Recent advances in sequencing technology is enabling fast and cost-effective generation of sequence data. Soon, whole-genome sequencing will become a routine assay, opening up new opportunities for biomedical research and related fields. The overall objective of this proposal is to develop accurate, scalable computational methods for whole-genome variation study, both by developing a new theoretical framework for studying population genetics models and by improving the key mathematical component underlying various statistical tools for genome analysis. A common thread that runs through this proposal is recombination. Both crossover and gene conversion recombinations will be considered.
The specific aims of the proposed research are: (1) Develop and apply a new theoretical framework that complements the standard coalescent theory when the rate of recombination is moderate to large, thus providing a new set of useful analytic tools to the population genomics community. (2) Devise principled methods to derive accurate multi-locus conditional sampling distributions directly from the underlying population genetics model. Improve the accuracy of a wide range of statistical methods for genome analysis that utilize conditional sampling distributions. (3) Develop scalable computational methods for joint estimation of crossover rates, gene conversion rates, and mean conversion tract lengths from population SNP data. Incorporate realistic biological scenarios into a model with overlapping gene conversions and extend the model to handle ectopic (or non-allelic) gene conversions in multigene families. The above goals will be achieved not by engineering modifications based on intuition or simulations, but by applying and generalizing recent mathematical results that are rigorous and accurate. The new theoretical framework developed in this research will allow one to carry out analytic computation, which was considered to be intractable in the standard coalescent theory with recombination. Furthermore, mathematically justified approximations based on diffusion processes will be devised and portable software packages will be developed for population genomics analysis.

Public Health Relevance

The ongoing large-scale sequencing projects will provide a comprehensive view of genomic variation in populations, helping to unravel the genetic basis of human biology and disease risk. Recombination is a major biological mechanism responsible for generating genetic variation in a population, and has important implications for many computational problems in genome analysis, including disease-association mapping and detecting signatures of natural selection. The proposed research will help with analyzing and interpreting whole-genome variation data, by developing novel mathematical frameworks and statistical tools for studying population genetics models with recombination.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genetic Variation and Evolution Study Section (GVE)
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Eckstrand, Irene A
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University of California Berkeley
Engineering (All Types)
Schools of Engineering
United States
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Jenkins, Paul A; Mueller, Jonas W; Song, Yun S (2014) General triallelic frequency spectrum under demographic models with variable population size. Genetics 196:295-311
Bhaskar, Anand; Clark, Andrew G; Song, Yun S (2014) Distortion of genealogical properties when the sample is very large. Proc Natl Acad Sci U S A 111:2385-90
Harris, Kelley; Sheehan, Sara; Kamm, John A et al. (2014) Decoding coalescent hidden Markov models in linear time. Res Comput Mol Biol 8394:100-114
Sheehan, Sara; Harris, Kelley; Song, Yun S (2013) Estimating variable effective population sizes from multiple genomes: a sequentially markov conditional sampling distribution approach. Genetics 194:647-62
Steinrucken, Matthias; Wang, Y X Rachel; Song, Yun S (2013) An explicit transition density expansion for a multi-allelic Wright-Fisher diffusion with general diploid selection. Theor Popul Biol 83:1-14
Song, Yun S; Steinrucken, Matthias (2012) A simple method for finding explicit analytic transition densities of diffusion processes with general diploid selection. Genetics 190:1117-29
Jenkins, Paul A (2012) Stopping-time resampling and population genetic inference under coalescent models. Stat Appl Genet Mol Biol 11:Article 9
Jenkins, Paul A; Song, Yun S (2011) The effect of recurrent mutation on the frequency spectrum of a segregating site and the age of an allele. Theor Popul Biol 80:158-73
Paul, Joshua S; Steinrucken, Matthias; Song, Yun S (2011) An accurate sequentially Markov conditional sampling distribution for the coalescent with recombination. Genetics 187:1115-28