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package org.broadinstitute.gatk.tools.walkers.haplotypecaller;
import org.apache.log4j.Logger;
import org.broadinstitute.gatk.tools.walkers.haplotypecaller.readthreading.ReadThreadingGraph;
import org.broadinstitute.gatk.utils.GenomeLoc;
import org.broadinstitute.gatk.utils.activeregion.ActiveRegion;
import org.broadinstitute.gatk.utils.collections.CountSet;
import org.broadinstitute.gatk.utils.haplotype.EventMap;
import org.broadinstitute.gatk.utils.haplotype.Haplotype;
import org.broadinstitute.gatk.utils.haplotype.HaplotypeSizeAndBaseComparator;
import htsjdk.variant.variantcontext.VariantContext;
import java.io.PrintWriter;
import java.io.StringWriter;
import java.util.*;
/**
* Collection of read assembly using several kmerSizes.
*
* <p>
* There could be a different assembly per each kmerSize. In turn, haplotypes are result of one of those
* assemblies.
* </p>
*
* <p>
* Where there is more than one possible kmerSize that generates a haplotype we consider the smaller one.
* </p>
*
* @author Valentin Ruano-Rubio <valentin@broadinstitute.com>
*/
public class AssemblyResultSet {
private final Map<Integer,AssemblyResult> assemblyResultByKmerSize;
private final Set<Haplotype> haplotypes;
private final Map<Haplotype,AssemblyResult> assemblyResultByHaplotype;
private ActiveRegion regionForGenotyping;
private byte[] fullReferenceWithPadding;
private GenomeLoc paddedReferenceLoc;
private boolean variationPresent;
private Haplotype refHaplotype;
private boolean wasTrimmed = false;
private final CountSet kmerSizes;
private TreeSet<VariantContext> variationEvents;
private boolean debug;
private static Logger logger = Logger.getLogger(AssemblyResultSet.class);
/**
* Constructs a new empty assembly result set.
*/
public AssemblyResultSet() {
assemblyResultByKmerSize = new LinkedHashMap<>(4);
haplotypes = new LinkedHashSet<>(10);
assemblyResultByHaplotype = new LinkedHashMap<>(10);
kmerSizes = new CountSet(4);
}
/**
* Change the debug status for this assembly-result-set.
* @param newValue new value for the debug status.
*/
void setDebug(final boolean newValue) {
debug = newValue;
}
/**
* Trims an assembly result set down based on a new set of trimmed haplotypes.
*
* @param trimmedActiveRegion the trimmed down active region.
*
* @throws NullPointerException if any argument in {@code null} or
* if there are {@code null} entries in {@code originalByTrimmedHaplotypes} for trimmed haplotype keys.
* @throws IllegalArgumentException if there is no reference haplotype amongst the trimmed ones.
*
* @return never {@code null}, a new trimmed assembly result set.
