public void ContainsSharedAllelesTester_TotalCopyNumberOnly()
{
var genotype1 = Genotype.Create(3);
var genotype2 = Genotype.Create(2);
Assert.NotEqual(genotype1, genotype2);
genotype2 = Genotype.Create(new PhasedGenotype(2, 1));
Assert.Equal(genotype1, genotype2);
genotype2 = Genotype.Create(3);
Assert.Equal(genotype1, genotype2);
}
public void ContainsSharedAllelesTester_PhasedGenotype()
{
var genotype1 = Genotype.Create(new PhasedGenotype(2, 1));
var genotype2 = Genotype.Create(new PhasedGenotype(2, 1));
Assert.Equal(genotype1, genotype2);
genotype2 = Genotype.Create(new PhasedGenotype(1, 2));
Assert.NotEqual(genotype1, genotype2);
genotype2 = Genotype.Create(new PhasedGenotype(1, 1));
Assert.NotEqual(genotype1, genotype2);
}
public static List <Genotype> GeneratePhasedGenotype(int numCnStates)
{
var genotypes = new List <Genotype>();
for (int cn = 0; cn < numCnStates; cn++)
{
for (int gt = 0; gt <= cn; gt++)
{
genotypes.Add(Genotype.Create(new PhasedGenotype(gt, cn - gt)));
}
}
return(genotypes);
}
/// <summary>
/// Estimate joint likelihood and most likely CN assignment within a pedigree using total CN Genotype likelihoods and transition matrix
/// </summary>
/// <param name="pedigreeInfo"></param>
/// <param name="copyNumbersLikelihoods"></param>
/// <returns></returns>
private (ISampleMap <Genotype> copyNumbersGenotypes, JointLikelihoods jointLikelihood) GetPedigreeCopyNumbers(PedigreeInfo pedigreeInfo, ISampleMap <Dictionary <Genotype, double> > copyNumbersLikelihoods)
{
int nHighestLikelihoodGenotypes = pedigreeInfo != null && pedigreeInfo.OffspringIds.Count >= 2 ? 3 : _callerParameters.MaximumCopyNumber;
copyNumbersLikelihoods = copyNumbersLikelihoods.SelectValues(l => l.OrderByDescending(kvp => kvp.Value).Take(nHighestLikelihoodGenotypes).ToDictionary());
var sampleCopyNumbersGenotypes = new SampleMap <Genotype>();
var jointLikelihood = new JointLikelihoods();
if (!pedigreeInfo.HasFullPedigree())
{
return(sampleCopyNumbersGenotypes, jointLikelihood);
}
// parent 1 total CNs and likelihoods
foreach (var copyNumberParent1 in copyNumbersLikelihoods[pedigreeInfo.ParentsIds.First()])
{
// parent 2 total CNs and likelihoods
foreach (var copyNumberParent2 in copyNumbersLikelihoods[pedigreeInfo.ParentsIds.Last()])
{
// for offspring in addition to querying likelihoods using total CNs, iterate over all possible genotype combination (CopyNumberA/B) for a given
// CN and estimate likely transition probabilities using TransitionMatrix
foreach (var offspringGtStates in pedigreeInfo.OffspringPhasedGenotypes)
{
if (!pedigreeInfo.OffspringIds.All(id => copyNumbersLikelihoods[id].ContainsKey(
Genotype.Create(Math.Min(offspringGtStates[pedigreeInfo.OffspringIds.IndexOf(id)].PhasedGenotype.CopyNumberA + offspringGtStates[pedigreeInfo.OffspringIds.IndexOf(id)].PhasedGenotype.CopyNumberB,
_callerParameters.MaximumCopyNumber - 1)))))
{
// unavailable total CN
continue;
}
// For a given combination of offspring copy numbers, only the genotypes that result in the maximum likelihood contribute to the final result."
