Loss of heterozygosity results in rapid but variable genome homogenization across yeast genetic backgrounds
- Université de Strasbourg, CNRS, GMGM UMR 7156, France
- Institut Universitaire de France (IUF), France
Figures
Figure 1 with 5 supplements
Overall distribution of loss of heterozygosity (LOH) in the 169 mutation accumulation (MA) lines.
(A) LOH event tract size distribution across all 169 MA lines, the average tract sizes of the interstitial LOH (I-LOH) events (7.4 kb) and terminal LOH (T-LOH) events (55.3 kb), respectively. The …
Figure 1—figure supplement 1
Distribution of the heterozygous single nucleotide polymorphism (SNP) densities as a fraction of total heterozygous SNPs in 5 kb windows across the ancestral diploids as described in Table 1.
Figure 1—figure supplement 2
Chromosome-wide distribution of loss of heterozygosity (LOH) events across all mutation accumulation (MA) lines.
(A) All LOH events, (B) terminal LOH (T-LOH), events, and (C) interstitial LOH (I-LOH) events.
Figure 1—figure supplement 3
A terminal LOH (T-LOH) events are significantly larger than interstitial LOH (I-LOH) in the 169 mutation accumulation (MA) lines all backgrounds except H4 (Wilcoxon test, *p < 0.05; **p < 0.01; ***p<0.001; ****p < 0.0001; ns – not significant).
Figure 1—figure supplement 4
Boxplot depicting the fraction genome under loss of heterozygosity (LOH) in the nearly homozygous lines is significantly greater than the rest of the mutation accumulation (MA) lines (Wilcoxon test, p=6.1×10−10).
Figure 1—figure supplement 5
Chromosome-wide loss of heterozygosity (LOH) plots across representative lines from H1, H3, H4, and H9.
Orange and blue colors represent single nucleotide polymorphisms (SNPs) fixed toward either of the parents as described in Table 1 and Supplementary file 1. All the 14 nearly homozygous (NH) lines …
Figure 2 with 3 supplements
Genetic background-dependent variation in the loss of heterozygosity (LOH) repertoire.
(A) The frequency of total LOH events across the nine genetic backgrounds are highly variable (Kruskal-Wallis test, p<2×10−16). (B) Variability in interstitial and terminal LOH events counts across …
Figure 2—figure supplement 1
The frequency of interstitial LOH (I-LOH) events increases with increasing chromosome size for all backgrounds except for H1 and H9; no such correlation was observed for terminal LOH (T-LOH) events.
Figure 2—figure supplement 2
Overall fraction of interstitial and terminal loss of heterozygosity (LOH) tracts across the nine genetic backgrounds.
Figure 2—figure supplement 3
Fraction of the genome fixed toward either of the parental genomes across the nine genetic backgrounds.
Biased fixation was only observed in H4 and H5 backgrounds (binomial test, p<0.05).
Figure 3 with 1 supplement
Loss of heterozygosity (LOH) accumulation is associated with spore fertility.
(A) Total LOH events accumulated in mutation accumulation (MA) lines derived from ancestral diploids with high spore fertility, that is, meiotic spore viability greater than or equal to 75% and the f…
Figure 3—figure supplement 1
The total number of interstitial LOH (I-LOH) and terminal LOH (T-LOH) events are significantly greater in the mutation accumulation (MA) lines derived from ancestral diploids with low fertility (Wilcoxon test, *p < 0.05; **p < 0.01; ***p<0.001; ****p < 0.0001; ns – not significant).
Figure 4 with 3 supplements
Mutation rates are constant across the backgrounds and within the nearly homozygous (NH) lines (range 0.67–1.9 × 10−10 mutations/site/division; Kruskal-Wallis test, p>0.05).
The overall, mean single nucleotide mutation (SNM) rate in the 169 MA lines 1.1 × 10−10 per site per division is not different from previous estimates in various diploid Saccharomyces cerevisiae …
Figure 4—figure supplement 1
SNM spectrum across the nine hybrid backgrounds.
(A) The spectrum of single nucleotide mutations (SNMs) in the mutation accumulation (MA) lines is variable across all genetic backgrounds (Chi-square test, p<0.05; Supplementary file 5–6). (B) The …
Figure 4—figure supplement 2
The frequency of mutations was significantly impacted at C/G sites than A/T sites by the neighboring nucleotides (Chi-square test, p<0.05; Supplementary file 5–6).
