Simulation of Genomes: A Review
---
paper_title: Significant variation in haplotype block structure but conservation in tagSNP patterns among global populations

paper_content:

The initial belief that haplotype block boundaries and haplotypes were largely shared across populations was a foundation for constructing a haplotype map of the human genome using common SNP markers. The HapMap data document the generality of a block-like pattern of linkage disequilibrium (LD) with regions of low and high haplotype diversity but differences among the populations. Studies of many additional populations demonstrate that LD patterns can be highly variable among populations both across and within geographic regions. Because of this variation, emphasis has shifted to the generalizability of tagSNPs, those SNPs that capture the bulk of variation in a region. We have examined the LD and tagSNP patterns based upon over 2000 individual samples in 38 populations and 134 SNPs in 10 genetically independent loci for a total of 517 kb with an average density of 1 SNP/5 kb. Four different ‘block’ definitions and the pairwise LD tagSNP selection algorithm have been applied. Our results not only confirm large variation in block partition among populations from different regions (agreeing with previous studies including the HapMap) but also show that significant variation can occur among populations within geographic regions. None of the block-defining algorithms produces a consistent pattern within or across all geographic groups. In contrast, tagSNP transferability is much greater than the similarity of LD patterns and, although not perfect, some generalizations of transferability are possible. The analyses show an asymmetric pattern of tagSNP transferability coinciding with the subsetting of variation attributed to the spread of modern humans around the world.
---
paper_title: Haplotype Block Structures Show Significant Variation Among Populations

paper_content:

Recent studies suggest that haplotypes tend to have block-like structures throughout the human genome. Several methods were proposed for haplotype block partitioning and for tagging single-nucleotide polymorphism (SNP) identification. In population genetics studies, several research groups compared block structures across human populations. However, the measures used to quantify population similarity are either less than satisfactory or nonexistent. In this article, we propose several similarity measures to facilitate the comparisons of haplotype structures, namely block boundaries and tagging SNPs, across populations. With these measures, we can more objectively compare haplotype block structures and tagging SNP sets between different populations. In addition, these measures allow us to compare the results of different methods for block partition and tagging SNP identification. When we applied these measures to a real data set on chromosome 10 in 16 worldwide populations, we found that in this genome region: 1) haplotype block boundaries vary among populations, with European and some African populations showing similar boundaries but other populations showing other patterns; 2) tagging SNP sets are generally similar for populations with similar haplotype block structures but differ if the block structures differ; and 3) all but one of the block finding methods we tested yield consistent results, although variations exist regarding consistency. Our tentative results show that at least in the genome region studied, it is unlikely that a common haplotype pattern exists for all human populations: many populations, even in the same geographical region, may have different haplotype patterns. Genet. Epidemiol. & 2004 Wiley-Liss, Inc.
---
paper_title: A haplotype map of the human genome

paper_content:

Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.
---
paper_title: Simulations Provide Support for the Common Disease–Common Variant Hypothesis

paper_content:

The success of mapping genes involved in complex diseases, using association or linkage disequilibrium methods, depends heavily on the number and frequency of susceptibility alleles of these genes. These methods will be economically and statistically feasible if common diseases are usually influenced by one or a few susceptibility alleles at each locus (common disease–common variant, CDCV, hypothesis), but not so if there is a high degree of allelic heterogeneity. Here, we use forward-time population simulations to investigate the impact of various genetic and demographic factors on the allelic spectra of human diseases, on the basis of two models proposed by Reich and Lander and by Pritchard. Factors considered are more complex demographies, a finite-allele mutation model, population structure and migration, and interaction between disease susceptibility loci. The conclusion is that the CDCV hypothesis holds and that the phenomenon is caused by transient effects of demography (population expansion). As a result, we devise a multilocus generalization of the Reich and Lander model and demonstrate how interaction between loci with respect to their response to selection may lead to complex effects. We discuss the implications for mapping of complex diseases.
---
paper_title: A second generation human haplotype map of over 3.1 million SNPs

paper_content:

