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Detection of adaptive gene introgression

Principal advisor: Joachim Hermisson

Our previous work focusses on the introgression probability of the beneficial allele and on the hitchhiking probability of single linked deleterious or neutral variants (Uecker et al., 2015). We also developed a method to detect footprints of adaptive introgression from genome-wide polymorphism data (Setter 2018). In a current data-driven project led by K. Stankiewicz and in collaboration with M. Nordborg, these methods are adapted and applied to genome-wide sequence data from Arabidopsis. We plan to complement this project by a model/theory-driven approach with the aim to describe the haplotype structure after adaptive introgression. We will address questions such as: What is the distribution of introgression tract lengths around the beneficial allele for a single successful introgression event? How many distinct pieces of introgressed material do we expect to find – and at which distance to the beneficial allele? How do linked deleterious alleles (which may either hitchhike or not) affect these results? We will use analytical theory based on branching processes (Uecker et al., 2015), and coalescent simulations. Knowledge about the haplotype pattern is relevant, in particular, to distinguish introgression patterns from patterns of long-term balancing selection.

Related literature:

  • Setter D. Footprints of adaptive introgression. PhD thesis (Univ. of Vienna, 2018)
  • Uecker H, Setter D and Hermisson J. Adaptive gene introgression after secondary contact. J. Math. Biol. 70(7), 1523–1580. (2015) doi: 10.1007/s00285-014-0802-y

Footprints of polygenic adaptation

Principal advisor: Joachim Hermisson

The standard model in molecular population genetics assumes that selection on a phenotypic trait leads to simple directional selection on its genetic basis. This leads to (hard or soft) selective sweeps as a footprint of selection in DNA polymorphism data. In contrast, polygenic adaptation refers to a scenario where phenotypic adaptation results from a collective change in the allele frequencies at many underlying genes (e.g., Boyle and Pritchard, 2017). If selection on single loci is constrained by epistatic interaction with its genetic background, allele frequency trajectories (and resulting footprints) differ strongly from the sweep paradigm. Empirical evidence indicates that this may often be the case. Literature on polygenic adaptation assumes a deterministic model for allele frequency changes (Chevin and Hospital, 2008; Jain and Stephan, 2017). However, our previous results (Hermisson and Pennings, 2017; Höllinger et al., 2018 in prep.) show that genetic drift is crucial for the pattern. In Höllinger et al. (2018 in prep.), we have developed an analytical approach to address this problem based on Yule branching processes. In the next funding period, we will apply this approach to various selection scenarios on quantitative traits, including spatially and temporally heterogeneous selection (“moving optimum”, see Jones et al. 2014, Matuszewski et al. 2015) and truncation selection. Based on these results, we will develop statistical frameworks to detect footprints of polygenic adaptation from replicated evolution experiments.

Related literature:

  • Boyle EA, Li YI and Pritchard JK. An expanded view of complex traits: From polygenic to omnigenic. Cell. (2017) doi: 10.1016/j.cell.2017.05.038
  • Chevin LM and Hospital F. Selective sweep at a quantitative trait locus in the presence of background genetic variation. Genetics 180(3), 1645–1660. (2008) doi: 10.1534/genetics.108.093351
  • Hermisson J and Pennings PS. Soft sweeps and beyond: understanding the patterns and probabilities of selection footprints under rapid adaptation. Methods Ecol. Evol. 8(6), 700–716. (2017) doi: 10.1111/2041-210X.12808
  • Höllinger I, Pennings PS, Hermisson J: Polygenic adaptation: From sweeps to subtle frequency shifts. bioRxiv 450759. (2018) doi: 10.1101/450759
  • Jain K and Stephan W. Rapid adaptation of a polygenic trait after a sudden environmental shift. Genetics 206(1), 389–406. (2017) doi: 10.1534/genetics.116.196972
  • Jones AG, Bürger R and Arnold SJ. Epistasis and natural selection shape the mutational architecture of complex traits. Nat. Commun. 5, 3709. (2014) doi: 10.1038/ncomms4709
  • Matuszewski S, Hermisson J and Kopp M. Catch me if you can: Adaptation from standing genetic variation to a moving phenotypic optimum. Genetics 200(4), 1255–1274. (2015) doi: 10.1534/genetics.115.178574

Inference of selection parameters using whole genome data

Principal advisor: Claus Vogl

We will extend existing models to allow for exact inference of directional selection (or equivalently GC-biased gene conversion) in addition to mutation and drift using allele frequency spectra. Even short introns and fourfold degenerate sites, the best candidates for neutrally evolving nucleotide sites, show deviation from neutrality but can be described by the nearly neutral theory. A model with directional selection (or equivalently GC-biased gene conversion) with a scaled selection strength of about one, however fits the data (Vogl and Bergman, 2015; and unpublished data analyses). So far, we assumed mutation-selection-drift equilibrium for maximum marginal likelihood inference (Vogl and Bergman, 2015). To this end, we developed a model, where a single mutation segregates in a moderately sized sample (Bergman et al., 2018). This model is identical to a first order Taylor series expansion for small scaled mutation rates of the general mutation-drift model. We extended this model to splitting populations and non-equilibrium scenarios using orthogonal polynomials and now propose to incorporate also directional selection in this framework. We will apply the method to data from cosmopolitan and sub-Saharan African Drosophila populations to infer concurrently mutation, selection, and population demography.

Related literature:

  • Bergman J, Schrempf D, Kosiol C and Vogl C. Inference in population genetics using forward and backward, discrete and continuous time processes. J. Theor. Biol. 439, 166–180. (2018) doi: 10.1016/j.jtbi.2017.12.008
  • Vogl C and Bergman J. Inference of directional selection and mutation parameters assuming equilibrium. Theor. Popul. Biol. 106, 71–82. (2015) doi: 10.1016/j.tpb.2015.10.003

Evolution of gene expression

Principal advisor: Christian Schlötterer

While variation in gene expression is a major source of phenotypic diversity, our understanding of the processes driving changes in gene expression are still poorly understood. With the new sequencing technologies it will be possible to address many important questions about the evolution of gene expression.

The successful candidate will be part of a team of scientists studying adaptation of experimental Drosophila populations to temperature stress. She/he can build on several highly replicated Drosophila populations that have evolved under various temperature regimes.  We are planning to address the importance of plasticity in gene expression for adaptation to novel temperature regimes and how expression differences translate into fitness.

Related literature:

  • Jaksic, A.M., and Schlötterer, C. (2016). The interplay of temperature and genotype on patterns of alternative splicing in Drosophila melanogaster. Genetics 204, 315-325.
  • Chen, J., Nolte, V., and Schlötterer, C. (2015a). Temperature stress mediates decanalization and dominance of gene expression in Drosophila melanogaster. PLoS Genetics 11, e1004883. 10.1371
  • Chen, J., Nolte, V., and Schlötterer, C. (2015b). Temperature related reaction norms of gene expression: regulatory architecture and functional implications. Molecular Biology and Evolution 32, 2393-2402.

Functional characterization of beneficial alleles in Drosophila

Principal advisors: Kirsten-André Senti, Christian Schlötterer

One of the most amazing feats in biology is how natural selection enabled the adaption of species to different natural environments. Yet even a single Drosophila species thrives in diverse climates as equatorial Africa or Europe. From the natural variation within such species, we can – in principle - learn how evolution has shaped environmental adaption. Yet until recently finding the link between phenotype and genotype was a rare and difficult undertaking (1). However, today’s next generation sequencing offers an unprecedented view on the genetic variability. Combining phenotypic analyses with sequencing, Genome Wide Association Studies (GWAS) for instance enabled the identification of beneficial human alleles that protect against diseases (2).
Using paradigms such as starvation resistance and adaption to different temperatures, we have performed both GWAS as well as experimental evolution in combination with whole-genome re-sequencing of natural Drosophila populations (3). These experiments have established a number naturally occurring alleles that are associated with either increased survival under starvation stress or improved adaption to warmer or colder climates.
To validate these associations, we aim to employ the powerful CRISPR/Cas9 mediated genome engineering to functionally test if these natural gene variants indeed provide fitness advantages in well-controlled experimental settings. First, this project will establish a stable genome modification platform for natural Drosophila strains. Secondly, it will provide genetic and functional proof for beneficial adaptive alleles. Finally and in conjunction with our previous work, this approach will uncover those biological mechanisms that evolution tinkered with during adaption of natural populations.

