New paper on resistance against CRISPR gene drives
July 20, 2017
Gene drive systems provide a wide array of potential applications, including new strategies for the control of vector-borne diseases. However, resistance alleles can also be generated during this process, which may pose a major obstacle to the practical use of such gene drives. In our new study published today in PLoS Genetics, we developed two CRISPR/Cas9 gene drive constructs using different promoters and target sites in the model organism Drosophila melanogaster to study the mechanisms and rates by which such resistance alleles are generated. We observed that resistance alleles arise at high rates both in the germline and post-fertilization in the embryo. Additionally, conversion efficiency and resistance allele formation rates varied substantially among genetically diverse fly lines. The design of effective CRISPR gene drives will therefore require new approaches that reduce the formation of resistance alleles, particularly when applied to genetically diverse natural populations. This is the first experimental study of our lab and major congratulations go to postdoc Jackson Champer, who spearheaded this work and has been the driving force in setting up our experimental program. The paper is also accompanied by a perspective article by Jim Bull and Harmit Malik in the same issue and has already received extensive press coverage, including articles in The Economist, Science News, Gizmodo, and GEN.
May 26, 2017
Congratulations to Andrew Marderstein for graduating with Honors in Biological Sciences from Cornell’s College of Agriculture and Life Sciences. Andrew has been a student in the lab since early 2016. In his honors thesis “Approximate Bayesian Computation for Studying Selective Sweep Signatures in Local Coalescence Trees”, Andrew explored whether we can distinguish hard and soft sweeps from the shape of the local coalescence tree at the sweep locus. For this purpose, he developed an Approximate Bayesian Computation (ABC) approach that can reliably distinguish these sweep types and infer their evolutionary parameters. In the Fall, Andrew will be starting as a graduate student in the Tri-Institutional PhD program for Computational Biology and Medicine from Cornell University, Weill Cornell Medical College, and Memorial Sloan Kettering Cancer Center. We congratulate Andrew on his impressive achievements and wish him the best in his future endeavors!
Commentary on gene drive resistance paper
March 1, 2017
In a commentary in the March issue of GENETICS, Floyd Reed discusses our recent paper Unckless et al. (2017), “Evolution of resistance against CRISPR/Cas9 gene drive,” which was published in the February issue of the journal. Reed highlights the issue of resistance against CRISPR gene drive approaches and proposes a possible path forward by synergistically combining the relative advantages of multiple gene drive systems. For example, Reed suggests that a CRISPR gene drive could be combined with an underdominance system, which cannot increase in frequency when rare but can proceed to fixation once a “threshold” allele frequency is surpassed. The CRISPR drive would then initially propel the drive, while the underdominance drive could continue to drive the system at higher frequencies.
New paper on gene drive resistance
February 2, 2017
CRISPR/Cas9 gene drive (CGD) promises a highly adaptable approach to controlling pests or disease vectors by spreading genetically engineered alleles throughout a species. In a new paper with co-authors Rob Unckless and Andy Clark we examine the likelihood that resistance to gene drive evolves prior to driver fixation, potentially limiting the ability of the driver to transform whole populations. The results shed light on possible strategies for engineering drivers with lower potential for resistance as well as the potential use of resistance as a mechanism for controlling CGD. We are excited to see that our paper was chosen as an issue highlight. And check out that stunning cover art depicting the attack of the 50-foot mosquito (unmistakeably inspired by the famous B-movie “Attack of the 50 Foot Women“) from artist friend Kent Smith, who we commissioned to illustrate our article. This work was also recently featured in a News story by Ewen Callaway in Nature.
SLiM 2 paper published in MBE
January 9, 2017
Modern population genomic datasets hold immense promise for revealing the evolutionary processes operating in natural populations, but a crucial prerequisite for this goal is the ability to model realistic evolutionary scenarios and predict their expected patterns in genomic data. To that end, we present SLiM 2: an evolutionary simulation framework that combines a powerful, fast engine for forward population genetic simulations with the capability of modeling a wide variety of complex evolutionary scenarios. SLiM achieves this flexibility through scriptability, which provides control over most aspects of the simulated evolutionary scenarios with a simple R-like scripting language called Eidos. SLiM 2 also includes a graphical user interface for simulation construction, interactive runtime control, and dynamic visualization of simulation output, facilitating easy and fast model development with quick prototyping and visual debugging. Our paper describing SLiM 2 is now available in Molecular Biology and Evolution. Also check out this nice blogpost by SLiM developer and Messer lab member Ben Haller.
