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Sasha (Alexandra) Khristich

@khristich.bsky.social
108 followers 245 following 136 posts

postdoc at the Petrov lab at Stanford studying evolution & evolvability

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Reposted by Sasha (Alexandra) Khristich
Mark Bitter @markcbitter.bsky.social · 01/10/2026
New Perspective w/ @petrovadmitri.bsky.social and Paul Schmidt! We ask what evolution-in-action studies tell us about an old question: what genetic variation matters for fitness, and what maintains it? ecoevorxiv.org/repository/v...
ecoevorxiv.org
Common, consequential, and actively maintained: a neo-balance view of genetic variation
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
And thank you for reading! We would love to know what you think!
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Thanks again to all who worked on this project: @jccvila.bsky.social, @shaili-mathur.bsky.social, @abhishdt.bsky.social, Marion Garin, @schacherer.bsky.social, @petrovadmitri.bsky.social, and @oliviamghosh.bsky.social (co-first author).
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Stay tuned for our future projects, and here is our manuscript with more details: www.biorxiv.org/content/10.1....
biorxiv.org
Adaptive evolution can overwrite initial natural fitness variation only in highest-fitness yeast isolates
The fitness of an organism determines its likelihood of succeeding in short-term competition, but many other factors can influence its long-term success. In this study, we investigate the relative con...
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
* What would happen if we model priority effects by introducing strains at different timepoints and frequencies? * How would ecological interactions affect the evolutionary dynamics we see?
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
* How precisely can we measure evolvability differences? * What is the mechanistic basis for these differences if they do exist? * Can we predict chances of long-term success from knowing fitness and distribution of adaptive mutations’ fitness effects of a given strain?
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
This project raises many exciting questions that we are looking forward to answering in the future:
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Taken together, we showed that: 1. Initial fitness definitely matters for long-term success; 2. Large-effect adaptive mutations can and do rewrite small fitness differences, but only among the highest-fitness strains; 3. Evolvability differences between natural strains might indeed exist!
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Is it possible that the fact that AMA is a triploid is related to its apparent higher evolvability? We don’t know. But it’s fun to speculate that maybe a heterozygous triploid has access to more haplotype combinations it can convert to, and is able to fine-tune allele dosage.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
LOH tracts in AMA, an overperforming strain, were particularly intriguing because this strain is not diploid like the other finalists, but triploid! And, we observed that sometimes an LOH event in AMA converted an initially single-copy allele to a fully homozygous state.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
LOH is a known mechanism for adaptation, and it might play a large role in the evolvability of our natural strains: the LOH rate is higher than the mutation rate, and LOH events can uncover cryptic genetic variation, often at many loci at the same time.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
In this example, we suspect that conversion to the frameshift variant in AZR1 was the driver mutation. A functional AZR1 gene is required for fluconazole resistance, but it makes cells less fit in media without fluconazole (like M3 and M3-5GLU).
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
We also noticed that some of the tracts localized in the same place across different strains, like these tracts from strains evolved in M3 and M3-5GLU media (here each line is an LOH event from one strain and colors separate independent isolates):
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
The initially heterozygous variants that became homozygous clustered together in often massive tracts spanning up to 868 kb!
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
To make sure evolution actually happened in our finalist strains, we whole-genome sequenced them and discovered many interesting mutations: aneuploidies, large chromosomal rearrangements, point mutations, indels, and loss-of-heterozygosity (LOH) events.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
We observed such systematic overperformance and underperformance of certain strains in several other environments, and it strongly hints at possible evolvability differences between natural strains!
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Third interesting observation: CCV and CGB both started with lower fitness than BBK, but CCV stuck around for about 60 transfers (until it eventually died out), and CGB rose to high frequency in one replicate:
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Second interesting observation: BBK was the 5th fittest strain but did not persist at measurable frequency even until the 23rd transfer:
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
First interesting observation: AMA and BFB had approximately the same fitness. Despite BFB starting with a slightly higher frequency, AMA ended up more common in the final pool composition! In AMA’s and BFB’s trajectories across replicates, we can see when adaptive mutations arise:
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Zooming in on the final average frequencies of the finalists in M3, we noticed that for the fittest 5% of strains, initial fitness was not a great predictor of long-term success (here, finalists are colored and other strains from the top 5% are white):
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
And in M3 (minimal glucose-limited media), we saw a combination of coexistence and alternative states:
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
In SC-HU (synthetic complete media with hydroxyurea), there seemed to be several alternative states where one of three strains dominated in different replicates:
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
For example, looking at the population composition at the last timepoint of M3-5GLU (minimal media with excess glucose) replicates, we observed possible long-term coexistence among several strains:
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Nonetheless, it wasn’t all that simple! Looking at how the finalists were distributed across replicates, we saw a diversity of competition outcomes.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
So, what were these finalists? Turns out, every finalist came from the fittest 5% of strains in its environment. This means that initial fitness variation in our strains was meaningful, and all but the initially fittest strains were effectively doomed to extinction.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
At the end, we sequenced the last timepoints and identified the ‘finalists’ of our competitions in each environment: strains that remained at > 1% frequency in at least one final replicate.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