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.
---
paper_title: Ancestral alleles and population origins: inferences depend on mutation rate.

paper_content:

Previous studies have found that at most human loci, ancestral alleles are "African," in the sense that they reach their highest frequency there. Conventional wisdom holds that this reflects a recent African origin of modern humans. This paper challenges that view by showing that the empirical pattern (of elevated allele frequencies within Africa) is not as pervasive as has been thought. We confirm this African bias in a set of mainly protein-coding loci, but find a smaller bias in Alu insertion polymorphisms, and an even smaller bias in noncoding loci. Thus, the strong bias that was originally observed must reflect some factor that varies among data sets--something other than population history. This factor may be the per-locus mutation rate: the African bias is most pronounced in loci where this rate is high. The distribution of ancestral alleles among populations has been studied using 2 methods. One of these involves comparing the fractions of loci that reach maximal frequency in each population. The other compares the average frequencies of ancestral alleles. The first of these methods reflects history in a manner that depends on the mutation rate. When that rate is high, ancestral alleles at most loci reach their highest frequency in the ancestral population. When that rate is low, the reverse is true. The other method--comparing averages--is unresponsive. Average ancestral allele frequencies are affected neither by mutation rate nor by the history of population size and migration. In the absence of selection and ascertainment bias, they should be the same everywhere. This is true of one data set, but not of 2 others. This also suggests the action of some factor, such as selection or ascertainment bias, that varies among data sets.
---
paper_title: Meiotic recombination hot spots and human DNA diversity

paper_content:

Meiotic recombination plays a key role in the maintenance of sequence diversity in the human genome. However, little is known about the fine-scale distribution and processes of recombination in human chromosomes, or how these impact on patterns of human diversity. We have therefore developed sperm typing systems that allow human recombination to be analysed at very high resolution. The emerging picture is that human crossovers are far from randomly distributed but instead are targeted into very narrow hot spots that can profoundly influence patterns of haplotype diversity in the human genome. These hot spots provide fundamental information on processes of human crossover and gene conversion, as well as evidence that they can violate basic rules of Mendelian inheritance.
---
paper_title: Islands of linkage disequilibrium

paper_content:

A detailed knowledge of patterns of linkage disequilibrium in human populations is widely seen as a prerequisite for effective population-based disease gene mapping. New data suggest that linkage disequilibrium is highly structured into discrete blocks of sequence separated by hot spots of recombination.
---
paper_title: Brief communication: the Thule migration: rejecting population histories using computer simulation.

paper_content:

Locked within our genetic code are the histories of our genes and the genes of our ancestors. Deciphering a population's history from genetic data often involves lengthy investigations of many loci for many individuals. We test hypothetical population histories of the Thule expansion using a new coalescent simulation method that uses little more than mitochondrial haplogroup data. This new methodology rejects a severe bottleneck at expansion and reveals the range of probable population histories on which to focus future research.
---
paper_title: Strong correlation between meiotic crossovers and haplotype structure in a 2.5-Mb region on the long arm of chromosome 21.

paper_content:

Although the haplotype structure of the human genome has been studied in great detail, very little is known about the mechanisms underlying its formation. To investigate the role of meiotic recombination on haplotype block formation, single nucleotide polymorphisms were selected at a high density from a 2.5-Mb region of human chromosome 21. Direct analysis of meiotic recombination by high-throughput multiplex genotyping of 662 single sperm identifies 41 recombinants. The crossovers were nonrandomly distributed within 16 small areas. All, except one, of these crossovers fall in areas where the haplotype structure exhibits breakdown, displaying a strong statistically positive association between crossovers and haplotype block breaks. The data also indicate a particular clustered distribution of recombination hotspots within the region. This finding supports the hypothesis that meiotic recombination makes a primary contribution to haplotype block formation in the human genome.
---
paper_title: Genealogical trees, coalescent theory and the analysis of genetic polymorphisms

paper_content:

Key Points Genetic polymorphism results from mutations along the branches of unknown genealogical trees, so genealogical models are needed for the analysis of polymorphism data. The stochastic process known as 'the coalescent' has become the primary tool for modelling genealogies. An extension of classical population-genetics models, the coalescent views lineages as randomly choosing parents going backwards in time. The coalescent is a flexible model that accommodates phenomena such as recombination, age structure, geographical structure and population size change. Efficient simulations and inference based on the coalescent allow tests about causes of genetic variation and estimation of demographic parameters, such as migration rates. Unlike methods borrowed from phylogenetics that attempt to draw inferences from estimated genealogies, the coalescent treats genealogies as random and can naturally handle complex models that incorporate phenomena such as migration, selection and recombination. In the age of genomic polymorphism data, coalescent-based methods will acquire greater roles in such areas as the inference of evolutionary history, the study of linkage disequilibrium in the human genome and the population genetics of infectious disease.AbstractImprovements in genotyping technologies have led to the increased use of genetic polymorphism for inference about population phenomena, such as migration and selection. Such inference presents a challenge, because polymorphism data reflect a unique, complex, non-repeatable evolutionary history. Traditional analysis methods do not take this into account. A stochastic process known as the 'coalescent' presents a coherent statistical framework for analysis of genetic polymorphisms.
---
paper_title: CoaSim: A flexible environment for simulating genetic data under coalescent models

paper_content:

Background: Coalescent simulations are playing a large role in interpreting large scale intraspecific sequence or polymorphism surveys and for planning and evaluating association studies. Coalescent simulations of data sets under different models can be compared to the actual data to test the importance of different evolutionary factors and thus get insight into these. Results: We have created the CoaSim application as a flexible environment for Monte Carlo simulation of various types of genetic data under equilibrium and non-equilibrium coalescent processes for a variety of applications. Interaction with the tool is through the Guile version of the Scheme scripting language. Scheme scripts for many standard and advanced applications are provided and these can easily be modified by the user for a much wider range of applications. A graphical user interface with less functionality and flexibility is also included. It is primarily intended as an exploratory and educational tool Conclusion: CoaSim is a powerful tool because of its flexibility and ease of use. This is illustrated through very varied uses of the application, e.g. evaluation of association mapping methods, parametric bootstrapping, and design and choice of markers for specific questions
---
paper_title: Fast "coalescent" simulation

paper_content:

BackgroundThe amount of genome-wide molecular data is increasing rapidly, as is interest in developing methods appropriate for such data. There is a consequent increasing need for methods that are able to efficiently simulate such data. In this paper we implement the sequentially Markovian coalescent algorithm described by McVean and Cardin and present a further modification to that algorithm which slightly improves the closeness of the approximation to the full coalescent model. The algorithm ignores a class of recombination events known to affect the behavior of the genealogy of the sample, but which do not appear to affect the behavior of generated samples to any substantial degree.ResultsWe show that our software is able to simulate large chromosomal regions, such as those appropriate in a consideration of genome-wide data, in a way that is several orders of magnitude faster than existing coalescent algorithms.ConclusionThis algorithm provides a useful resource for those needing to simulate large quantities of data for chromosomal-length regions using an approach that is much more efficient than traditional coalescent models.
---
paper_title: Coalescing into the 21st Century: An Overview and Prospects of Coalescent Theory

paper_content:

Abstract Coalescent theory represents the most significant progress in theoretical population genetics in the past two decades of this century. It is now widely recognized as a cornerstone for rigorous statistical analyses of molecular data from populations. In the future, challenges from the rapidly expanding body of molecular data will continue to inject fresh blood into the development of coalescent theory. As the 21st century looms, we review recent progress in coalescent theory and discuss some prospects for future developments, particularly with regard to human population genetics.
---
paper_title: splatche: a program to simulate genetic diversity taking into account environmental heterogeneity

paper_content:

