Sequence-level population simulations over large genomic regions

Abstract

Simulation is an invaluable tool for investigating the effects of various population genetics modeling assumptions on resulting patterns of genetic diversity, and for assessing the performance of statistical techniques, for example those designed to detect and measure the genomic effects of selection. It is also used to investigate the effectiveness of various design options for genetic association studies. Backward-in-time simulation methods are computationally efficient and have become widely used since their introduction in the 1980s. The forward-in-time approach has substantial advantages in terms of accuracy and modeling flexibility, but at greater computational cost. We have developed flexible and efficient simulation software and a rescaling technique to aid computational efficiency that together allow the simulation of sequence-level data over large genomic regions in entire diploid populations under various scenarios for demography, mutation, selection, and recombination, the latter including hotspots and gene conversion. Our forward evolution of genomic regions (FREGENE) software is freely available from www.ebi.ac.uk/projects/BARGEN together with an ancillary program to generate phenotype labels, either binary or quantitative. In this article we discuss limitations of coalescent-based simulation, introduce the rescaling technique that makes large-scale forward-in-time simulation feasible, and demonstrate the utility of various features of FREGENE, many not previously available.

Figure 1.—

Trajectories of selected variants that reached fixation in simulation studies (Table 1). Red curves correspond to negatively selected alleles (s < 0).

Figure 2.—

Per-site homozygosity over generations for simulations described in Table 1. The dashed horizontal line shows the theoretical equilibrium value for the neutral simulations. Vertical dotted lines indicate the generations at which, in the scaled directional simulation, selected sites with s > 0.05 went to fixation.

Figure 3.—

Tajima's D in 50-kb windows after 300,000 generations (top) and 150,000 generations (bottom). The vertical dotted line (top) indicates the location of the unique site under positive selection that went to fixation within the final 3000 generations. The vertical dashed lines (bottom) indicate selected sites that were polymorphic throughout the preceding 10,000 generations.