New paper on adaptive Neandertal introgression
November 29, 2016
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. However, strong evidence of positive selection in the OAS region is still lacking. In a new paper that just came out in Genome Biology, we used a broad array of selection tests in concert with neutral coalescent simulations to clearly demonstrate a signal of adaptive introgression at the OAS locus. In collaboration with Luis Barreiro’s lab at the University of Montreal, we also 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. This haplotype is associated with functional consequences at the level of transcriptional regulation of innate immune responses. Notably, we suggest that the Neandertal-introgressed haplotype likely 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. Here is a link to a great article in The Scientist by Anna Azvolinsky, summarizing our work for a broader audience.
Can gene drives survive in the wild?
September 27, 2016
Nicole Haloupek, a science writer and molecular biologist at UC Berkeley, recently wrote this great article about our research on the population dynamics of gene drives in natural population, which has just been published on the Genes to Genomes blog of the Genetics Society of America.
Monday, September 19, 2016
Congratulations to postdoc Aaron Sams, who just started his new job as Scientist at the exciting animal health startup Embark Veterinary. Embark was founded by our collaborator and Cornell colleague Adam Boyko together with his brother Ryan and produces DNA testing kits for dogs that will include information about a canine’s ancestry and disease risk. The company has been on a stellar trajectory since its launch. While we are of course sad to see Aaron go, we are also very happy that he landed this amazing opportunity at Embark. Aaron has been a postdoc in the lab since early 2015 and has done amazing research on adaptive introgression from Neanderthals into modern humans. We wish him all the best for his new adventure.
Genetic Engineering to Clash With Evolution
September 8, 2016
Science journalist Brooke Borel wrote a very thoughtful and comprehensive article about our research on gene drives for Quanta Magazine. In contrast to many of the other recent articles on this topic, this article does a really good job at conveying the evolutionary complexities and unknowns of gene drive approaches. You can check out the article here.
New paper on genetics of blue-winged and yellow-winged warblers
August 18, 2016
For decades, conservationists have considered blue-winged warblers to be a threat to golden-winged warblers, a species being considered for federal Endangered Species protection. Blue-winged warbler populations have declined 66 percent since 1968, according to the North American Breeding Bird Survey. In a study led by Dave Toews and Scott Taylor from the Cornell Lab of Ornithology, which was just published in Current Biology, we show that blue-winged and golden-winged warblers are genetically almost identical. Across the entire genomes of both species, we found only six regions (or less than .03 percent) that showed strong differences, and thus likely cause the striking phenotype differences between them. One of those differentiating regions, for example, has a gene that controls yellow/white versus black throat coloration. We further showed that these two species have probably been intermixing, at least intermittently, for thousands of years, well before Europeans colonized North America. Here is a nice summary our study in the Cornell Chronicle, and here is one from the Cornell Lab of Ornithology. The matter of golden-wing/blue-wing genetic similarity may pose a tricky question for the American Ornithologists’ Union, too, should its North American Classification Committee be asked to consider this evidence in a proposal to lump golden-wings and blue-wings into a single species.
Seeing the upside in gene drives’ fatal flaw
July 15, 2016
Can population genetics adapt to rapid evolution?
July 10, 2016
Population genetics largely rests on a standard model in which random genetic drift is the dominant force, selective sweeps occur infrequently, and deleterious mutations are purged from the population by purifying selection. Studies of phenotypic evolution in nature, however, increasingly reveal a rather different picture, with strong selection and rapid heritable trait changes being common. Many recent studies have now shown that phenotypic traits can often change dramatically over the course of only a few generations. In a review article that was just been published in Trends in Genetics, we discuss whether such rapid phenotypic evolution undermines the standard model and how new techniques and research in understanding rapid evolution can help us refine current population genetic models. We argue that population-level sequencing will be instrumental in this context by allowing us to dissect the genetic basis of phenotypic evolution and study the evolutionary dynamics of genetic variation through direct measurement of polymorphism trajectories over time. This paper was a joint project with Nelson Hairston and Stephen Ellner from the Department of Ecology and Evolutionary Biology at Cornell. We were excited to see that our paper made the journal cover, even though we still do not really understand what these cichlid fish have to do with it. They certainly do look pretty.
