Biology subjects

Bendixsen, D. P.

Publications and source records attributed to Bendixsen, D. P..

8 recordsLinked to original sources

bioRxiv2025

Divergent ecological selection causes partial reproductive isolation and vast genomic instability in yeast

Populations evolving independently in divergent environments accumulate genetic differences and potentially evolve reproductive isolation as a by-product of divergence. The speed and mechanisms underlying this process are difficult to investigate because we rarely get the opportunity to witness them in natural settings, and histories of selection and gene flow between populations are often unknown. Here, we experimentally evolved yeast for 1000 generations of evolution in both divergent and parallel environments. At regular time points during experimental evolution, we made crosses between parallel- and divergent-evolving populations to measure postzygotic reproductive isolation (gamete viability). We used whole genome population sequencing to determine the mutational load, the number and types of structural variation, and other genomic features of the parent, F1, and F2 intraspecific hybrids. We found evidence for large scale phenotypic and genome-wide differentiation in response to divergent laboratory selection. Divergent-selected populations produced hybrids with reduced gamete viability - a classic signature of postzygotic reproductive isolation in the form of hybrid breakdown. Parallel-selected populations on the other hand remained more reproductively compatible (with exceptions). We found that F2 hybrid genomes contained vast genomic instability, i.e., new structural variants (especially insertions, deletions, and interchromosomal translocations) that were not observed in parent and F1 genomes, which is likely a result of chromosome missegregation and recombination errors in hybrid meiosis. Our results provide phenotypic and genomic evidence that partial reproductive isolation evolved due to adaptation to divergent environments, consistent with predictions of ecological speciation theory.

evolutionary biology↗

bioRxiv2024

Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer

Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. We comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N=324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing novel candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we also find high mtDNA mutation loads associated with shorter patient survival, and acting in combination with alterations in the nuclear genome to impact prognosis and suggesting new strategies for patient stratification.

cancer biology↗

bioRxiv2023

Hybrid adaptation is hampered by Haldane's sieve

Hybrids between species exhibit plastic genomic architectures that foster phenotypic diversity. Their genomic instability also incurs costs, potentially limiting adaptation. When challenged to evolve in an environment containing a UV mimetic drug, yeast hybrids have reduced adaptation rates compared to parents. We hypothesized that this reduction could result from a faster accumulation of genomic changes, but we found no such association. Alternatively, we proposed that hybrids might lack access to adaptive mutations occurring in the parents, yet, we identified mutations in the same genes (PDR1 and YRR1), suggesting similar molecular adaptation mechanisms. However, mutations in these genes tended to be homozygous in the parents but heterozygous in the hybrids. We hypothesized that a lower rate of loss of heterozygosity (LOH) in hybrids could limit fitness gain. Using genome editing, we demonstrated that mutations display incomplete dominance, requiring homozygosity to show full impact and to circumvent Haldanes sieve, which favors the fixation of dominant mutations. We used frozen fossils to track genotype frequency dynamics and confirmed that LOH occurs at a slower pace in hybrids than in parents. Together, these findings show that Haldanes sieve slows down adaptation in hybrids, revealing an intrinsic constraint of hybrid genomic architecture that can limit the role of hybridization in adaptive evolution.

evolutionary biology↗

bioRxiv2022

RNA sequence to structure analysis from comprehensive pairwise mutagenesis of multiple self-cleaving ribozymes

Self-cleaving ribozymes are RNA molecules that catalyze the cleavage of their own phosphodiester backbones. These ribozymes are found in all domains of life and are also a tool for biotechnical and synthetic biology applications. Self-cleaving ribozymes are also an important model of sequence to function relationships for RNA because their small size simplifies synthesis of genetic variants and self-cleaving activity is an accessible readout of the functional consequence of the mutation. Here we used a high-throughput experimental approach to determine the relative activity for every possible single and double mutant of five self-cleaving ribozymes. From this data, we comprehensively identified non-additive effects between pairs of mutations (epistasis) for all five ribozymes. We analyzed how changes in activity and trends in epistasis map to the ribozyme structures. The variety of structures studied provided opportunities to observe several examples of common structural elements, and the data was collected under identical experimental conditions to enable direct comparison. Heat-map based visualization of the data revealed patterns indicating structural features of the ribozymes including paired regions, unpaired loops, non-canonical structures and tertiary structural contacts. The data also revealed signatures of functionally critical nucleotides involved in catalysis. The results demonstrate that the data sets provide structural information similar to chemical or enzymatic probing experiments, but with additional quantitative functional information. The large-scale data sets can be used for models predicting structure and function and for efforts to engineer self-cleaving ribozymes.

molecular biology↗

bioRxiv2022

The dynamics of adaptation to stress from standing genetic variation and de novo mutations

Adaptation from standing genetic variation is an important process underlying evolution in natural populations but we rarely get the opportunity to observe the dynamics of fitness changes in real time. Here, we used the power of microbial experimental evolution and whole population sequencing to track the phenotypic and genomic changes of genetically diverse yeast populations in environments with different stress levels. We found that populations rapidly and in parallel increased in fitness in stressful environments. The founders genetic diversity was quickly depleted, however, not to the same degree in all populations and environments. Some populations fixed all ancestral variation in < 30 generations while others maintained diversity across hundreds of generations. We also observed parallelism at the gene and pathway level. Specifically, we detected up to seven genes harbouring multiple independent mutations in different populations, and a general enrichment for mutations affecting downstream effectors of the high-osmolarity-glycerol pathway in three out of four environments. Adaptation to the most stressful environment was characterised by the fast evolution of functional haploidy, likely driven by standing genetic variation. Almost 40% of all populations contained aneuploidies (losses or gains of chromosomes) at least once during experimental evolution. Some aneuploidies were maintained for hundreds of generations in parallel in different replicates, suggesting they were adaptive. This work shows that experimental evolution is a great tool to address the interplay between standing variation and the influx of de novo mutations, leading to a better understanding of the demographic and environmental drivers and constraints of a populations capacity to adapt to environmental change.

evolutionary biology↗

bioRxiv2020

Tracking the origin of Baker's yeast: Seven new long-read genomes of highly divergent, wild Saccharomyces cerevisiae strains from East Asia

Comparative genome analyses have suggested East Asia to be the cradle of the domesticated microbe Brewers yeast (Saccharomyces cerevisiae), used in the food and biotechnology industry worldwide. Here, we provide seven new, high quality long read genomes of non-domesticated yeast strains isolated from primeval forests and other natural environments in China and Taiwan. In a comprehensive analysis of our new genome assemblies, along with other long read Saccharomycetes genomes available, we show that the newly sequenced East Asian strains are among the closest living relatives of the ancestors of the global diversity of Brewers yeast, confirming predictions made from short read genomic data. Three of these strains (termed the East Asian Clade IX Complex here) share a recent ancestry and evolutionary history suggesting an early divergence from other S. cerevisiae strains before the larger radiation of the species, and prior to its domestication. Our genomic analyses reveal that the wild East Asian strains contain elevated levels of structural variations. The new genomic resources provided here contribute to our understanding of the natural diversity of S. cerevisiae, expand the intraspecific genetic variation found in this this heavily domesticated microbe, and provide a foundation for understanding its origin and global colonization history. Significance statementBrewers yeast (Saccharomyces cerevisiae) is a domesticated microbe and research model organism with a global distribution, and suspected origin in East Asia. So far only limited genomic resources are available from non-domesticated lineages. This study provides seven new, high quality long read genomes of strains isolated from primeval forests and other natural environments in China and Taiwan. Comparative genomics reveal elevated levels of structural variation in this group, and early phylogenetic branching prior to the global radiation of the species. These new genomic resources expand our understanding of the evolutionary history of Brewers yeast, and illustrate what the ancestors of this highly successful microbe may have looked like.

genomics↗

bioRxiv2019

Universal assay for measuring vertebrate telomeres by real-time quantitative PCR

Telomere length dynamics are an established biomarker of health and aging in animals. The study of telomeres in numerous species has been facilitated by methods to measure telomere length by real-time quantitative PCR (qPCR). In this method, telomere length is determined by quantifying the amount of telomeric DNA repeats in a sample and normalizing this to the total amount of genomic DNA. This normalization requires the development of genomic reference primers suitable for qPCR, which remains challenging in non-model organism with genomes that have not been sequenced. Here we report reference primers that can be used in qPCR to measure telomere lengths in any vertebrate species. We designed primer pairs to amplify genetic elements that are highly conserved between evolutionarily distant taxa and tested them in species that span the vertebrate tree of life. We report five primer pairs that meet the specificity and reproducibility standards of qPCR. In addition, we demonstrate how to choose the best primers for a given species by testing the primers on multiple individuals within a species and applying an established computational tool. These reference primers can facilitate the application of qPCR-based telomere length measurements in any vertebrate species of ecological or economic interest.

molecular biology↗

bioRxiv2018

Genotype network intersections promote evolutionary innovation

Evolutionary innovations are qualitatively novel traits that emerge through evolution and increase biodiversity. The genetic mechanisms that lead to innovation remain poorly understood. A systems view of innovation requires the analysis of genotype networks - the vast networks of genetic variants that produce the same phenotype. Innovations can occur at the intersection of two different genotype networks. Here, we use high-throughput sequencing to study the fitness landscape at the intersection of the genotype networks of two catalytic RNA molecules (ribozymes). We determined the ability of numerous neighboring RNA sequences to catalyze two different chemical reactions. We find extensive functional overlap, and over half the genotypes can catalyze both functions to some extent. We demonstrate through evolutionary simulations that these numerous points of intersection facilitate the discovery of a new function. Our study reveals the properties of a fitness landscape where genotype networks intersect, and the consequences for evolutionary innovations.

evolutionary biology↗