@phdthesis{200,
abstract = {This thesis is concerned with the inference of current population structure based on geo-referenced genetic data. The underlying idea is that population structure affects its spatial genetic structure. Therefore, genotype information can be utilized to estimate important demographic parameters such as migration rates. These indirect estimates of population structure have become very attractive, as genotype data is now widely available. However, there also has been much concern about these approaches. Importantly, genetic structure can be influenced by many complex patterns, which often cannot be disentangled. Moreover, many methods merely fit heuristic patterns of genetic structure, and do not build upon population genetics theory. Here, I describe two novel inference methods that address these shortcomings. In Chapter 2, I introduce an inference scheme based on a new type of signal, identity by descent (IBD) blocks. Recently, it has become feasible to detect such long blocks of genome shared between pairs of samples. These blocks are direct traces of recent coalescence events. As such, they contain ample signal for inferring recent demography. I examine sharing of IBD blocks in two-dimensional populations with local migration. Using a diffusion approximation, I derive formulas for an isolation by distance pattern of long IBD blocks and show that sharing of long IBD blocks approaches rapid exponential decay for growing sample distance. I describe an inference scheme based on these results. It can robustly estimate the dispersal rate and population density, which is demonstrated on simulated data. I also show an application to estimate mean migration and the rate of recent population growth within Eastern Europe. Chapter 3 is about a novel method to estimate barriers to gene flow in a two dimensional population. This inference scheme utilizes geographically localized allele frequency fluctuations - a classical isolation by distance signal. The strength of these local fluctuations increases on average next to a barrier, and there is less correlation across it. I again use a framework of diffusion of ancestral lineages to model this effect, and provide an efficient numerical implementation to fit the results to geo-referenced biallelic SNP data. This inference scheme is able to robustly estimate strong barriers to gene flow, as tests on simulated data confirm.},
author = {Ringbauer, Harald},
pages = {146},
publisher = {IST Austria},
title = {{Inferring recent demography from spatial genetic structure}},
doi = {10.15479/AT:ISTA:th_963},
year = {2018},
}
@article{565,
abstract = {We re-examine the model of Kirkpatrick and Barton for the spread of an inversion into a local population. This model assumes that local selection maintains alleles at two or more loci, despite immigration of alternative alleles at these loci from another population. We show that an inversion is favored because it prevents the breakdown of linkage disequilibrium generated by migration; the selective advantage of an inversion is proportional to the amount of recombination between the loci involved, as in other cases where inversions are selected for. We derive expressions for the rate of spread of an inversion; when the loci covered by the inversion are tightly linked, these conditions deviate substantially from those proposed previously, and imply that an inversion can then have only a small advantage. },
author = {Charlesworth, Brian and Barton, Nicholas H},
journal = {Genetics},
number = {1},
pages = {377 -- 382},
publisher = {Genetics },
title = {{The spread of an inversion with migration and selection}},
doi = {10.1534/genetics.117.300426},
volume = {208},
year = {2018},
}
@article{1111,
abstract = {Adaptation depends critically on the effects of new mutations and their dependency on the genetic background in which they occur. These two factors can be summarized by the fitness landscape. However, it would require testing all mutations in all backgrounds, making the definition and analysis of fitness landscapes mostly inaccessible. Instead of postulating a particular fitness landscape, we address this problem by considering general classes of landscapes and calculating an upper limit for the time it takes for a population to reach a fitness peak, circumventing the need to have full knowledge about the fitness landscape. We analyze populations in the weak-mutation regime and characterize the conditions that enable them to quickly reach the fitness peak as a function of the number of sites under selection. We show that for additive landscapes there is a critical selection strength enabling populations to reach high-fitness genotypes, regardless of the distribution of effects. This threshold scales with the number of sites under selection, effectively setting a limit to adaptation, and results from the inevitable increase in deleterious mutational pressure as the population adapts in a space of discrete genotypes. Furthermore, we show that for the class of all unimodal landscapes this condition is sufficient but not necessary for rapid adaptation, as in some highly epistatic landscapes the critical strength does not depend on the number of sites under selection; effectively removing this barrier to adaptation.},
author = {Heredia, Jorge and Trubenova, Barbora and Sudholt, Dirk and Paixao, Tiago},
issn = {00166731},
journal = {Genetics},
number = {2},
pages = {803 -- 825},
publisher = {Genetics Society of America},
title = {{Selection limits to adaptive walks on correlated landscapes}},
doi = {10.1534/genetics.116.189340},
volume = {205},
year = {2017},
}
@article{1077,