Related literature:

  1. Sawyer L.A. et al., (1997) Natural variation in a Drosophila clock gene and temperature compensation. Science 278, 5346, 2117-2120
  2. Harper A.R. et al. (2015) Protective alleles and modifier variants in human health and disease. Nature Reviews Genetics, doi:10.1038/nrg4017
  3. Schlötterer C. et al. (2015) Combining experimental evolution with next-generation sequencing: a powerful tool to study adaptation from standing genetic variation. Heredity 114, 431-440

Genomic architecture of reverse selection

Principal advisor: Christian Schlötterer

Experimental evolution provides an excellent approach to study the adaptive response of selected alleles. Little is known about the dynamics of these selected alleles, when the selection pressure is reversed. In this project the genomic signatures will be studied using genomic time series allele frequency data from populations that evolved from the same founder in two opposing temperature regimes (hot and cold). Furthermore, allele frequency trajectories will be studied from populations, which experienced a reversed selection regime (first cold and then hot). The genomic data will be complemented with phenotypic data, such as life history traits and gene expression. The goal of this project is to determine if adaptation to hot and cold temperatures only reflects a different trait optimum or whether this are two different traits, each with a specific set of genes driving adaptation.

Related literature:

  • Teotonio, H., Chelo, I. M., Bradic, M., Rose, M. R. & Long, A. D. Experimental evolution reveals natural selection on standing genetic variation. Nature genetics 41, 251-257, doi:10.1038/ng.289 (2009)
  • Mallard, F., Nolte, V., Tobler, R., Kapun, M. & Schlötterer, C. A simple genetic basis of adaptation to a novel thermal environment results in complex metabolic rewiring in Drosophila. Genome biology 19, 119, doi:10.1186/s13059-018-1503-4 (2018)

Incipient speciation during adaptation to a new environment

Principal advisor: Christian Schlötterer

The emergence of new species is one of the most fundamental questions in biology, that is still not fully resolved. This project builds on the observation that flies which evolved for less than 200 generations in a novel environment are less likely to mate with flies from the ancestral population. In combination with the diverged gene expression of genes involved in sexual selection, these data suggest that the evolved flies are becoming reproductively isolated. The project will use state of the art phenotyping, including video-based behavioral assays, CHC and gene expression analyses and metabolomics to study this case of incipient speciation and shed light on the process of reproductive isolation occurring on time scales shorter than 200 generations.

Long-term dynamics of adaptive alleles

Principal advisor: Christian Schlötterer

Experimental evolution is a powerful approach to detect selection signatures in evolving populations. Nevertheless, most studies focus on rather short-term evolution encompassing only a moderate number of generations. Computer simulations demonstrated that experiments over a larger number of generations provide much more power to detect the true target of selection. This project builds on Drosophila populations, which evolved for more than 200 generations in a novel temperature environment. With replicated time-series allele frequency data this project will take advantage of an unmatched data set in a naturally outcrossing species. The goal of this project is to characterize the genetic basis of temperature adaptation in Drosophila and the long-term dynamics of adaptive alleles.
Related literature:

  • Barghi, N. et al. Genetic redundancy fuels polygenic adaptation in Drosophila. PLoS biology 17, e3000128, doi:10.1371/journal.pbio.3000128 (2019)
  • Mallard, F., Nolte, V., Tobler, R., Kapun, M. & Schlötterer, C. A simple genetic basis of adaptation to a novel thermal environment results in complex metabolic rewiring in Drosophila. Genome biology 19, 119, doi:10.1186/s13059-018-1503-4 (2018)
  • Orozco-terWengel, P. et al. Adaptation of Drosophila to a novel laboratory environment reveals temporally heterogeneous trajectories of selected alleles. Molecular ecology 21, 4931-4941, doi:10.1111/j.1365-294X.2012.05673.x (2012)

Multi-measurement experimental evolution: How to combine evidence from different sources?

