3) (b) and spore viability (c) of the living ancestor, its mutation accumulation lines (n = 8), its mitotically growing clones (T0, n = 6) and return-to-growth clones (n = 12). Box plots are as in Fig. 2. Right, spore viability of each single living ancestor’s mutation accumulation line. One line (A887R29) has a huge increase in spore viability owing to tetraploidization. The pink dotted line indicates the spore viability of the living ancestor. d, Coverage plots of chromosome XI of a tetraploid (A887R29) and a diploid (A887R30) mutation accumulation lines. The plots show a balanced chromosome number for the A887R30 diploid clone (1 copy of S. cerevisiae and 1 copy of S. paradoxus) and an unbalanced one for the A887R29 tetraploid clone (3 copies of S. cerevisiae and 1 copy of S. paradoxus). Dots represent mean coverage values in 10-kb non-overlapping windows. Lines represent whole-chromosome coverage medians.
Extended Data Fig. 7 Reconstruction of the hybridization-to-introgression model.
a, Grey-dotted box contains a representation of the classic model for the origin of introgressions. The discovery of the living ancestor rewrote part of this mechanistic process and enabled us to test the downstream stages. For each stage of the model, we indicate the measured median gamete viability (percentage). The initial S. cerevisiae–S. paradoxus F1 hybrid derived from an outbreeding event and this has been shown to be rare38,70, thus one or very few hybridizations initiated the process. Next, the F1 hybrid expanded clonally to a possibly large population size. This mitotic clonal expansion was followed by the genome instability and LOH formation phase. Genome instability of such magnitude might be rare and produce unviable combinations, probably reducing the ancestral hybrid population with LOH to one or few individuals. Next, the hybrid with LOH expanded mitotically, generating a population that kept evolving, for example, by accumulating additional LOH. Part of the population was maintained as asexual descendant, whereas part went through sexual reproduction and produced the Alpechin lineage. It is likely that the sporulation step was at the population level, therefore producing many spores. Next, one or more spores backcrossed to S. cerevisiae, which might occur rarely since it requires outbreeding. We propose that this step bottlenecked the population to few individuals, consistent with our data showing that Alpechin strains share many of the LOH blocks. The living ancestor gametes were more fertile with S. cerevisiae than with S. paradoxus. We also crossed three living ancestor gametes to a haploid derivative of an Alpechin strain (CPG) and found fertility to be higher than in backcrosses with the S. cerevisiae lineage lacking introgressions. This is consistent with the Alpechin lineage being closer to the living ancestor. b, Sporulation efficiency after 3 days in sporulating conditions of hybridization-to-introgression stages. Box plots are as in Fig. 2. n = biologically independent samples. Sc, n = 1; Sp, n = 2; F1 hybrid, n = 2; LA, n = 1; LA gametes, n = 25; Bc Sc, n = 8; Bc Sp, n = 8; Alpechin (Alp) n = 16; LA gametes × Alp, n = 3; Sc × Alp, n = 1; Sp × Alp, n = 1. The S. cerevisiae × Alpechin cross is a slow sporulator, consistent with the presence of inefficient sporulation alleles71. c, Sporulation efficiency (at day 3) of living ancestor gametes grouped by number of aneuploidies. Box plots are as in Fig. 2. 0 aneuploidies (n = 5), 1 aneuploidy (n = 6), 2 aneuploidies (n = 12), 3 aneuploidies (n = 1), 4 aneuploidies (n = 1). Pink dots indicate spores with an additional copy of chromosome III, which remained haploid and thus do not sporulate. d, Spore viability of hybridization-to-introgression stages. Box plots are as in Fig. 2. Sc, n = 1; Sp, n = 2; F1 hybrid, n = 2; LA, n = 1; LA gametes, n = 13; Bc Sc, n = 8; Bc Sp, n = 8; Alp, n = 4; LA gametes × Alp, n = 3; Sc × Alp, n = 1; Sp × Alp, n = 1. e, Percentage of viable spores for haploid-stable living ancestor gametes backcrossed to S. cerevisiae (blue line boxes) or S. paradoxus (red line boxes), grouped by their number of aneuploidies. Box plots are as in Fig. 2. n = biologically independent samples. 0 aneuploidies (n = 6), 1 aneuploidy (n = 6), 2 aneuploidies (n = 2), 3 aneuploidies (n = 2).