double currentLikelihood = copyNumberParent1.Value * copyNumberParent2.Value;
var totalCopyNumberGenotypes = new List <Genotype>();
for (var counter = 0; counter < pedigreeInfo.OffspringIds.Count; counter++)
{
var child = pedigreeInfo.OffspringIds[counter];
var copyNumberGenotypeChild = Genotype.Create(Math.Min(offspringGtStates[counter].PhasedGenotype.CopyNumberA + offspringGtStates[counter].PhasedGenotype.CopyNumberB,
_callerParameters.MaximumCopyNumber - 1));
totalCopyNumberGenotypes.Add(copyNumberGenotypeChild);
currentLikelihood *= pedigreeInfo.TransitionMatrix[copyNumberParent1.Key.TotalCopyNumber][offspringGtStates[counter].PhasedGenotype.CopyNumberA] *
pedigreeInfo.TransitionMatrix[copyNumberParent2.Key.TotalCopyNumber][offspringGtStates[counter].PhasedGenotype.CopyNumberB] *
copyNumbersLikelihoods[child][copyNumberGenotypeChild];
}
currentLikelihood = Double.IsNaN(currentLikelihood) || Double.IsInfinity(currentLikelihood) ? 0 : currentLikelihood;
var genotypesInPedigree = new SampleMap <Genotype>
{
{ pedigreeInfo.ParentsIds.First(), copyNumberParent1.Key },
{ pedigreeInfo.ParentsIds.Last(), copyNumberParent2.Key }
};
pedigreeInfo.OffspringIds.Zip(totalCopyNumberGenotypes).ForEach(sampleIdGenotypeKvp => genotypesInPedigree.Add(sampleIdGenotypeKvp.Item1, sampleIdGenotypeKvp.Item2));
genotypesInPedigree = genotypesInPedigree.OrderBy(pedigreeInfo.AllSampleIds);
jointLikelihood.AddJointLikelihood(genotypesInPedigree, currentLikelihood);
double currentLogLikelihood = Math.Log(currentLikelihood);
if (currentLogLikelihood > jointLikelihood.MaximalLogLikelihood)
{
jointLikelihood.MaximalLogLikelihood = currentLogLikelihood;
sampleCopyNumbersGenotypes = genotypesInPedigree;
}
}
}
}
if (sampleCopyNumbersGenotypes.Empty())
{
throw new IlluminaException("Maximal likelihood was not found");
}
return(sampleCopyNumbersGenotypes, jointLikelihood);
}
public void TestCommonCnvAssignment_DeNovoVariants()
{
var bins = new List <SampleGenomicBin>
{
new SampleGenomicBin("chr1", 1, 2, 100),
new SampleGenomicBin("chr1", 1, 2, 100),
new SampleGenomicBin("chr1", 1, 2, 100)
};
var balleles = new Balleles(new List <Ballele> {
new Ballele(5501, 30, 30)
});
var segmentParent1 = new CanvasSegment("chr1", 1, 2, bins, balleles)
{
CopyNumber = 2
};
bins = new List <SampleGenomicBin>
{
new SampleGenomicBin("chr1", 1, 2, 100),
new SampleGenomicBin("chr1", 1, 2, 100),
new SampleGenomicBin("chr1", 1, 2, 100)
};
balleles = new Balleles(new List <Ballele> {
new Ballele(5501, 30, 30)
});
var segmentParent2 = new CanvasSegment("chr1", 1, 2, bins, balleles)
{
CopyNumber = 2
};
bins = new List <SampleGenomicBin>
{
new SampleGenomicBin("chr1", 1, 2, 0),
new SampleGenomicBin("chr1", 1, 2, 0),
new SampleGenomicBin("chr1", 1, 2, 0)
};
balleles = new Balleles(new List <Ballele> {
new Ballele(5501, 0, 0)
});
var segmentProband = new CanvasSegment("chr1", 1, 2, bins, balleles)
{
CopyNumber = 0
};
var pedigreeSegments = new SampleMap <CanvasSegment>
{
{ new SampleId("parent1"), segmentParent1 },
{ new SampleId("parent2"), segmentParent2 },
{ new SampleId("proband"), segmentProband }
};
var sampleMetricsParent1 = SampleMetrics.GetSampleInfo(new List <CanvasSegment> {
segmentParent1
},
ploidyBedPath: null,
numberOfTrimmedBins: 2, id: new SampleId("parent1"));
var sampleMetricsParent2 = SampleMetrics.GetSampleInfo(new List <CanvasSegment> {
segmentParent2
},
ploidyBedPath: null,
numberOfTrimmedBins: 2, id: new SampleId("parent2"));
var sampleMetricsProband = SampleMetrics.GetSampleInfo(new List <CanvasSegment> {
segmentProband
},
ploidyBedPath: null,
numberOfTrimmedBins: 2, id: new SampleId("proband"));
var sampleMetrics = new SampleMap <SampleMetrics>
{
{ new SampleId("parent1"), sampleMetricsParent1 },
{ new SampleId("parent2"), sampleMetricsParent2 },
{ new SampleId("proband"), sampleMetricsProband }
};
bool isCommonCnv = global::CanvasPedigreeCaller.CanvasPedigreeCaller.IsSharedCnv(pedigreeSegments, sampleMetrics,
new List <SampleId> {
new SampleId("parent1"), new SampleId("parent2")
},
new SampleId("proband"), maximumCopyNumber: 5);
Assert.False(isCommonCnv);
var pedigreeGenotypes = new SampleMap <Genotype>
{
{ new SampleId("parent1"), Genotype.Create(new PhasedGenotype(1, 1)) },
{ new SampleId("parent2"), Genotype.Create(new PhasedGenotype(1, 1)) },
{ new SampleId("proband"), Genotype.Create(new PhasedGenotype(0, 1)) }
};
isCommonCnv = global::CanvasPedigreeCaller.CanvasPedigreeCaller.IsSharedCnv(pedigreeGenotypes, pedigreeSegments,
sampleMetrics, new List <SampleId> {
new SampleId("parent1"), new SampleId("parent2")
},
new SampleId("proband"), maximumCopyNumber: 5);
Assert.False(isCommonCnv);
pedigreeGenotypes = new SampleMap <Genotype>
{
{ new SampleId("parent1"), Genotype.Create(new PhasedGenotype(2, 1)) },
{ new SampleId("parent2"), Genotype.Create(new PhasedGenotype(1, 1)) },
{ new SampleId("proband"), Genotype.Create(new PhasedGenotype(0, 1)) }
};
isCommonCnv = global::CanvasPedigreeCaller.CanvasPedigreeCaller.IsSharedCnv(pedigreeGenotypes, pedigreeSegments,
sampleMetrics, new List <SampleId> {
new SampleId("parent1"), new SampleId("parent2")
},
new SampleId("proband"), maximumCopyNumber: 5);
Assert.False(isCommonCnv);
}