Principal advisor: Andreas Futschik

A typical Evolve and resequence (E&R) experiment involves replicate populations for which allele frequency changes are measured. Common methods to test for selection are either applied to each population separately or assume a consistent signal across replicates. However, inconsistent signals are frequently encountered across replicates. Methods that assume consistent allele frequency changes are then not very efficient. It is therefore of interest to develop new approaches that can combine evidence from different replicates and provide good power both for consistent and inconsistent signals. As a starting point, we will use the omnibus test developed by Futschik et al. (2018) which is based on independent p-values. This test provides good power no matter for how many tests k (≥1) the null hypothesis is false. An advantage of the method is its modularity, i.e., p-values from any statistical test can be taken as input, provided they are uniformly distributed under the null model. We intend to extend this approach in several directions: For instance, (i) by considering a whole time series of measurements simultaneously; (ii) by considering spatial response patterns along the chromosome, and taking into account linkage and haplotype structure; (iii) by simultaneous consideration of gene sets (as defined e.g., by GO-categories) to obtain the combined evidence for a GO-category; and (iv) by simultaneously considering different types of –omics data for genes that show a signal of selection in at least one of these categories while still controlling for multiple testing. Finally, as measurements at the single-cell level are currently becoming available, we intend to combine the evidence across cells to determine the genes that exhibit a response in at least some of the cells. Our intended method will not dilute sparse signals by averaging across all cells.

Related literature:

  •  Futschik A, Taus T and Zehetmayer S. An omnibus test for the global null hypothesis. Stat. Methods Med. Res. (2018) arXiv: 1709.00960

Long term dynamics of transposable element invasions

Principal advisor: Robert Kofler

The activity of transposable elements (TEs) is suppressed by small RNAs, the so-called piRNAs (Brennecke et al., 2007; Gunawardane et al., 2007). These piRNAs are generated at distinct genomic loci, the piRNA clusters (Malone et al., 2009). It is assumed that a TE invasion proceeds until insertions in piRNA clusters occur, which suppress the activity of the TE (Bergman et al., 2006; Kofler et al., 2018).
This project will use computer simulations to evaluate the predicted TE dynamics of the “trap model”. One prediction is that several distinct piRNA cluster insertions silencing a particular TE are segregating in a population just after the invasion is being controlled by the piRNA defense. In small populations, cluster insertions may be lost by drift in some individuals, resulting in a reactivation of the invading TE. We will compare the invasion dynamics for different population sizes to evaluate the extent of TE reactivation. Another scenario is the combination of the trap model with negative selection. Ectopic recombination among TEs causes negative selection against TE insertions, including cluster insertions. We will test the hypothesis that this negative selection can reactivate TEs by loss of cluster insertions. A further prediction of the “trap model” is that cluster insertions eventually become fixed by genetic drift, resulting in a permanent TE silencing. We will estimate the time required for fixation of such cluster insertions and thus determine the period of time for which a residual activity of a TE can be expected. The results of the computer simulations will be compared to data from recent P-element invasions in natural and laboratory Drosophila populations.

