IST Austria
Am Campus 1
Klosterneuburg, A-3400
Austria
Phone: +43 2243 9000
Fax: +43 2243 9000 2000
Last Updated: 6 July 2011
The following is a brief overview of current, future, and a sampling of past research projects.
Current projects
Project 1: Estimating the intensity of selection for drug resistance in human influenza A. (Bollback, Leigh-Brown, Lycett)
Project 2: Modelling sequence evolution that incorporates CpG bias and positive selection. (Hellmann, Kupczok, Bollback, Nielsen)
Project 3: Patterns of positive selection in S. aureus - a whole genome analysis. (Lowder, Bollback, Fitzgerald)
Project 4: Modelling the evolutionary dynamics of the CRISPR locus (Kupczok, Bollback)
Future projects
Project 1: Evolutionary dynamics of sexual and asexual populations. (Bollback)
Project 2: Population genetics of natural populations of bacteriophages. (Bollback)
Past projects
Recurrent mutation alleviates clonal interference (MBE, 2007, 24(6):1397–1406)
When a beneficial mutation is fixed in a population that lacks recombination, the genetic background linked to that mutation is fixed. As a result, beneficial mutations on different backgrounds experience competition, or "clonal interference", that can cause asexual populations to evolve more slowly than their sexual counterparts. Factors such as a large population size (N) and high mutation rates (µ) increase the number of competing beneficial mutations, and hence are expected to increase the intensity of clonal interference. However, recent theory suggests that, with very large values of Nµ, the severity of clonal interference may instead decline. The reason is that, with large Nµ, genomes including both beneficial mutations are rapidly created by recurrent mutation, obviating the need for recombination. Here, we analyze data from experimentally evolved asexual populations of a bacteriophage and find that, in these nonrecombining populations with very large Nµ, recurrent mutation does appear to ameliorate this cost of asexuality.
Large populations of the bacteriophage MS2 were selected for adaptation to high temperatures. MS2 has a high mutation rate. Below you can see the time-series sequence data of adaptive mutations in MS2 during adaptation. Clonal interference is fairly extreme, however, recurrent mutation builds up these mutations on a common genetic background alleviating this cost.
Interactions among adaptive mutations
MS2 is a bacteriophage in the coliphage family Leviviridae. It is has a positive single-stranded RNA genome that is 3,569 nucleotides in length. The genome encodes 4 proteins. This little phage has been one of the workhorses in my experimental evolution research and has been used by others for similar purposes.
Mutations can interact in a number of different ways: 1) the fitness effects of each are independent of the other; 2) the fitness effect of one mutation becomes positive in the presence of another mutation (positive epistasis); and 3) they are beneficial in the absence of each other, but are deleterious when combined on a common genetic background (negative epistasis).
During adaptation of MS2 to high temperature growth two beneficial mutations in the major coat protein went to fixation. However, these two mutations never appeared on the same genetic background and only one or the other was fixed in each of the replicate lines. This strongly siuggests negative epistasis between these mutations. This hypothesis becomes more interesting when we visualize where these mutations occur on the structure of the major coat protein -- their adjacent proximity suggests that a single functional adaptive change in the capsid protein in the FG loop is beneficial, but two changes in this region is deleterious.
Parallel evolution (Genetics, 2009, 181:225–234)
Parallel evolution is the acquisition of identical adaptive traits in independently evolving populations. Understanding whether the genetic changes underlying adaptation to a common selective environment are parallel within and between species is interesting because it sheds light on the degree of evolutionary constraints. If parallel evolution is perfect, then the implication is that forces such as functional constraints, epistasis, and pleiotropy play an important role in shaping the outcomes of adaptive evolution. In addition, population genetic theory predicts that the probability of parallel evolution will decline with an increase in the number of adaptive solutions - if a single adaptive solution exists, then parallel evolution will be observed among highly divergent species. For this reason, it is predicted that close relatives - which likely overlap more in the details of their adaptive solutions - will show more parallel evolution. By adapting three related bacteriophage species to a novel environment we find (1) a high rate of parallel genetic evolution at orthologous nucleotide and amino acid residues within species, (2) parallel beneficial mutations do not occur in a common order in which they fix or appear in an evolving population, (3) low rates of parallel evolution and convergent evolution between species, and (4) the probability of parallel and convergent evolution between species is strongly effected by divergence.
