- By
**tom** - Follow User

- 83 Views
- Uploaded on

Download Presentation
## PowerPoint Slideshow about ' FINE SCALE MAPPING' - tom

**An Image/Link below is provided (as is) to download presentation**

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript

Bayesian framework (3)

Outline

- Introduction: fine scale mapping using high-density SNP haplotype data.
- Bayesian framework.
- Gene trees and the coalescent process.
- Genetic heterogeneity and shattered gene trees.
- Markov chain Monte Carlo (MCMC) algorithm.
- SNP genotype data.
- Example: cystic fibrosis.

Introduction

- Candidate region of the order of 1Mb in length.
- Refine location of putative disease locus within region.
- Make use of high-density maps of single nucleotide polymorphisms (SNPs).
- Type sample of affected cases and unaffected controls.

Once upon a time…

- Disease predisposition determined by single locus in candidate region.
- Each case chromosome carries a copy of a disease allele, resulting from a single recent mutation event at disease locus.
- Each control chromosome carries a copy of the ancient normal allele at the disease locus.

In an ideal world…

- Excess sharing of SNP haplotypes in the vicinity of the disease locus, among cases and not among controls.
- Decreased probability of sharing as distance from disease locus increases.
- Approximate location of disease locus inferred.

Problems…

- Gene tree and ancestral haplotypes are unknown.
- Marker mutations lead to mismatch of alleles within preserved regions.
- Multiple disease genes, multiple mutations, and dominance.

Example: Cystic fibrosis (CF)

- Fully penetrant recessive disorder, incidence ~1/2500 live births in white populations, less common in other populations.
- Preliminary linkage analysis suggested 1.8Mb candidate region for a single CF gene on chromosome 7q31.
- More recently, a 3bp deletion, ΔF508, has been identified in the CFTR gene at ~0.88Mb into the candidate region.
- Now known that ΔF508 accounts for ~66% of all chromosomal mutations in individuals with CF.
- Remainder of CF chromosomes carry copies of many other rare mutations in the same gene.
- 23 RFLPs used to identify haplotypes in 92 control chromosomes and 94 case chromosomes, 62 of which have been confirmed to carry ΔF508.

Challenges…

- The ΔF508 locus does not lie at the centre of the region of high LD.
- Non-ΔF508 case chromosomes are not expected to share the same founder marker haplotype.
- Useful test-data set for fine-scale mapping methods…

Challenges…

- The ΔF508 locus does not lie at the centre of the region of high LD.
- Non-ΔF508 case chromosomes are not expected to share the same founder marker haplotype.
- Useful test-data set for fine-scale mapping methods…

Bayesian framework (1)

- Assume disease locus exists in candidate region: aim is then to estimate its location.
- Approximate the posteriordistribution of location.
- Allows assignment of probabilities that disease locus lies in any particular area of the candidate region.

Bayesian framework (2)

- Aim is to approximate the posterior density of location of the disease locus, given SNP haplotypes in cases A and controls U, denoted f(x|A,U).
- Depends on other model parameters M, including gene tree, population haplotype frequencies, etc…
- Recover marginal posterior density by integration over these nuisance parameters,

f(x|A,U) = ∫f(x,M|A,U)dM

Bayesian framework (3)

- By Bayes’ Theorem…

f(x,M|A,U) = C f(A,U|x,M) f(x,M)

- Normalising constant.
- Likelihood of haplotype data given model parameters M and location x.
- Prior density of M and x.

Bayesian framework (3)

- By Bayes’ Theorem…

f(x,M|A,U) = C f(A,U|x,M) f(x,M)

- Normalising constant.
- Likelihood of haplotype data given model parameters M and location x.
- Prior density of M and x.

Bayesian framework (3)

- By Bayes’ Theorem…

f(x,M|A,U) = C f(A,U|x,M) f(x,M)

- Normalising constant.
- Likelihood of haplotype data given model parameters M and location x.
- Prior density of M and x.

- By Bayes’ Theorem…

f(x,M|A,U) = C f(A,U|x,M) f(x,M)

- Normalising constant.
- Likelihood of haplotype data given model parameters M and location x.
- Prior density of M and x.

Control chromosomes

- Assumed to carry an ancient normal allele at the disease locus.
- Effects of recent shared ancestry of less importance, so simple model assumed:

f(A,U|x,M) = f(A|x,M) f(U|h)

- The likelihood, f(U|h), depends only on population SNP haplotype frequencies, h.
- For many SNPs, the number of possible haplotypes is large, so frequencies are parameterised in terms of allele frequencies and first-order LD between pairs of adjacent loci.