New paper on adaptive Neandertal introgression
May 5, 2016
The genomes of humans living outside of Africa contain roughly two percent of Neandertal DNA. However, it is unclear to what extent this admixed DNA impacts human biology. In a collaboration with the Barreiro lab at the University of Montreal, we studied this question by focusing on one of the most striking example of Neandertal introgression – the 2’-5’ oligoadenylate synthetase (OAS) locus. Neandertal haplotypes are found at particularly high frequency at this locus, which encodes enzymes that are critical to fight viral infections. In our preprint just published on bioRxiv, we first studied the patterns of genetic diversity at OAS to demonstrate that the introgressed Neandertal haplotype was indeed adaptive in modern humans. We then used RNA sequencing and qPCR to show experimentally that this haplotype is also associated with striking functional consequences on human immune response to infection. Specifically, we found that the Neandertal haplotype encodes an ancestral splice variant of the OAS1 gene that is common in Africa, but almost perfectly linked to the Neandertal haplotype outside of Africa, suggesting that archaic introgression reintroduced an important splice variant that may have been lost during the out-of-Africa migration. Our work supports previous arguments for the importance of introgression in maintaining critical variation in the immune system across closely related lineages. Additionally, it speaks to the need for novel methods in identifying signatures of adaptive introgression, which can differ quite dramatically from traditional selective sweeps. First author on the paper is postodc Aaron Sams, who just won the Outstanding Trainee Presentation in Anthropological Genetics award for presenting this work at the 2016 AAPA meeting. Congratulations Aaron on this prestigious prize and great paper!
Detecting signatures of selective sweeps in dogs
January 11, 2016
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. In our new study that was just published in Molecular Ecology, we analyzed the population genomic signatures observed around the causal mutations for several of these loci in different dog breeds. We found that artificial selection during dog domestication has left characteristic signatures in the polymorphism patterns around these 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 selection 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. The project is a collaboration with Adam Boyko from the College of Veterinary Medicine at Cornell and was performed by graduate student Florencia Schlamp and undergraduate students Julian van der Made, Rebecca Stambler and Lewis Chesebrough. Needless to say that “Poochie” made it on the journal cover.
New gene drive technology evokes hopes and fears
October 7, 2015
Engineered genetic elements that can spread through populations by cheating Mendelian segregation have great potential for biological control. There is, however, cause for concern of unintended consequences of these genetic drive systems. In a paper that was just published in Genetics we study the spread of alleles through this, so-called, mutagenic chain reaction (MCR) and describe several different outcomes depending on parameters assumed. We find that under many circumstances, the timeframe to fixation of an allele is very fast, but also that polymorphism in natural populations may introduce sources of natural resistance to MCR invasion. Our paper made it on the cover of Genetics and was chosen an issue highlight. Here’s an interview with the first author Rob Unckless. The coauthors on the paper are Philipp Messer, Tim Connallon and Andy Clark.
New paper on soft selective sweeps in Drosophila
February 26, 2015
Evolutionary adaptation is a process in which beneficial mutations increase in frequency in response to selective pressures. If these mutations were previously rare or absent from the population, adaptation should generate a characteristic signature in the genetic diversity around the adaptive locus, known as a selective sweep. Such selective sweeps can be distinguished into hard selective sweeps, where only a single adaptive mutation rises in frequency, or soft selective sweeps, where multiple adaptive mutations at the same locus sweep through the population simultaneously. In a paper that just came out in PLoS Genetics, we designed a new statistical method that can identify both hard and soft sweeps in population genomic data and applied this method to a Drosophila melanogaster population genomic dataset consisting of 145 sequenced strains collected in North Carolina. We found that selective sweeps were abundant in the recent history of this population. Interestingly, we also found that practically all of the strongest and most recent sweeps show patterns that are more consistent with soft rather than hard sweeps.
SMBE Symposium: Population genomics of rapid adaptation
January 8, 2015
Philipp Messer and Dmitri Petrov are organizing a symposium on “Population genomics of rapid adaptation” at the Society for Molecular Biology and Evolution (SMBE) meeting, July 12-16 in Vienna, Austria. Applications to give a talk as part of this symposium will be accepted through February 8; for details concerning how to submit an abstract, see: http://smbe2015.at/.
One of the most puzzling observations in evolutionary biology is that organisms can often adapt surprisingly quickly to environmental challenges. Classical examples of such rapid adaptations include the domestication of plants and animals and the evolution of pesticide or drug resistance. It is now becoming increasingly clear that the potential for rapid adaptation is a ubiquitous feature of evolution across a wide spectrum of systems, ranging from experimental evolution in microbes, to the progression of cancer cells in the human body, to the rapid responses of species under climate change. The growing number of systems where rapid adaptations are directly observable presents us with the fascinating opportunity to study evolution in real time and to make progress in understanding what limits the rate of evolution and determines its likely outcome. In this symposium, we will focus on (i) novel approaches to detect and study rapid adaptation using population genomic data, (ii) case studies of rapid adaptation in natural populations, and (iii) experimental studies of rapid adaptation in model systems. Although rapid adaptation has long been associated primarily with the evolution of polygenic traits that can adapt quickly by using standing genetic variation, we will also highlight recent work showing that adaptation at times can be rapid despite relying on de novo mutations.