Related literature:

  • Bergman CM, Quesneville H, Anxolabéhère D and Ashburner M. Recurrent insertion and duplication generate networks of transposable element sequences in the Drosophila melanogaster genome. Genome Biol. 7(11), R112. (2006) doi: 10.1186/gb-2006-7-11-r112
  • Brennecke J, Aravin AA, Stark A, Dus M, Kellis M, Sachidanandam R and Hannon GJ. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128(6), 1089–1103. (2007) doi: 10.1016/j.cell.2007.01.043
  • Gunawardane LS, Saito K, Nishida KM, Miyoshi K, Kawamura Y, Nagami T, Siomi H and Siomi MC. A slicer-mediated mechanism for repeat-associated siRNA 5′ end formation in Drosophila. Science 315(5818), 1587–1590. (2007) doi: 10.1126/science.1140494
  • Kofler R, Senti K-A, Nolte V, Tobler R and Schlötterer C. Molecular dissection of a natural transposable element invasion. Genome Res. gr.228627.117. (2018) doi: 10.1101/gr.228627.117
  • Malone CD, Brennecke J, Dus M, Stark A, McCombie WR, Sachidanandam R and Hannon GJ. Specialized piRNA pathways act in germline and somatic tissues of the Drosophila ovary. Cell 137(3), 522–535. (2009) doi: 10.1016/j.cell.2009.03.040

The molecular basis of recurring, multi-trait plant adaptation to substrate

Principal advisor: Ovidiu Paun

The radiation of ca 25 species of persimmons (Diospyros, Ebenaceae) on New Caledonia, one of the areas with the highest plant endemism in the world, has largely been driven by divergent adaptation to distinct substrates (i.e., ultramafic, volcanic, schist, limestone and serpentine), that happened iteratively within this clade (Paun et al., 2016). Serpentine and ultramafic soils are characterized by dramatically skewed elemental contents and we will focus here on two pairs of sister species within this radiation that show divergent adaptation to these types of soils (ie, volcanic vs. ultramafic). In this project we will test the roles and the inter-relationships between pre- and post-transcriptional mechanisms in recurrent adaptation to stressful substrates. With RNA-Seq and smRNA-Seq we will investigate differential expression, alternative splicing and adaptive sequence evolution for the two species pairs. The molecular data will be complemented by profiling soil chemistry and quantifying mineral nutrient uptake, in particular in reciprocal transplants. Altogether, we will test if the responses to challenging mineral compositions involve exclusion or accumulation of different elements, aiming for understanding the molecular pathways that are affected.

Background reading:

  • Balao F, Trucchi E, Wolfe TM, Hao BH, Lorenzo MT, Baar J, Sedman L, Kosiol C, Amman F, Chase MW, Hedrén M and Paun O. Adaptive sequence evolution is driven by biotic stress in a pair of orchid species (Dactylorhiza) with distinct ecological optima. Mol. Ecol. 26(14), 3649–3662. (2017) doi: 10.1111/mec.14123
  • Paun O, Turner B, Trucchi E, Munzinger J, Chase MW and Samuel R. Processes driving the adaptive radiation of a tropical tree (Diospyros, Ebenaceae) in New Caledonia, a biodiversity hotspot. Syst. Biol. 65(2), 212–227. (2016) doi: 10.1093/sysbio/syv076

The sources of variation fueling adaptive radiation after long-distance dispersal

Principal advisor: Ovidiu Paun

Adaptive radiations are dynamic interplays between speciation, expansion and extinction, often starting from long-distance dispersal events, when an alien lineage invades an array of previously unfilled niches. In such cases, habitat heterogeneity and ecological opportunity, although essential, appear by no means sufficient to explain adaptive diversifications. Springboards to explosive ecological radiation may be particular genomic configurations and the amount of phenotypic variation available to selection, together with the speed at which new variation originates, accelerating diversification rates (Schluter, 2000). Nevertheless, in the case of isolated areas like remote oceanic islands, the initial founder population is likely to have an extreme Ne, with little starting variation that can be selected to result in novel and divergent adaptations. Hence, the evolution of island biotas is intuitively expected to be shaped by neutral processes rather than natural selection. Still, species-rich adaptive diversifications are not uncommon on islands, unveiling adaptive radiation as a common process in such areas. The radiation of ca 25 species of persimmons (Diospyros, Ebenaceae) on New Caledonia, a biodiversity hotspot, is largely driven by divergent adaptation to distinct substrates (i.e., ultramafic, volcanic, schist, limestone and serpentine), that happened iteratively within this clade (Paun et al., 2016). The most puzzling aspect of this radiation is what differentiates the radiating group from three congeneric, but evolutionary lethargic lineages present on the archipelago? Due to a significant difference in genome size, that is not associated to ploidy increase, the answer may relate to a difference in the speed of accumulation of phenotypic variation, specific for each of the founders of the four long distance dispersal events. In this project, we will use whole genome resequencing to disentangle potential sources of adaptive variation, such as i) lineage-specific de novo evolution of alleles, ii) TE-induced structural variation with potential regulatory effects, together with iii) environment-specific sorting of ancestral genetic variation and/or iv) introgression of adaptive alleles (ie, gene reuse, Martin & Orgogozo, 2013) from related species, from within or outside the radiation, that share similar environments.