Adaptive mutations stabilize secondary structure in a critical regulatory region
Not all silent mutations are neutral. The beneficial silent mutation U1685C was observed in each of three replicate lines during adaptation to high temperature growth. Inspection of the genetic grounds on which these mutations appeared revealed no evidence that its fixation was due to hitchhiking. U1685 occurs in a stem loop region that has been shown to be important in the regulation of expression of the lysis gene - the structure prohibits access of the ribosome to the start codon suppressing expression. Previous mutagenesis studies by other groups have shown that mutations in this region that destabilize the hairpin leads to early lysis and lower burst sizes, while mutations that stabilize this region leads to delayed lysis. Given a number of factors, such as host density, their is likely an optimal timing of lysis. We hypothesize that growth of the wild-type phage at higher temperatures experiences a destabilization of the hair pin. U1685C restores the optimal stability of this region. You can see below the predicted destabilization of the wild-type stem-loop region at the selected temperature (43C), and the derived stability at 43C in the high temperature adapted phage.
A method for estimating 2Nes from temporal allele frequency data (Genetics, 2008, 179:497–502)
We develop a new method for estimating effective population sizes, Ne, and selection coefficients, s, from time-series data of allele frequencies sampled from a single diallelic locus. The method is based on calculating transition probabilities, using a numerical solution of the diffusion process, and assuming independent binomial sampling from this diffusion process at each time point. We apply the method in two example applications. First, we estimate selection coefficients acting on the CCR5-Δ32 mutation on the basis of published samples of contemporary and ancient human DNA. We show that the data are compatible with the assumption of s = 0, although moderate amounts of selection acting on this mutation cannot be excluded. In our second example (see below), we estimate the selection coefficient acting on a mutation segregating in an experimental phage population. We show that the selection coefficient acting on this mutation is s ≅ 0.43.
Time-series data for C206U:
Likelihood surface:
Current projects
Project 1: Estimating the intensity of selection for drug resistance in human influenza A. (Bollback, Leigh-Brown, Lycett)
Project 2: Modelling sequence evolution that incorporates CpG bias and positive selection. (Hellmann, Kupczok, Bollback, Nielsen)
Project 3: Patterns of positive selection in S. aureus - a whole genome analysis. (Lowder, Bollback, Fitzgerald)
Project 4: Modelling the evolutionary dynamics of the CRISPR locus (Kupczok, Bollback)
Future projects
Project 1: Evolutionary dynamics of sexual and asexual populations. (Bollback)
Project 2: Population genetics of natural populations of bacteriophages. (Bollback)
Past projects
Recurrent mutation alleviates clonal interference (MBE, 2007, 24(6):1397–1406)
When a beneficial mutation is fixed in a population that lacks recombination, the genetic background linked to that mutation is fixed. As a result, beneficial mutations on different backgrounds experience competition, or "clonal interference", that can cause asexual populations to evolve more slowly than their sexual counterparts. Factors such as a large population size (N) and high mutation rates (µ) increase the number of competing beneficial mutations, and hence are expected to increase the intensity of clonal interference. However, recent theory suggests that, with very large values of Nµ, the severity of clonal interference may instead decline. The reason is that, with large Nµ, genomes including both beneficial mutations are rapidly created by recurrent mutation, obviating the need for recombination. Here, we analyze data from experimentally evolved asexual populations of a bacteriophage and find that, in these nonrecombining populations with very large Nµ, recurrent mutation does appear to ameliorate this cost of asexuality.
Large populations of the bacteriophage MS2 were selected for adaptation to high temperatures. MS2 has a high mutation rate. Below you can see the time-series sequence data of adaptive mutations in MS2 during adaptation. Clonal interference is fairly extreme, however, recurrent mutation builds up these mutations on a common genetic background alleviating this cost.