Invited speakers: Graham Coop and Sasha Levy
Please do not hesitate to contact us with any questions. We hope to see you this summer!
Conundrum of Jumbled Mosquito Genomes
January 2, 2015
In this week’s issue of Science, Philipp Messer and Andy Clark wrote a perspective on two interesting papers that study the evolutionary genomics of mosquitos. The papers by Neafsey et al. and Fontaine et al. generate and analyze the genome sequences of 16 species of anopheline mosquitoes. Surprisingly, they reveal a complex pattern of evolution that defies the classic concept of a phylogenetic tree. Instead, the pattern of evolution seen in the An. gambiae species complex appears to rather resembles a network. These types of evolutionary networks are often referred to as reticulate evolution and are commonly observed in bacteria, where genetic exchange can be so pervasive that the concept of species becomes quite slippery. Even though reticulate evolution has also been seen in other species groups, the pattern in the gambiae complex of mosquitoes is so extreme that it, too, challenges any clear definition of species in this group. The two papers do a great job in advancing Anopheles genomics and providing baseline resources to answer many additional questions.
New paper on Soft sweeps and demography
August 6, 2014
Our new paper on “Soft selective sweeps in complex demographic scenarios” just came out in Genetics. In this paper, Ben Wilson, Dmitri Petrov, and Philipp investigate how changes in population size over time affect the dynamics of adaptation from de novo mutation.
When adaptation involves de novo mutations, the rate at which these mutations occur becomes very important for determining how adaptation proceeds. If beneficial mutations at a given locus arise frequently in the population, it is possible that several beneficial mutations originate independently in different individuals and sweep through the population at the same time, a phenomenon known as a soft selective sweep.
Soft selective sweeps are becoming an increasingly important model of adaptation as they have been observed in many case studies of rapid adaptation. Theory predicts that such soft sweeps should be observable in very large populations or when there are many mutations at a particular gene that can give rise to the adaptation, such as adaptive loss-of-function mutations or mutations that affect the expression level of a gene.
While the number of different mutations that give rise to a particular adaptation is typically fixed, the population size is not. In nature, population sizes often fluctuate by many orders of magnitude over timescales that overlap those during which adaptation occurs, for example during pathogen transmission or during population cycles over a season.
In our paper we develop a mathematical framework for predicting the likelihood of observing soft sweeps when population size changes over time. Using this framework, we show that in fluctuating populations soft selective sweeps that start during population booms can turn into hard sweeps when low frequency mutations drift out of the population during population busts. One striking consequences of this is that stronger adaptations are then more likely to produce soft sweeps than weaker adaptations, because strongly beneficial mutations can sweep to fixation between population crashes. Our results highlight the importance of understanding the recent demography of a species since it can be key for understanding the population genetic signatures that adaptation leaves in the data.
Evolution of drug resistance program at KITP
July 28, 2014
For the next five weeks Philipp is attending the evolution of drug resistance program at the Kavli Institute for Theoretical Physics in Santa Barbara. The workshop brings together researchers from the medical, biological, and physical sciences in order to understand the circumstances under which drug resistance evolves and how it spreads. The program consists of four units, on bacterial and viral drug resistance, resistance in parasites such as malaria, and finally resistance in cancer. There is a nice wikispace where you can watch and download recordings of most presentations given during the program.
Philipp presenting at SMBE 2014
June 11, 2014
Philipp gave a presentation today at the annual Society for Molecular Biology and Evolution (SMBE) meeting with title: “New statistical scans detect both hard and soft sweeps in Malaria parasites”. This year’s meeting was held in beautiful San Juan, Puerto Rico. The project is a collaboration with Ian Cheeseman and Tim Anderson from the Texas Biomedical Research Institute, in which we study the population genomic signatures of adaptation at known drug resistance loci in the Plasmodium falciparum genome. In addition to his own presentation, Philipp was co-author on three more talks at the conference from Ben Wilson, David Enard, and Nandita Garud (photo credit).
Credit to Alex Cagan (@ATJCagan) for this great sketch of my presentation.