Gene trees

- Representation of the recent shared ancestry of case chromosomes at the disease locus.
- Star shaped tree: each case chromosome descends independently from founder. Assumes there is too much information in sample about ancestral recombination and mutation events.
- Bifurcating tree: shared ancestral recombination and mutation events between chromosomes appear only once in their shared ancestry.

Gene trees

- Representation of the recent shared ancestry of case chromosomes at the disease locus.
- Star shaped tree: each case chromosome descends independently from founder. Assumes there is too much information in sample about ancestral recombination and mutation events.
- Bifurcating tree: shared ancestral recombination and mutation events between chromosomes appear only once in their shared ancestry.

Tree specification

- Topology T: the branching pattern of the tree.
- Branch lengths, τ, determined by the waiting times, w, between merging events in the gene tree.
- Scaled in units of 2N generations, where N is effective population size.

Root

Leaf nodes

Prior probability model

- Uniform prior probability model for population haplotype frequencies, the location of disease locus, and the effective population size.
- Each gene tree topology has equal prior probability.
- Prior probability model reduces to:

f(x,M) = C f(w)

- Need prior probability model for waiting times between merging events.

The coalescent process (1)

- Time between merging event from k to k-1 lineages.
- Scaled in units of 2N generations.
- Exponential distribution with rate k(k-1)/2.

The coalescent process (1)

- Time between merging event from k to k-1 lineages.
- Scaled in units of 2N generations.
- Exponential distribution with rate k(k-1)/2.

Exponential: rate 8x7/2 = 28

Expected time: 0.0357

The coalescent process (1)

- Time between merging event from k to k-1 lineages.
- Scaled in units of 2N generations.
- Exponential distribution with rate k(k-1)/2.

Exponential: rate 7x6/2=21

Expected time: 0.0476

The coalescent process (1)

- Time between merging event from k to k-1 lineages.
- Scaled in units of 2N generations.
- Exponential distribution with rate k(k-1)/2.

Exponential: rate 2x1/2=1

Expected time: 1

The coalescent process (2)

- Assumes constant effective population size, N.
- Flexible: can allow for exponential population growth and population sub-structure.
- Assumes sample is ascertained at random from the population. Problem: case chromosomes ascertained because they carry a copy of the disease mutation.
- Assumes sample has single common ancestor. Problem: genetic heterogeneity.

The shattered coalescent model

- Generalisation of the coalescent process to allow branches of the gene tree to be removed.
- Introduce indicator variable, zb, for each node, b, taking the value 1 if b has a parent in the gene tree and 0 otherwise.
- Allows for singleton leaf nodes, corresponding to sporadic case chromosomes, and disconnected sub-trees, corresponding to independent mutation events at the same disease locus.
- Assume number of branches of gene tree not removed in the shattered coalescent process given by binomial distribution, with shattering parameterρ.

Ancestral haplotypes

- Haplotypes, I, carried by internal nodes of the gene tree are unknown.
- To calculate posterior probability, need to integrate over distribution of possible ancestral haplotypes, which depends on gene tree and other model parameters.
- Treated as augmented data in Bayesian framework: enters posterior probability through likelihood…

f(x|A,U) = ∫ ∫ f(x,M,I|A,U)dMdI

and…

f(x,M,I|A,U) = C f(A,U,I|x,M) f(x,M)

Likelihood calculations

- If node has no parent in shattered gene tree, treat as a random chromosome from the population (sporadic or founder for mutation).
- If node has parent in genealogy, depends on marker haplotype carried by the parental node, and the occurrence of recombination and mutation events along the connecting branch.

Likelihood calculations

- If node has no parent in shattered gene tree, treat as a random chromosome from the population (sporadic or founder for mutation).
- If node has parent in genealogy, depends on marker haplotype carried by the parental node, and the occurrence of recombination and mutation events along the connecting branch.

MCMC algorithm (1)

- Need to calculate joint posterior distribution f(x,h,T,w,z,N,ρ,I|A,U).
- Parameter space extremely complex, so cannot be calculated analytically.
- Markov chain Monte Carlo (MCMC) algorithm approximates the posterior distribution by sampling from f(x,h,T,w,z,N,ρ,I|A,U).
- Computationally intensive, but becoming more practical with improvements in computing power.
- Can handle missing SNP data: treat as augmented data in the same way as ancestral haplotypes.

MCMC algorithm (2)

- Let S denote current set of model parameters {x,h,T,w,z,N,ρ,I}.
- Propose “small” change to model parameters, S*.
- Accept S* in place of S with probability f(S*|A,U)/f(S|A,U).
- If S* is not accepted, the current parameter S is retained.
- Initial burn-in to allow convergence of f(S|A,U) from random starting parameter set.
- Subsequent sampling period, parameter set recorded every rth step of the algorithm: each recorded output represents a random draw from f(S|A,U).

MCMC algorithm (3)

Tree height

Location

ρ

N

101 0.47374 2557.62766 4.24189612 10849.19083 0.78104 -1769.51173 102 0.40629 2112.19993 4.16846454 8804.63049 0.79777 -1788.66623 103 0.46534 1679.71719 4.30423786 7229.90233 0.75364 -1854.19049 104 0.48211 2229.24788 4.33740414 9669.14899 0.78009 -1763.70173 105 0.43808 2402.10599 4.29011844 10305.31919 0.82178 -1760.56671 106 0.44607 2275.33453 4.03331587 9177.14285 0.82601 -1775.90300 107 0.41822 3016.70273 4.39000994 13243.35496 0.77768 -1844.20629 108 0.40934 2534.50113 4.07270615 10322.27832 0.81590 -1861.97411 109 0.41032 3122.91416 4.25386813 13284.46504 0.82479 -1814.27448 110 0.45020 3209.14218 4.34316471 13937.83307 0.78422 -1801.44160

Log posterior

probability

MCMC algorithm (3)

Tree height

Location

ρ

N

101 0.47374 2557.62766 4.24189612 10849.19083 0.78104 -1769.51173 102 0.40629 2112.19993 4.16846454 8804.63049 0.79777 -1788.66623 103 0.46534 1679.71719 4.30423786 7229.90233 0.75364 -1854.19049 104 0.48211 2229.24788 4.33740414 9669.14899 0.78009 -1763.70173 105 0.43808 2402.10599 4.29011844 10305.31919 0.82178 -1760.56671 106 0.44607 2275.33453 4.03331587 9177.14285 0.82601 -1775.90300 107 0.41822 3016.70273 4.39000994 13243.35496 0.77768 -1844.20629 108 0.40934 2534.50113 4.07270615 10322.27832 0.81590 -1861.97411 109 0.41032 3122.91416 4.25386813 13284.46504 0.82479 -1814.27448 110 0.45020 3209.14218 4.34316471 13937.83307 0.78422 -1801.44160

Log posterior

probability

Cystic fibrosis: revisited

- Assume a fixed recombination rate of 0.5cM per Mb and a marker mutation rate of 2.5 x 10-5 per locus, per generation.
- Each run of MCMC algorithm begins with 20,000 step burn-in period: thrown away.
- Subsequent 200,000 step sampling period, output recorded every 50th step of the algorithm: 4000 outputs.
- Two analyses of CF data performed: control chromosomes (92) and (i) ΔF508 case chromosomes (62) only; (ii) all case chromosomes (94).

Cystic fibrosis: genetic heterogeneity

- Structure of shattered gene tree provides information about genetic heterogeneity at disease locus.
- For each output of MCMC algorithm, record shattered gene tree.
- For each pair of chromosomes, record whether they appear in the same sub-tree.
- Over all outputs, estimate probability that each pair of chromosomes carry the same allele at the disease locus.
- Cluster chromosomes according to these probabilities: cladogram to represent genetic heterogeneity.

SNP genotype data

- SNP haplotype rarely available.
- Could infer haplotypes from SNP genotype data: PHASE, SNPHAP, HAPLOTYPER algorithms.
- Better to treat haplotypes as augmented data in Bayesian framework…

f(x|G) = ∫ ∫ ∫ ∫ f(x,M,I,A,U|G)dMdIdAdU

and…

f(x,M,I,A,U|G) = C f(A,U,I|x,M) f(x,M)

Cystic fibrosis: revisited – again!

- Create genotype data from original CF haplotype data.
- Pair together case chromosmes at random.
- Pair together control chromosomes at random.
- Total sample: 46 controls and 47 cases.

Limitations

- Computationally intensive – limited to sample sizes ~100 cases and controls with up to 20 SNPs.
- Alternative approach: do not model gene tree explicitly – estimate shattered gene tree using standard clustering methods.

Summary

- High density SNP map of the human genome now available.
- Fine scale mapping of disease loci requires effective modelling of shared ancestry of sample of case and control chromosomes.
- Methods exist for haplotype and genotype data: MCMC algorithms are very computationally intensive and are currently limited to relatively small sample sizes.
- Further development is necessary…

Download Presentation

Connecting to Server..