We present a program called SPLATCHE (SPatiaL And Temporal Coalescences in Heterogeneous Environments) to simulate the molecular diversity of samples of genes in an environmentally heterogeneous world. Simulations are performed by, first, simulating the colonization of the world using environmental information to constrain migrations and local densities. These simulated densities and migration rates recorded over time and space are then used to simulate genetic diversity under a coalescent framework. The program thus virtually allows the translation of ecological information into molecular diversity, a novel approach that can be used to study the effect of climatic change on genetic diversity.
---
paper_title: Population Dynamics of HIV-1 Inferred From Gene Sequences

paper_content:

A method for the estimation of population dynamic history from sequence data is described and used to investigate the past population dynamics of HIV-1 subtypes A and B. Using both gag and env gene alignments the effective population size of each subtype is estimated and found to be surprisingly small. This may be a result of the selective sweep of mutations through the population, or may indicate an important role of genetic drift in the fixation of mutations. The implications of these results for the spread of drug-resistant mutations and transmission dynamics, and also the roles of selection and recombination in shaping HIV-1 genetic diversity, are discussed. A larger estimated effective population size for subtype A may be the result of differences in time of origin, transmission dynamics, and/or population structure. To investigate the importance of population structure a model of population subdivision was fitted to each subtype, although the improvement in likelihood was found to be nonsignificant.
---
paper_title: SelSim: a program to simulate population genetic data with natural selection and recombination

paper_content:

Summary: SelSim is a program for Monte Carlo simulation of DNA polymorphism data for a recombining region within which a single bi-allelic site has experienced natural selection. SelSim allows simulation from either a fully stochastic model of, or deterministic approximations to, natural selection within a coalescent framework. A number of different mutation models are available for simulating surrounding neutral variation. The package enables a detailed exploration of the effects of different models and strengths of selection on patterns of diversity. This provides a tool for the statistical analysis of both empirical data and methods designed to detect natural selection. ::: ::: Availability: http://www.stats.ox.ac.uk/mathgen/software.html ::: ::: Supplementary information: http://www.stats.ox.ac.uk/mathgen/software.html
---
paper_title: Generating samples under a Wright-Fisher neutral model of genetic variation

paper_content:

Summary: A Monte Carlo computer program is available to generate samples drawn from a population evolving according to a Wright–Fisher neutral model. The program assumes an infinite-sites model of mutation, and allows recombination, gene conversion, symmetric migration among subpopulations, and a variety of demographic histories. The samples produced can be used to investigate the sampling properties of any sample statistic under these neutral models. Availability: The source code for the program (in the language C) is available at http://home.uchicago.edu/
---
paper_title: Genetics and population analysis Serial SimCoal : A population genetics model for data from multiple populations and points in time

paper_content:

Summary: We present Serial SimCoal, a program that models population genetic data from multiple time points, as with ancient DNA data. An extension of SIMCOAL, it also allows simultaneous modeling of complex demographic histories, and migration between multiple populations. Further, we incorporate a statistical package to calculate relevant summary statistics, which, for the first time allows users to investigate the statistical power provided by, conduct hypothesis-testing with, and explore sample size limitations of ancient DNA data. ::: ::: Availability: Source code and Windows/Mac executables at http://www.stanford.edu/group/hadlylab/ssc.html ::: ::: contact: senka@stanford.edu
---
paper_title: Perfect Simulation From Nonneutral Population Genetic Models: Variable Population Size and Population Subdivision

paper_content:

We show how the idea of monotone coupling from the past can produce simple algorithms for simulating samples at a nonneutral locus under a range of demographic models. We specifically consider a biallelic locus and either a general variable population size mode or a general migration model for population subdivision. We investigate the effect of demography on the efficacy of selection and the effect of selection on genetic divergence between populations.
---
paper_title: Positive Selection Versus Demography: Evolutionary Inferences Based on an Unusual Haplotype Structure in Drosophila simulans

paper_content:

Coalescent simulations were used to investigate the possible role of population subdivision and history in shaping nucleotide variation in a recombining 88-kb genomic fragment of Drosophila simulans displaying an unusual large-scale haplotype structure. The multilocus analysis, based on summary statistics using specific demographic null models under recombination, indicates that the observed levels of linkage disequilibrium differed significantly from the values expected under different bottleneck and population admixture scenarios. These results indicate that demography alone may not account for the observed pattern of variation and support the previous claim that the data are better described by a model in which an adaptive mutation has not yet gone to fixation.
---
paper_title: Haplotype Evolution and Linkage Disequilibrium: A Simulation Study

paper_content:

We simulated the evolution of a three-site haplotype system, two restriction fragment length polymorphisms flanking one short tandem repeat polymorphism, under five different demographic scenarios, three with constant population size and two with population growth. The simulation was designed to observe the effects of population history, recombination fraction, and mutation rate on allele and haplotype frequencies, haplotype diversity, frequency of ancestral alleles, and linkage disequilibrium. The known ancestral haplotypes were often found at low frequencies and even became extinct after 5, 000 generations, especially with small effective population sizes. The original linkage disequilibrium was eroded and even reversed.
---
paper_title: Sequence-Level Population Simulations Over Large Genomic Regions

paper_content:

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.
---
paper_title: Forward-Time Simulations of Human Populations with Complex Diseases

paper_content:

Due to the increasing power of personal computers, as well as the availability of flexible forward-time simulation programs like simuPOP, it is now possible to simulate the evolution of complex human diseases using a forward-time approach. This approach is potentially more powerful than the coalescent approach since it allows simulations of more than one disease susceptibility locus using almost arbitrary genetic and demographic models. However, the application of such simulations has been deterred by the lack of a suitable simulation framework. For example, it is not clear when and how to introduce disease mutants—especially those under purifying selection—to an evolving population, and how to control the disease allele frequencies at the last generation. In this paper, we introduce a forward-time simulation framework that allows us to generate large multi-generation populations with complex diseases caused by unlinked disease susceptibility loci, according to specified demographic and evolutionary properties. Unrelated individuals, small or large pedigrees can be drawn from the resulting population and provide samples for a wide range of study designs and ascertainment methods. We demonstrate our simulation framework using three examples that map genes associated with affection status, a quantitative trait, and the age of onset of a hypothetical cancer, respectively. Nonadditive fitness models, population structure, and gene–gene interactions are simulated. Case-control, sibpair, and large pedigree samples are drawn from the simulated populations and are examined by a variety of gene-mapping methods.
---
paper_title: The limits of theoretical population genetics.

paper_content:

THE purpose here is to discuss the limits of theoretical population genetics. This 100-year-old field now sits close to the heart of modern biology. Theoretical population genetics is the framework for studies of human history (Reich et al. 2002) and the foundation for association studies, which aim to map the genes that cause human disease (Jorde 1995). Arguably of more importance, theoretical population genetics underlies our knowledge of within-species variation across the globe and for all kinds of life. In light of its many incarnations and befitting its ties to evolutionary biology, the limits of theoretical population genetics are recognized to be changing over time, with a number of new paths to follow. Stepping into this future, it will be important to develop new approximations that reflect new data and not to let well-accepted models diminish the possibilities.
---

Title: Simulation of Genomes: A Review

Section 1: INTRODUCTION
Description 1: This section elaborates on the growing importance of simulations in population genetics, specifically in understanding evolutionary patterns and the impact of historical factors on genetic data.

Section 2: COALESCENT SIMULATORS
Description 2: This section discusses various coalescent-based simulation tools, their efficiencies, specific features, and applications to simulate large DNA fragments under complex evolutionary models.

Section 3: FORWARD SIMULATORS
Description 3: This section examines forward simulation methods, detailing their advantages over coalescent simulations, various available tools, and their capacities to simulate complex genetic and evolutionary scenarios.

Section 4: CONCLUSIONS
Description 4: This section summarizes the significance of simulation software in evolutionary biology research, future directions, and the anticipated development of more sophisticated algorithms to handle genome evolution studies.