Horizontal red lines indicate mean events.
Figure 4—figure supplement 3
The frequency of aneuploid chromosomes across the nine genetic backgrounds (H1–H9).
Two backgrounds carried ancestral trisomies, H3 (+1 chrIX) and H9 (+1 chrIX; +1 chrXVI).
Author response image 1
Tables
Table 1
Hybrid mutation accumulation (MA) lines.
| Hybrid | Cross* | Het positions | No. of sequenced lines | No. of bottlenecks | Total no. of divisions |
|---|---|---|---|---|---|
| H1 | ABS × BKL | 9972 | 20 | 100 | 2446 |
| H2 | ABP × BFQ | 18789 | 12 | 75 | 1842 |
| H3 | BAP × BAN | 20875 | 20 | 75 | 1863 |
| H4 | BTI × ABA | 49412 | 20 | 75 | 1772 |
| H5 | ACD × AKQ | 52223 | 20 | 75 | 1777 |
| H6 | ACK × CMQ | 55570 | 20 | 100 | 2392 |
| H7 | ACG × BAK | 69456 | 19 | 75 | 1844 |
| H8 | CGD × AKE | 113241 | 19 | 75 | 1769 |
| H9 | BAM × CPG | 116475 | 19 | 100 | 2452 |
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* Standardized names from Peter et al., 2018.
Author response table 1
Mean event counts for 5 kb at chromosome ends vs rest of the genome.
| Hybrid Background | Mean density at chr_ends | Mean density rest_genome |
|---|---|---|
| H1 | 3.66 | 3.98 |
| H2 | 7.06 | 6.81 |
| H3 | 7.57 | 9.26 |
| H4 | 15.00 | 22.19 |
| H5 | 20.05 | 23.67 |
| H6 | 20.27 | 22.80 |
| H7 | 31.54 | 31.78 |
| H8 | 36.20 | 46.73 |
| H9 | 46.58 | 47.70 |
Additional files
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Supplementary file 1
Haploid strains used to generate the nine hybrid diploids, standardized names as per Peter et al., 2018.
- https://cdn.elifesciences.org/articles/70339/elife-70339-supp1-v2.xlsx
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Supplementary file 2
Mean growth rate estimates at bottleneck 0 and at the end of the experiment for the nine genetic backgrounds.
These estimates were used to determine the number of divisions at every bottleneck (see Materials and methods).
- https://cdn.elifesciences.org/articles/70339/elife-70339-supp2-v2.xlsx
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Supplementary file 3
All loss of heterozygosity (LOH) tracts across the 169 mutation accumulation (MA) lines supported by at least two single nucleotide polymorphisms (SNPs).
Tracts were merged if consecutive tracts were disrupted by less than two SNPs. LOH tracts in nearly homozygous lines highlighted in yellow.
- https://cdn.elifesciences.org/articles/70339/elife-70339-supp3-v2.xlsx
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Supplementary file 4
Meiotic spore viability in the mutation accumulation (MA) lines, H9-8 and H9-11 excluded as they did not sporulate.
SV-percentage spore viability in the MA lines; statistical significance of differences in spore viability between ancestral diploid and the derived MA lines were determined using the p-values from Fisher’s exact test (GraphPad prism). N – number of tetrads analyzed for spore viability, ns – not significant; p>0.05.
- https://cdn.elifesciences.org/articles/70339/elife-70339-supp4-v2.xlsx
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Supplementary file 5
Mutations detected in the 169 mutation accumulation (MA) lines.
Multi-nucleotide mutations (MNMs) highlighted in purple.
- https://cdn.elifesciences.org/articles/70339/elife-70339-supp5-v2.xlsx
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Supplementary file 6
Chi-square test p-values for the single nucleotide mutation (SNM) spectrum variation.
Chi-square test was performed using the Microsoft excel function Chisq.test().
- https://cdn.elifesciences.org/articles/70339/elife-70339-supp6-v2.xlsx
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Supplementary file 7
List of strains used in this study.
- https://cdn.elifesciences.org/articles/70339/elife-70339-supp7-v2.xlsx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/70339/elife-70339-transrepform-v2.docx