Interactions among adaptive mutations
MS2 is a bacteriophage in the coliphage family Leviviridae. It is has a positive single-stranded RNA genome that is 3,569 nucleotides in length. The genome encodes 4 proteins. This little phage has been one of the workhorses in my experimental evolution research and has been used by others for similar purposes.
Mutations can interact in a number of different ways: 1) the fitness effects of each are independent of the other; 2) the fitness effect of one mutation becomes positive in the presence of another mutation (positive epistasis); and 3) they are beneficial in the absence of each other, but are deleterious when combined on a common genetic background (negative epistasis).
During adaptation of MS2 to high temperature growth two beneficial mutations in the major coat protein went to fixation. However, these two mutations never appeared on the same genetic background and only one or the other was fixed in each of the replicate lines. This strongly siuggests negative epistasis between these mutations. This hypothesis becomes more interesting when we visualize where these mutations occur on the structure of the major coat protein -- their adjacent proximity suggests that a single functional adaptive change in the capsid protein in the FG loop is beneficial, but two changes in this region is deleterious.
Parallel evolution (Genetics, 2009, 181:225–234)
Parallel evolution is the acquisition of identical adaptive traits in independently evolving populations. Understanding whether the genetic changes underlying adaptation to a common selective environment are parallel within and between species is interesting because it sheds light on the degree of evolutionary constraints. If parallel evolution is perfect, then the implication is that forces such as functional constraints, epistasis, and pleiotropy play an important role in shaping the outcomes of adaptive evolution. In addition, population genetic theory predicts that the probability of parallel evolution will decline with an increase in the number of adaptive solutions - if a single adaptive solution exists, then parallel evolution will be observed among highly divergent species. For this reason, it is predicted that close relatives - which likely overlap more in the details of their adaptive solutions - will show more parallel evolution. By adapting three related bacteriophage species to a novel environment we find (1) a high rate of parallel genetic evolution at orthologous nucleotide and amino acid residues within species, (2) parallel beneficial mutations do not occur in a common order in which they fix or appear in an evolving population, (3) low rates of parallel evolution and convergent evolution between species, and (4) the probability of parallel and convergent evolution between species is strongly effected by divergence.
Adaptive mutations stabilize secondary structure in a critical regulatory region
Not all silent mutations are neutral. The beneficial silent mutation U1685C was observed in each of three replicate lines during adaptation to high temperature growth. Inspection of the genetic grounds on which these mutations appeared revealed no evidence that its fixation was due to hitchhiking. U1685 occurs in a stem loop region that has been shown to be important in the regulation of expression of the lysis gene - the structure prohibits access of the ribosome to the start codon suppressing expression. Previous mutagenesis studies by other groups have shown that mutations in this region that destabilize the hairpin leads to early lysis and lower burst sizes, while mutations that stabilize this region leads to delayed lysis. Given a number of factors, such as host density, their is likely an optimal timing of lysis. We hypothesize that growth of the wild-type phage at higher temperatures experiences a destabilization of the hair pin. U1685C restores the optimal stability of this region. You can see below the predicted destabilization of the wild-type stem-loop region at the selected temperature (43C), and the derived stability at 43C in the high temperature adapted phage.
A method for estimating 2Nes from temporal allele frequency data (Genetics, 2008, 179:497–502)
We develop a new method for estimating effective population sizes, Ne, and selection coefficients, s, from time-series data of allele frequencies sampled from a single diallelic locus. The method is based on calculating transition probabilities, using a numerical solution of the diffusion process, and assuming independent binomial sampling from this diffusion process at each time point. We apply the method in two example applications. First, we estimate selection coefficients acting on the CCR5-Δ32 mutation on the basis of published samples of contemporary and ancient human DNA. We show that the data are compatible with the assumption of s = 0, although moderate amounts of selection acting on this mutation cannot be excluded. In our second example (see below), we estimate the selection coefficient acting on a mutation segregating in an experimental phage population. We show that the selection coefficient acting on this mutation is s ≅ 0.43.
Time-series data for C206U:
Likelihood surface: