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Monte Carlo methods for estimating population genetic parameters Rasmus Nielsen University of Copenhagen
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Outline Idiosyncratic history and background on ML estimation of demographic parameters based on DNA sequence data. Idiosyncratic history and background on ML estimation of demographic parameters based on DNA sequence data. A new computational approach/modification. A new computational approach/modification. Idiosyncratic history and background on ML estimation of demographic parameters based on SNP data. Idiosyncratic history and background on ML estimation of demographic parameters based on SNP data. Ascertainment and large scale SNP data sets. Ascertainment and large scale SNP data sets.
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Felsenstein’s Equation So where G i, i=1,2,…k, has been simulated from p(G| ).
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Coefficient of Variation
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Importance Sampling So where G i, i=1,2,…k, has been simulated from h(G).
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Griffiths and Tavare Recursion Simulate mutation (coalescent) from and correct using importance sampling.
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Example (Nielsen 1998) Infinite sites modelInfinite sites model Estimation of TEstimation of T Estimation of population phylogeniesEstimation of population phylogenies
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Integro-recursion Ugliest equation ever published in a biological journal…
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MLE: T=1.8 (36,000 years)
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Data from the Caribean Hawksbill Turtle
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MCMC Set up a Markov chain on state space on all supported values of and G and with stationary distribution p( , G | X). Now since this can easily be done using Metropolis-Hastings sampling, i.e. updates to and G are proposed from a proposal distribution q( , G → ’, G’) and accepted with probability
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Some problems… Histogram estimator or other smoothing must be used. Likelihood ratios hard to estimate (e.g. M=0).
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A new method It is possible to calculate the marginal prior probability of a genealogy It turns out that this math is doable, for most components of Θ such as and M. The we can sample from the marginal posterior of G using the previously discussed MCMC procedures. Slide inspired by Jody Hey
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We then recover the posterior for using Approximated by Slide inspired by Jody Hey
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Advantages Eliminates problems with covariance between parameters leading to mixing problems. Provides a smooth posterior/likelihood function useful for optimization and likelihood ratio estimation. Disadvantages Requires more calculation in each MCMC iteration
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Likelihood ratio estimation 6 loci, 15 gene copies, H 0 : m 1 =m 2
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Other approaches Kuhner and Felsenstein use a combination of MCMC and importance sampling to estimate surfaces (no prior for the parameters). PAC methods suggested by Stephens and Donnelly samples from a close approximation to to estimate an approximate likelihood. ABC (Beaumont, Pritchard, Tavare and others) methods are a very popular and promising class of methods based on (1) reducing the data to summary statistics, (2) simulate new data from the prior, (3) accepting the parameter value under which the data was simulated if the difference between simulated and true statistics is less than .
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SNP Data Nielsen and Slatkin (2000)
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A more efficient method.. Griffiths and Tavare (1998), Nielsen (2000)
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Ascertainment Sample vs. Typed Sample Ascertainment sample Typed sample
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0.5 0.6 0.7 0.8 0.9 1.0 012345678910 =2Nc E[D'] no ascertainment bias ascertainment bias
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Correcting for ascertainment biases Now, for simplicity, consider the case without a sweep, then where (in the simplest possible case) and
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In this simple case, the maximum likelihood estimate of P is simply given by, k = 1, 2, …, n – 1, where n k is the number of SNPs with allele frequency k. Selective sweeps: Similarly define
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10,000 simulated SNPs with n = 20 and d = 5
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Hudson’s (2001) Estimator when n = 100, m = 5, = 5, and #SNP pairs = 200. Corrected Uncorrected
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Complications Double-hit ascertainment (HapMap) Ascertainment based on chimpanzee (HapMap) Panel depth may vary among SNPs and/or among regions (HapMap). Ascertainment method may vary among SNPs (HapMap). Population structure (HapMap). Loss of information regarding asc. scheme (HapMap??).
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HapMap ascertainment depth distrb. (ignores many important components)
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Perlegen HapMap
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Data Directly sequenced polymorphism data from 20 European-Americans, 19 African-Americans and one chimpanzee from 9,316 protein coding genes Data set previously described in Bustamante, C.D. et al. 2005. Natural selection on protein-coding genes in the human genome. Nature 437, 1153- 7.
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Demographic model European-AmericansAfrican-Americans Bottleneck Population growth migration Admixture
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Estimation, Sampling probabilities from the 2D frequency spectrum Number of SNPs with pattern j in the 2D frequency spectrum SNPs within a gene are correlated. But estimator is consistent. The estimate has the same properties as a real likelihood estimator except that it converges slightly slower because of the correlation (Wiuf 2006).
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African-Americans
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European-Americans Godness-of-fit: p = 0.6
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Acknowledgements Jody Hey, John Wakeley, Melissa Hubisz, Andy Clark, Carlos Bustamante, Scott Williamson, Aida Andres, Amit Andip, Adam Boyko, Anders Albrechtsen,Mark Adams, Michelle Cargill and other staff at Celera Genomics and Applied Biosystems.
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