abstract = {Viral capsids are structurally constrained by interactions among the amino acids (AAs) of their constituent proteins. Therefore, epistasis is expected to evolve among physically interacting sites and to influence the rates of substitution. To study the evolution of epistasis, we focused on the major structural protein of the fX174 phage family by first reconstructing the ancestral protein sequences of 18 species using a Bayesian statistical framework. The inferred ancestral reconstruction differed at eight AAs, for a total of 256 possible ancestral haplotypes. For each ancestral haplotype and the extant species, we estimated, in silico, the distribution of free energies and epistasis of the capsid structure. We found that free energy has not significantly increased but epistasis has. We decomposed epistasis up to fifth order and found that higher-order epistasis sometimes compensates pairwise interactions making the free energy seem additive. The dN/dS ratio is low, suggesting strong purifying selection, and that structure is under stabilizing selection. We synthesized phages carrying ancestral haplotypes of the coat protein gene and measured their fitness experimentally. Our findings indicate that stabilizing mutations can have higher fitness, and that fitness optima do not necessarily coincide with energy minima.},
author = {Fernandes Redondo, Rodrigo A and Vladar, Harold and Włodarski, Tomasz and Bollback, Jonathan P},
issn = {17425689},
journal = {Journal of the Royal Society Interface},
number = {126},
publisher = {Royal Society of London},
title = {{Evolutionary interplay between structure, energy and epistasis in the coat protein of the fX174 phage family}},
doi = {10.1098/rsif.2016.0139},
volume = {14},
year = {2017},
}
@article{910,
abstract = {Frequency-independent selection is generally considered as a force that acts to reduce the genetic variation in evolving populations, yet rigorous arguments for this idea are scarce. When selection fluctuates in time, it is unclear whether frequency-independent selection may maintain genetic polymorphism without invoking additional mechanisms. We show that constant frequency-independent selection with arbitrary epistasis on a well-mixed haploid population eliminates genetic variation if we assume linkage equilibrium between alleles. To this end, we introduce the notion of frequency-independent selection at the level of alleles, which is sufficient to prove our claim and contains the notion of frequency-independent selection on haploids. When selection and recombination are weak but of the same order, there may be strong linkage disequilibrium; numerical calculations show that stable equilibria are highly unlikely. Using the example of a diallelic two-locus model, we then demonstrate that frequency-independent selection that fluctuates in time can maintain stable polymorphism if linkage disequilibrium changes its sign periodically. We put our findings in the context of results from the existing literature and point out those scenarios in which the possible role of frequency-independent selection in maintaining genetic variation remains unclear.
},
author = {Novak, Sebastian and Barton, Nicholas H},
journal = {Genetics},
number = {2},
pages = {653 -- 668},
publisher = {Genetics Society of America},
title = {{When does frequency-independent selection maintain genetic variation?}},
doi = {10.1534/genetics.117.300129},
volume = {207},
year = {2017},
}
@article{953,
abstract = {The role of natural selection in the evolution of adaptive phenotypes has undergone constant probing by evolutionary biologists, employing both theoretical and empirical approaches. As Darwin noted, natural selection can act together with other processes, including random changes in the frequencies of phenotypic differences that are not under strong selection, and changes in the environment, which may reflect evolutionary changes in the organisms themselves. As understanding of genetics developed after 1900, the new genetic discoveries were incorporated into evolutionary biology. The resulting general principles were summarized by Julian Huxley in his 1942 book Evolution: the modern synthesis. Here, we examine how recent advances in genetics, developmental biology and molecular biology, including epigenetics, relate to today's understanding of the evolution of adaptations. We illustrate how careful genetic studies have repeatedly shown that apparently puzzling results in a wide diversity of organisms involve processes that are consistent with neo-Darwinism. They do not support important roles in adaptation for processes such as directed mutation or the inheritance of acquired characters, and therefore no radical revision of our understanding of the mechanism of adaptive evolution is needed.},
author = {Charlesworth, Deborah and Barton, Nicholas H and Charlesworth, Brian},
journal = {Proceedings of the Royal Society of London Series B Biological Sciences},
number = {1855},
publisher = {Royal Society, The},
title = {{The sources of adaptive evolution}},
doi = {10.1098/rspb.2016.2864},
volume = {284},
year = {2017},
}
@article{1351,