*/
public AssemblyResultSet trimTo(final ActiveRegion trimmedActiveRegion) {
final Map<Haplotype,Haplotype> originalByTrimmedHaplotypes = calculateOriginalByTrimmedHaplotypes(trimmedActiveRegion);
if (refHaplotype == null) throw new IllegalStateException();
if (trimmedActiveRegion == null) throw new NullPointerException();
final AssemblyResultSet result = new AssemblyResultSet();
for (final Haplotype trimmed : originalByTrimmedHaplotypes.keySet()) {
final Haplotype original = originalByTrimmedHaplotypes.get(trimmed);
if (original == null)
throw new NullPointerException("all trimmed haplotypes must have an original one");
final AssemblyResult as = assemblyResultByHaplotype.get(original);
if (as == null) result.add(trimmed); else result.add(trimmed, as);
}
result.setRegionForGenotyping(trimmedActiveRegion);
result.setFullReferenceWithPadding(this.fullReferenceWithPadding);
result.setPaddedReferenceLoc(this.paddedReferenceLoc);
if (result.refHaplotype == null)
throw new IllegalStateException("missing reference haplotype in the trimmed set");
result.wasTrimmed = true;
return result;
}
private Map<Haplotype, Haplotype> calculateOriginalByTrimmedHaplotypes(final ActiveRegion trimmedActiveRegion) {
if ( debug ) logger.info("Trimming active region " + getRegionForGenotyping() + " with " + getHaplotypeCount() + " haplotypes");
final List<Haplotype> haplotypeList = getHaplotypeList();
// trim down the haplotypes
final Map<Haplotype,Haplotype> originalByTrimmedHaplotypes = new HashMap<>();
for ( final Haplotype h : haplotypeList ) {
final Haplotype trimmed = h.trim(trimmedActiveRegion.getExtendedLoc());
if ( trimmed != null ) {
if (originalByTrimmedHaplotypes.containsKey(trimmed)) {
if (trimmed.isReference()) {
originalByTrimmedHaplotypes.remove(trimmed);
originalByTrimmedHaplotypes.put(trimmed, h);
}
} else
originalByTrimmedHaplotypes.put(trimmed,h);
} else if (h.isReference())
throw new IllegalStateException("trimming eliminates the reference haplotype");
else if ( debug ) {
logger.info("Throwing out haplotype " + h + " with cigar " + h.getCigar() +
" because it starts with or ends with an insertion or deletion when trimmed to " +
trimmedActiveRegion.getExtendedLoc());
}
}
// create the final list of trimmed haplotypes
final List<Haplotype> trimmedHaplotypes = new ArrayList<>(originalByTrimmedHaplotypes.keySet());
// resort the trimmed haplotypes.
Collections.sort(trimmedHaplotypes,new HaplotypeSizeAndBaseComparator());
final Map<Haplotype,Haplotype> sortedOriginalByTrimmedHaplotypes = new LinkedHashMap<>(trimmedHaplotypes.size());
for (final Haplotype trimmed : trimmedHaplotypes)
sortedOriginalByTrimmedHaplotypes.put(trimmed,originalByTrimmedHaplotypes.get(trimmed));
if ( debug ) logger.info("Trimmed region to " + trimmedActiveRegion.getLocation() + " size " +
trimmedActiveRegion.getLocation().size() + " reduced number of haplotypes from " +
haplotypeList.size() + " to only " + trimmedHaplotypes.size());
if ( debug )
for ( final Haplotype remaining: trimmedHaplotypes )
logger.info("Remains: " + remaining + " cigar " + remaining.getCigar());
return sortedOriginalByTrimmedHaplotypes;
}
/**
* Query the reference haplotype in the result set.
* @return {@code null} if none wasn't yet added, otherwise a reference haplotype.
*/
public Haplotype getReferenceHaplotype() {
return refHaplotype;
}
/**
* Checks whether there is any variation present in the assembly result set.
*
* <p>
* This is equivalent to whether there is more than one haplotype.
* </p>
*
* @return {@code true} if there is variation present, {@code false} otherwise.
*/
public boolean isVariationPresent() {
return variationPresent && haplotypes.size() > 1;
}
/**
* Dumps debugging information into a print-writer.
*
* @param pw where to dump the information.
*
* @throws NullPointerException if {@code pw} is {@code null}.
*/
public void debugDump(final PrintWriter pw) {
if (getHaplotypeList().size() == 0) {
return;
}
pw.println("Active Region " + this.regionForGenotyping.getLocation());
pw.println("Extended Act Region " + this.getRegionForGenotyping().getExtendedLoc());
pw.println("Ref haplotype coords " + getHaplotypeList().get(0).getGenomeLocation());
pw.println("Haplotype count " + haplotypes.size());
final Map<Integer,Integer> kmerSizeToCount = new HashMap<>();
for (final Map.Entry<Haplotype,AssemblyResult> e : assemblyResultByHaplotype.entrySet()) {
final AssemblyResult as = e.getValue();
final int kmerSize = as.getGraph().getKmerSize();
if (kmerSizeToCount.containsKey(kmerSize)) {
kmerSizeToCount.put(kmerSize,kmerSizeToCount.get(kmerSize) + 1);
} else {
kmerSizeToCount.put(kmerSize,1);
}
}
pw.println("Kmer sizes count " + kmerSizeToCount.entrySet().size() );
Integer[] kmerSizes = new Integer[kmerSizeToCount.size()];
kmerSizes = kmerSizeToCount.keySet().toArray(kmerSizes);
Arrays.sort(kmerSizes);
pw.println("Kmer sizes values " + Arrays.toString(kmerSizes));
for (int size : kmerSizes) {
pw.println("Kmer size " + size + " count " + kmerSizeToCount.get(size));
}
}
/**
* Adds a haplotype to the result set without indicating a generating assembly result.