Extended Data Fig. 8 Mapping the slow growth phenotype in the Alpechin AQA strain.
a, Percentage of introgressed DNA in the Alpechin strains ranked for amount of heterozygous introgressions (grey, ordered first in the stack bar). Most introgressed material is in homozygous state (red, ordered second). Three strains, including AQA, have a considerable fraction of heterozygous introgressions. The rest of the genome up to 100% is S. cerevisiae background (blue, ordered third) and the y axis is cut at 10%. b, Tetrad dissection of the Alpechin AQA strain showing a 2:2 colony size segregation pattern (two slow-growing and two normal-growing colonies in each meiosis), consistent with a single heterozygous variant underlying the growth defect. c, Each dot represents the allele frequency (AF) difference of reference and non-reference alleles across the genome between pools of big and small spores. Two regions show fixation of the opposite alleles in the big and small pools and chromosome XII is compatible with the assumption that the deleterious allele associated with the small phenotype has the lowest frequency in the S. cerevisiae population. d, Chromosome XII allele frequency zoom and map of homozygous (red) and heterozygous (grey) introgressions on a S. cerevisiae genome backbone (blue) of the Alpechin strain AQA. The growth defect maps to the SFI1 gene, which is far from the closest introgression, indicating that the slow growth phenotype is not driven by a deleterious effect of heterozygous introgressions masked by the S. cerevisiae allele. The white circle indicates the centromere. Genomic coordinates are based on the S. cerevisiae DBVPG6765 genome assembly.
Extended Data Fig. 9 The competitive fitness of the living ancestor.
a, Mitotic growth (absolute doubling time, h) of the living ancestor (n = 40) as compared to the closest extant relatives of its S. cerevisiae DBVPG6765 (top left, n = 8) and S. paradoxus N17 (top middle, n = 16) parents and a diploid experimental F1 hybrid between the two (top right, n = 16), the living ancestor’s diploid gametes (bottom left, n = 200) and backcrosses of its haploid-stable gametes to S. cerevisiae (bottom middle, n = 64) and S. paradoxus parents (bottom right, n = 64). The number of observations (n) results from the combination of the strains in each group and the number of replicates performed in the experiment. Significant differences enumerated in the main text are indicated by asterisks or name (two-tailed Welsh test, FDR q = 0.05) and presented in Supplementary Table 7. For the living ancestor gametes, we instead indicate (red text) the rare environments where no significant difference was found. b, The percentage of surviving cells (mean ± s.d.) for each step of the hybridization-to-introgression process during a 25-day chronological lifespan experiment. n = biologically independent samples. S. cerevisiae (n = 1), S. paradoxus (n = 2), experimental first-generation (F1) hybrid (n = 2), living ancestor (n = 1), living ancestor gametes (n = 25), backcross to S. cerevisiae (n = 8), backcross to S. paradoxus (n = 8), Alpechin (n = 16). c, Gating strategy used for the estimation of the percentage of surviving cells shown in b.
Extended Data Fig. 10 The adaptive value of introgressions.
a, Heat map of the relative doubling time (mean of n = 40 replicates for the living ancestor and n = 8 replicates for all the other strains) of the living ancestor, its modern Alpechin descendants and the closest living relatives of its S. cerevisiae and S. paradoxus parents. Strains were grouped (left) on the basis of doubling time similarity using hierarchical clustering (Pearson’s r, complete linkage) and branch colours highlight four major clusters. Environments in which the living ancestor grows significantly (two-tailed Welsh test, FDR q = 0.05) faster (green) or slower (red) than the Alpechins are coloured. b, Difference in relative doubling time between Alpechins (n = 128) and S. cerevisiae (n = 8) in the environments which favour Alpechins’ growth (two-tailed Welsh test, FDR q = 0.05). Box plots are as in Fig. 2. The number of observations (n) results from the combination of the strains in each group and the number of replicates performed in the experiment. Each dot represents the average among the 8 replicates of each of the 16 Alpechins. c, Genotype maps of the Alpechin, Mexican agave, French Guiana and Brazilian bioethanol clades in a shared introgressed region containing the IRC7 (YFR055W) gene. This gene was previously reported to be introgressed in strains belonging to the Wine/European clade72. The IRC7 gene present in the Alpechins has a European S. paradoxus ancestry, while Mexican Agave, Brazilian Bioethanol and French Guiana lineages inherited the S. paradoxus American allele, underlying an independent introgression and maintenance of IRC7 that supports adaptive introgression. Blue and red colours indicate S. cerevisiae and S. paradoxus regions, respectively. Subtelomeric regions are masked genome wide because they lack synteny between S. cerevisiae and S. paradoxus and cannot be aligned for markers genotyping, although inspection of this specific VI-R subtelomeric region in both S. cerevisiae and S. paradoxus genomes indicates that the telomeric repeats are very close to IRC724. The bottom panel shows genetic features annotation of this region from the S. cerevisiae Wine/European strain DBVPG6765.
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D’Angiolo, M., De Chiara, M., Yue, JX. et al. A yeast living ancestor reveals the origin of genomic introgressions. Nature 587, 420–425 (2020). https://doi.org/10.1038/s41586-020-2889-1
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DOI: https://doi.org/10.1038/s41586-020-2889-1
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