abstract = {The behaviour of gene regulatory networks (GRNs) is typically analysed using simulation-based statistical testing-like methods. In this paper, we demonstrate that we can replace this approach by a formal verification-like method that gives higher assurance and scalability. We focus on Wagner’s weighted GRN model with varying weights, which is used in evolutionary biology. In the model, weight parameters represent the gene interaction strength that may change due to genetic mutations. For a property of interest, we synthesise the constraints over the parameter space that represent the set of GRNs satisfying the property. We experimentally show that our parameter synthesis procedure computes the mutational robustness of GRNs—an important problem of interest in evolutionary biology—more efficiently than the classical simulation method. We specify the property in linear temporal logic. We employ symbolic bounded model checking and SMT solving to compute the space of GRNs that satisfy the property, which amounts to synthesizing a set of linear constraints on the weights.},
author = {Giacobbe, Mirco and Guet, Calin C and Gupta, Ashutosh and Henzinger, Thomas A and Paixao, Tiago and Petrov, Tatjana},
issn = {00015903},
journal = {Acta Informatica},
number = {8},
pages = {765 -- 787},
publisher = {Springer},
title = {{Model checking the evolution of gene regulatory networks}},
doi = {10.1007/s00236-016-0278-x},
volume = {54},
year = {2017},
}
@inproceedings{1112,
abstract = {There has been renewed interest in modelling the behaviour of evolutionary algorithms by more traditional mathematical objects, such as ordinary differential equations or Markov chains. The advantage is that the analysis becomes greatly facilitated due to the existence of well established methods. However, this typically comes at the cost of disregarding information about the process. Here, we introduce the use of stochastic differential equations (SDEs) for the study of EAs. SDEs can produce simple analytical results for the dynamics of stochastic processes, unlike Markov chains which can produce rigorous but unwieldy expressions about the dynamics. On the other hand, unlike ordinary differential equations (ODEs), they do not discard information about the stochasticity of the process. We show that these are especially suitable for the analysis of fixed budget scenarios and present analogs of the additive and multiplicative drift theorems for SDEs. We exemplify the use of these methods for two model algorithms ((1+1) EA and RLS) on two canonical problems(OneMax and LeadingOnes).},
author = {Paixao, Tiago and Pérez Heredia, Jorge},
booktitle = {Proceedings of the 14th ACM/SIGEVO Conference on Foundations of Genetic Algorithms},
isbn = {978-145034651-1},
location = {Copenhagen, Denmark},
pages = {3 -- 11},
publisher = {ACM},
title = {{An application of stochastic differential equations to evolutionary algorithms}},
doi = {10.1145/3040718.3040729},
year = {2017},
}
@article{954,
abstract = {Understanding the relation between genotype and phenotype remains a major challenge. The difficulty of predicting individual mutation effects, and particularly the interactions between them, has prevented the development of a comprehensive theory that links genotypic changes to their phenotypic effects. We show that a general thermodynamic framework for gene regulation, based on a biophysical understanding of protein-DNA binding, accurately predicts the sign of epistasis in a canonical cis-regulatory element consisting of overlapping RNA polymerase and repressor binding sites. Sign and magnitude of individual mutation effects are sufficient to predict the sign of epistasis and its environmental dependence. Thus, the thermodynamic model offers the correct null prediction for epistasis between mutations across DNA-binding sites. Our results indicate that a predictive theory for the effects of cis-regulatory mutations is possible from first principles, as long as the essential molecular mechanisms and the constraints these impose on a biological system are accounted for.},
author = {Lagator, Mato and Paixao, Tiago and Barton, Nicholas H and Bollback, Jonathan P and Guet, Calin C},
issn = {2050084X},
journal = {eLife},
publisher = {eLife Sciences Publications},
title = {{On the mechanistic nature of epistasis in a canonical cis-regulatory element}},
doi = {10.7554/eLife.25192},
volume = {6},
year = {2017},
}
@article{1199,
abstract = {Much of quantitative genetics is based on the ‘infinitesimal model’, under which selection has a negligible effect on the genetic variance. This is typically justified by assuming a very large number of loci with additive effects. However, it applies even when genes interact, provided that the number of loci is large enough that selection on each of them is weak relative to random drift. In the long term, directional selection will change allele frequencies, but even then, the effects of epistasis on the ultimate change in trait mean due to selection may be modest. Stabilising selection can maintain many traits close to their optima, even when the underlying alleles are weakly selected. However, the number of traits that can be optimised is apparently limited to ~4Ne by the ‘drift load’, and this is hard to reconcile with the apparent complexity of many organisms. Just as for the mutation load, this limit can be evaded by a particular form of negative epistasis. A more robust limit is set by the variance in reproductive success. This suggests that selection accumulates information most efficiently in the infinitesimal regime, when selection on individual alleles is weak, and comparable with random drift. A review of evidence on selection strength suggests that although most variance in fitness may be because of alleles with large Nes, substantial amounts of adaptation may be because of alleles in the infinitesimal regime, in which epistasis has modest effects.},
author = {Barton, Nicholas H},
journal = {Heredity},
pages = {96 -- 109},
publisher = {Nature Publishing Group},
title = {{How does epistasis influence the response to selection?}},
doi = {10.1038/hdy.2016.109},
volume = {118},
year = {2017},
}