*
* <p>
* It is possible to call this method with the same haplotype several times. In that the second and further
* calls won't have any effect (thus returning {@code false}).
* </p>
*
* @param h the haplotype to add to the assembly result set.
*
* @throws NullPointerException if {@code h} is {@code null}
* @throws IllegalArgumentException if {@code h} does not have a genome location.
*
* @return {@code true} if the assembly result set has been modified as a result of this call.
*/
public boolean add(final Haplotype h) {
if (h == null) throw new NullPointerException("input haplotype cannot be null");
if (h.getGenomeLocation() == null)
throw new IllegalArgumentException("the haplotype provided must have a genomic location");
if (haplotypes.contains(h))
return false;
haplotypes.add(h);
updateReferenceHaplotype(h);
return true;
}
/**
* Adds simultaneously a haplotype and the generating assembly-result.
*
* <p>
* Haplotypes and their assembly-result can be added multiple times although just the first call will have
* any effect (return value is {@code true}).
* </p>
*
*
* @param h haplotype to add.
* @param ar assembly-result that is assumed to have given rise to that haplotype.
*
* @throws NullPointerException if {@code h} or {@code ar} is {@code null}.
* @throws IllegalArgumentException if {@code h} has not defined genome location.
*
* @return {@code true} iff this called changes the assembly result set.
*/
public boolean add(final Haplotype h, final AssemblyResult ar) {
if (h == null) throw new NullPointerException("input haplotype cannot be null");
if (ar == null) throw new NullPointerException("input assembly-result cannot be null");
if (h.getGenomeLocation() == null)
throw new IllegalArgumentException("the haplotype provided must have a genomic location");
final boolean assemblyResultAdditionReturn = add(ar);
if (haplotypes.contains(h)) {
final AssemblyResult previousAr = assemblyResultByHaplotype.get(h);
if (previousAr == null) {
assemblyResultByHaplotype.put(h, ar);
return true;
} else if (!previousAr.equals(ar))
throw new IllegalStateException("there is already a different assembly result for the input haplotype");
else
return assemblyResultAdditionReturn;
} else {
haplotypes.add(h);
assemblyResultByHaplotype.put(h,ar);
updateReferenceHaplotype(h);
if (h.isNonReference()) variationPresent = true;
return true;
}
}
/**
* Add a assembly-result object.
*
* @param ar the assembly result to add.
*
* @throws NullPointerException if {@code ar} is {@code null}.
* @throws IllegalStateException if there is an assembly result with the same kmerSize.
* @return {@code true} iff this addition changed the assembly result set.
*/
public boolean add(final AssemblyResult ar) {
if (ar == null)
throw new NullPointerException();
final int kmerSize = ar.getKmerSize();
if (assemblyResultByKmerSize.containsKey(kmerSize)) {
if (!assemblyResultByKmerSize.get(kmerSize).equals(ar))
throw new IllegalStateException("a different assembly result with the same kmerSize was already added");
return false;
} else {
assemblyResultByKmerSize.put(kmerSize, ar);
kmerSizes.add(kmerSize);
return true;
}
}
/**
* Returns the current region for genotyping.
*
* @return might be {@code null}.
*/
public ActiveRegion getRegionForGenotyping() {
return regionForGenotyping;
}
/**
* Sets the region for genotyping.
*
* @param regionForGenotyping the new value.
