Biology subjects

Philipp W Messer

Publications and source records attributed to Philipp W Messer.

5 recordsLinked to original sources

bioRxiv2016

Evolution of resistance against CRISPR/Cas9 gene drive

The idea of driving genetically modified alleles to fixation in a population has fascinated scientists for over 40 years1,2. Potential applications are broad and ambitious, including the eradication of disease vectors, the control of pest species, and the preservation of endangered species from extinction3. Until recently, these possibilities have remained largely abstract due to the lack of an effective drive mechanism. CRISPR/Cas9 gene drive (CGD) now promise a highly adaptable approach for driving even deleterious alleles to high population frequency, and this approach was recently shown to be effective in small laboratory populations of insects4-7. However, it remains unclear whether CGD will also work in large natural populations in the face of potential resistance mechanisms. Here we show that resistance against CGD will inevitably evolve unless populations are small and repair of CGD-induced cleavage via nonhomologous end joining (NHEJ) can be effectively suppressed, or resistance costs are on par with those of the driver. We specifically calculate the probability that resistance evolves from variants at the target site that are not recognized by the driver's guide RNA, either because they are already present when the driver allele is introduced, arise by de novo mutation, or are created by the driver itself when NHEJ introduces mutations at the target site. Our results shed light on strategies that could facilitate the engineering of a successful drive by lowering resistance potential, as well as strategies that could promote resistance as a possible mechanism for controlling a drive. This study highlights the need for careful modeling of CGD prior to the actual release of a driver construct into the wild.

Evolutionary Biology↗

bioRxiv2016

Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans.

The 2-5 oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes (OAS1-3) involved in innate immune response. This region harbors high amounts of Neandertal ancestry in non-African populations; yet, strong evidence of positive selection in the OAS region is still lacking. Here we used a broad array of selection tests in concert with neutral coalescent simulations to firmly demonstrate a signal of adaptive introgression at the OAS locus. Furthermore, we characterized the functional consequences of the Neandertal haplotype in the transcriptional regulation of OAS genes at baseline and infected conditions. We found that cells from people with the Neandertal-like haplotype express lower levels of OAS3 upon infection, as well as distinct isoforms of OAS1 and OAS2. Notably, the Neandertal-introgressed haplotype reintroduced an ancestral splice variant of OAS1 encoding a more active protein, suggesting that adaptive introgression occurred as a means to resurrect adaptive variation that had been lost outside Africa.

Evolutionary Biology↗

bioRxiv2015

Evaluating the performance of selection scans to detect selective sweeps in domestic dogs

Selective breeding of dogs has resulted in repeated artificial selection on breed-specific morphological phenotypes. A number of quantitative trait loci associated with these phenotypes have been identified in genetic mapping studies. We analyzed the population genomic signatures observed around the causal mutations for 12 of these loci in 25 dog breeds, for which we genotyped 25 individuals in each breed. By measuring the population frequencies of the causal mutations in each breed, we identified those breeds in which specific mutations most likely experienced positive selection. These instances were then used as positive controls for assessing the performance of popular statistics to detect selection from population genomic data. We found that artificial selection during dog domestication has left characteristic signatures in the haplotype and nucleotide polymorphism patterns around selected loci that can be detected in the genotype data from a single population sample. However, the sensitivity and accuracy at which such signatures were detected varied widely between loci, the particular statistic used, and the choice of analysis parameters. We observed examples of both hard and soft selective sweeps and detected strong selective events that removed genetic diversity almost entirely over regions >10 Mbp. Our study demonstrates the power and limitations of selection scans in populations with high levels of linkage disequilibrium due to severe founder effects and recent population bottlenecks.

Evolutionary Biology↗

bioRxiv2014

Quantification of GC-biased gene conversion in the human genome

Many lines of evidence indicate GC-biased gene conversion (gBGC) has a major impact on the evolution of mammalian genomes. However, up to now, this process had not been properly quantified. In principle, the strength of gBGC can be measured from the analysis of derived allele frequency spectra. However, this approach is sensitive to a number of confounding factors. In particular, we show by simulations that the inference is pervasively affected by polymorphism polarization errors, especially at hypermutable sites, and spatial heterogeneity in gBGC strength. Here we propose a new method to quantify gBGC from DAF spectra, incorporating polarization errors and taking spatial heterogeneity into account. This method is very general in that it does not require any prior knowledge about the source of polarization errors and also provides information about mutation patterns. We apply this approach to human polymorphism data from the 1000 genomes project. We show that the strength of gBGC does not differ between hypermutable CpG sites and non-CpG sites, suggesting that in humans gBGC is not caused by the base-excision repair machinery. We further find that the impact of gBGC is concentrated primarily within recombination hotspots: genome-wide, the strength of gBGC is in the nearly neutral area, but 2% of the human genome is subject to strong gBGC, with population-scaled gBGC coefficients above 5. Given that the location of recombination hotspots evolves very rapidly, our analysis predicts that in the long term, a large fraction of the genome is affected by short episodes of strong gBGC.

Evolutionary Biology↗

bioRxiv2014

Soft selective sweeps in complex demographic scenarios

Recent studies have shown that adaptation from de novo mutation often produces so-called soft selective sweeps, where adaptive mutations of independent mutational origin sweep through the population at the same time. Population genetic theory predicts that soft sweeps should be likely if the product of the population size and the mutation rate towards the adaptive allele is sufficiently large, such that multiple adaptive mutations can establish before one has reached fixation; however, it remains unclear how demographic processes affect the probability of observing soft sweeps. Here we extend the theory of soft selective sweeps to realistic demographic scenarios that allow for changes in population size over time. We first show that population bottlenecks can lead to the removal of all but one adaptive lineage from an initially soft selective sweep. The parameter regime under which such 'hardening' of soft selective sweeps is likely is determined by a simple heuristic condition. We further develop a generalized analytical framework, based on an extension of the coalescent process, for calculating the probability of soft sweeps under arbitrary demographic scenarios. Two important limits emerge within this analytical framework: In the limit where population size fluctuations are fast compared to the duration of the sweep, the likelihood of soft sweeps is determined by the harmonic mean of the variance effective population size estimated over the duration of the sweep; in the opposing slow fluctuation limit, the likelihood of soft sweeps is determined by the instantaneous variance effective population size at the onset of the sweep. We show that as a consequence of this finding the probability of observing soft sweeps becomes a function of the strength of selection. Specifically, in species with sharply fluctuating population size, strong selection is more likely to produce soft sweeps than weak selection. Our results highlight the importance of accurate demographic estimates over short evolutionary timescales for understanding the population genetics of adaptation from de novo mutation.

Evolutionary Biology↗