title: Critical assessment of coalescent simulators in modeling recombination hotspots in genomic sequences.
abstract: BACKGROUND
  Coalescent simulation is pivotal for understanding population evolutionary models and demographic histories, as well as for developing novel analytical methods for genetic association studies for DNA sequence data. A plethora of coalescent simulators are developed, but selecting the most appropriate program remains challenging.
  
  
  RESULTS
  We extensively compared performances of five widely used coalescent simulators - Hudson's ms, msHOT, MaCS, Simcoal2, and fastsimcoal, to provide a practical guide considering three crucial factors, 1) speed, 2) scalability and 3) recombination hotspot position and intensity accuracy. Although ms represents a popular standard coalescent simulator, it lacks the ability to simulate sequences with recombination hotspots. An extended program msHOT has compensated for the deficiency of ms by incorporating recombination hotspots and gene conversion events at arbitrarily chosen locations and intensities, but remains limited in simulating long stretches of DNA sequences. Simcoal2, based on a discrete generation-by-generation approach, could simulate more complex demographic scenarios, but runs comparatively slow. MaCS and fastsimcoal, both built on fast, modified sequential Markov coalescent algorithms to approximate standard coalescent, are much more efficient whilst keeping salient features of msHOT and Simcoal2, respectively. Our simulations demonstrate that they are more advantageous over other programs for a spectrum of evolutionary models. To validate recombination hotspots, LDhat 2.2 rhomap package, sequenceLDhot and Haploview were compared for hotspot detection, and sequenceLDhot exhibited the best performance based on both real and simulated data.
  
  
  CONCLUSIONS
  While ms remains an excellent choice for general coalescent simulations of DNA sequences, MaCS and fastsimcoal are much more scalable and flexible in simulating a variety of demographic events under different recombination hotspot models. Furthermore, sequenceLDhot appears to give the most optimal performance in detecting and validating cross-over hotspots.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
authors.affiliation: Center for Bioinformatics and Genomics, Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, Suite 2001, New Orleans, LA 70112, USA. tniu@tulane.edu.
authors.forename: Tianhua
authors.initials: T
authors.lastname: Niu
mesh_terms: D000465:Algorithms; D002874:Chromosome Mapping / Q000379:methods; D003198:Computer Simulation; D030541:Databases, Genetic; D019143:Evolution, Molecular; D005828:Genetics, Population / Q000379:methods*; D016678:Genome / Q000235:genetics; D023281:Genomics / Q000379:methods*; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA / Q000379:methods*