Related literature:

  • Martin A and Orgogozo V. The loci of repeated evolution: A catalog of genetic hotspots of phenotypic variation. Evolution 67(5), 1235–1250. (2013) doi: 10.1111/evo.12081
  • Paun O, Turner B, Trucchi E, Munzinger J, Chase MW and Samuel R. Processes driving the adaptive radiation of a tropical tree (Diospyros, Ebenaceae) in New Caledonia, a biodiversity hotspot. Syst. Biol. 65(2), 212–227. (2016) doi: 10.1093/sysbio/syv076
  • Schluter D. The Ecology of Adaptive Radiation. Oxford Ser. Ecol. Evol. (2000) doi: 10.2307/3558417

The genetics of local adaptation in Arabidopsis thaliana

Principal advisor: Magnus Nordborg

We have been carrying out a number of long-term field experiments in Sweden, using native Swedish lines of A. thaliana (Long et al., 2013). Rather than just growing plants in plots and measuring seed set as a proxy for fitness, we established “natural” sites where the plants can compete over multiple generations, and sampled individuals throughout the experiment. Over 10,000 plants have been sampled, and we are currently in the process of sequencing them in order to map genes responsible for fitness differences using genome-wide association. The results will be compared with phenotypes (including transcriptome and epigenome) data taken from common-garden experiments carried out at the same sites. This will make it possible to investigate whether loci that show signs of selection are also associated with particular phenotypes.

Related literature:

  •  Long Q, Rabanal FA, Meng D, Huber CD, Farlow A, Platzer A, Zhang Q, Vilhjálmsson BJ, Korte A, Nizhynska V, Voronin V, Korte P, Sedman L, Mandáková T, Lysak MA, Seren Ü, Hellmann I and Nordborg M. Massive genomic variation and strong selection in Arabidopsis thaliana lines from Sweden. Nat. Genet. 45(8), 884–890. (2013) doi: Doi 10.1038/Ng.2678

Transposon polymorphism in Arabidopsis thaliana

Principal advisor: Magnus Nordborg

Because transposons are too repetitive to be sequenced using short-read sequencing methods, our understanding of transposon polymorphism is extremely limited. This has led to a literature of transposon evolution that is almost exclusively based on comparison between reference genomes — which is the wrong time-scale for highly dynamic transposons. Arabidopsis thaliana has low transposon content compared to other plants (less than 25% of the reference genome consist of annotated transposons), and it has been argued that transposons are mostly inactive in this species. However, we now know that this is not correct. Our analysis of the 1001 Genomes data suggests that roughly 50% of the annotated transposons are polymorphic, and that most of the insertions are in fact quite rare, i.e. most individuals do not carry them (they carry other insertions instead). Furthermore, we have identified lines that appear to carry twice as many transposons as the reference lines. This highlights the need for better data, and we are thus sequencing 200 genomes de novo using long-read technologies in order to get a comprehensive picture of transposon polymorphism and better understand the dynamics of transposons in populations. Analyzing these data will be perfect for a motivated PhD student with keen interest in population genetics.

Fond zur Förderung der wissenschaftlichen Forschung
vetmed uni vienna
Gregor Mendel Institute of Molecular Plant Biology
Universität Wien