So that’s what we did! We pooled our strains and grew them in batch culture for up to 700 generations (90 2-day transfers) in 6 different media types and in up to 20 replicates per media. You can think of this experiment as a yeast ‘survivor’ game repeated many times.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
* Finally, we can perform such evolutionary competitions in several environments (media types) to decouple genotypes from fitnesses. So if we have a super-evolver in our collection, we would expect it to win regardless of its initial fitness.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
* We can then propagate them for a longer time and see which strain wins in the end. And by running many replicates, we can quantitatively estimate the chances of long-term success for each strain:
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
* Because these yeast strains come with strain-specific barcodes, we can pool them and measure their initial fitness (frequency change in the first 5 transfers) very well.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
What makes this collection great for our experiment: * It contains yeast strains collected worldwide from different ecological niches (bakeries, wineries, breweries, flowers and trees, insects’ guts, etc.), and is a good proxy for the species’ overall diversity:
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
To test these ideas, we used a collection of wild S. cerevisiae isolates, initially assembled by the @schacherer.bsky.social #haploteam lab (www.nature.com/articles/s41...) and subsequently barcoded by Abhishek and Marion for their recent paper: www.nature.com/articles/s41...
nature.com
Genome evolution across 1,011 Saccharomyces cerevisiae isolates - Nature
Whole-genome sequencing of 1,011 natural isolates of the yeast Saccharomyces cerevisiae reveals its evolutionary history, including a single out-of-China origin and multiple domestication events, and ...
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Thus, it is also possible that evolvability, rather than initial fitness, is the strongest predictor of evolutionary success in the long term.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
The measure of how fast an organism evolves adaptively is called evolvability. Many think that evolvability itself is subject to natural selection, and members of the same species vary in the rate and magnitude of the adaptive mutations they can acquire.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
In this case, the final population composition will be harder to predict, and the eventual winner could be different each time we ‘replay the tape of life’.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
We also know that species in a novel environment evolve and, at times, can acquire large-effect adaptive mutations very quickly. Such rapid adaptation might allow medium- and low-fitness genotypes to ‘leapfrog’ over fitter genotypes.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
If we assume no sex or recombination, the highest-fitness individual will ultimately outcompete everyone and ‘win’ in this evolutionary competition.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Imagine a species enters a totally new environment. If members of this species happen to vary in fitness in this environment, high-fitness individuals immediately get an advantage: they will grow and accumulate adaptive mutations faster than those with lower fitness.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Thanks to all of our collaborators who made this project possible: @jccvila.bsky.social, @shaili-mathur.bsky.social, @abhishdt.bsky.social, Marion Garin, @schacherer.bsky.social, and, of course, @petrovadmitri.bsky.social.
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Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
I’m excited to share our preprint with @oliviamghosh.bsky.social, where we explore what it takes to ‘win’ in long-term evolutionary competition: www.biorxiv.org/content/10.1...
biorxiv.org
Adaptive evolution can overwrite initial natural fitness variation only in highest-fitness yeast isolates
The fitness of an organism determines its likelihood of succeeding in short-term competition, but many other factors can influence its long-term success. In this study, we investigate the relative con...
14029
Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
And thank you for reading! We would love to know what you think!
000
Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Thanks again to all who worked on this project: @jccvila.bsky.social, @shaili-mathur.bsky.social, @abhishdt.bsky.social, Marion Garin, @schacherer.bsky.social, @petrovadmitri.bsky.social, and @oliviamghosh.bsky.social (co-first author).
100
Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Stay tuned for our future projects, and here is our manuscript with more details: www.biorxiv.org/content/10.1...
biorxiv.org
Adaptive evolution can overwrite initial natural fitness variation only in highest-fitness yeast isolates
The fitness of an organism determines its likelihood of succeeding in short-term competition, but many other factors can influence its long-term success. In this study, we investigate the relative con...
100
Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
* What would happen if we model priority effects by introducing strains at different timepoints and frequencies? * How would ecological interactions affect the evolutionary dynamics we see?
100
Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
* How precisely can we measure evolvability differences? * What is the mechanistic basis for these differences if they do exist? * Can we predict chances of long-term success from knowing fitness and distribution of adaptive mutations’ fitness effects of a given strain?
100
Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
This project raises many exciting questions that we are looking forward to answering in the future:
100
Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Taken together, we showed that: 1. Initial fitness definitely matters for long-term success; 2. Large-effect adaptive mutations can and do rewrite small fitness differences, but only among the highest-fitness strains; 3. Evolvability differences between natural strains might indeed exist!
100
Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
Is it possible that the fact that AMA is a triploid is related to its apparent higher evolvability? We don’t know. But it’s fun to speculate that maybe a heterozygous triploid has access to more haplotype combinations it can convert to, and is able to fine-tune allele dosage.
100
Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
LOH tracts in AMA, an overperforming strain, were particularly intriguing because this strain is not diploid like the other finalists, but triploid! And, we observed that sometimes an LOH event in AMA converted an initially single-copy allele to a fully homozygous state.
100
Sasha (Alexandra) Khristich @khristich.bsky.social · 22/09/2026
LOH is a known mechanism for adaptation, and it might play a large role in the evolvability of our natural strains: the LOH rate is higher than the mutation rate, and LOH events can uncover cryptic genetic variation, often at many loci at the same time.
100