*/
public void setRegionForGenotyping(final ActiveRegion regionForGenotyping) {
this.regionForGenotyping = regionForGenotyping;
}
/**
* Returns the current full reference with padding.
*
* @return might be {@code null}.
*/
public byte[] getFullReferenceWithPadding() {
return fullReferenceWithPadding;
}
/**
* Sets the full reference with padding base sequence.
*
* @param fullReferenceWithPadding the new value.
*/
public void setFullReferenceWithPadding(final byte[] fullReferenceWithPadding) {
this.fullReferenceWithPadding = fullReferenceWithPadding;
}
/**
* Returns the padded reference location.
*
* @return might be {@code null}
*/
public GenomeLoc getPaddedReferenceLoc() {
return paddedReferenceLoc;
}
/**
* Changes the padded reference location.
* @param paddedReferenceLoc the new value.
*/
public void setPaddedReferenceLoc(final GenomeLoc paddedReferenceLoc) {
this.paddedReferenceLoc = paddedReferenceLoc;
}
/**
* Returns the number of haplotypes in the assembly result set.
* @return {@code 0} or greater.
*/
public int getHaplotypeCount() {
return haplotypes.size();
}
/**
* Returns the haplotypes as a list.
*
* <p>
* The result is unmodifiable.
* </p>
*
* @return never {@code null}, but perhaps a empty list if no haplotype was generated during assembly.
*/
public List<Haplotype> getHaplotypeList() {
return Arrays.asList(haplotypes.toArray(new Haplotype[haplotypes.size()]));
}
/**
* Returns the maximum kmerSize available.
*
* @throws IllegalStateException if no assembly-result was added to the set, thus there is no kmerSize.
*
* @return greater than 0.
*/
public int getMaximumKmerSize() {
if (kmerSizes.size() == 0)
throw new IllegalStateException("there is yet no kmerSize in this assembly result set");
return kmerSizes.max();
}
/**
* Indicates whether there are more than one kmerSize in the set.
*
* @return {@code true} iff there is more than one kmerSize assembly in the set.
*/
public boolean hasMultipleKmerSizes() {
return kmerSizes.size() > 1;
}
/**
* Returns the minimum kmerSize available.
*
* @throws IllegalStateException if no assembly-result was added to the set, thus there is no kmerSize.
*
* @return greater than 0.
*/
public int getMinimumKmerSize() {
if (kmerSizes.size() == 0)
throw new IllegalStateException("there is yet no kmerSize in this assembly result set");
return kmerSizes.min();
}
/**
* Returns a read-threading graph in the assembly set that has a particular kmerSize.
*
* @param kmerSize the requested kmerSize.
*
* @return {@code null} if there is no read-threading-graph amongst assembly results with that kmerSize.
*/
public ReadThreadingGraph getUniqueReadThreadingGraph(final int kmerSize) {
final AssemblyResult assemblyResult = assemblyResultByKmerSize.get(kmerSize);
if (assemblyResult == null) return null;
return assemblyResult.getThreadingGraph();
}
/**
* Checks whether this assembly result set was trimmed.
*
* @return {@code true} iff this assembly result set was trimmed.
*/
public boolean wasTrimmed() {
return wasTrimmed;
}
/**
* Marks the assembly as not having variation even if it has more than one haplotype.
*/
public void resetVariationPresent() {
variationPresent = false;
}
/**
* Dumps debugging information into a logger.
*
* @param logger where to dump the information.
*
* @throws NullPointerException if {@code logger} is {@code null}.
*/
public void debugDump(final Logger logger) {
final StringWriter sw = new StringWriter();
final PrintWriter pw = new PrintWriter(sw);
debugDump(pw);
final String str = sw.toString();
final String[] lines = str.split("\n");
for (final String line : lines) {
if (line.isEmpty()) {
continue;
}
logger.debug(line);
}
}
/**
* Given whether a new haplotype that has been already added to {@link #haplotypes} collection is the
* reference haplotype and updates {@link #refHaplotype} accordingly.
*
* <p>
* This method assumes that the colling code has verified that the haplotype was not already in {@link #haplotypes}
* I.e. that it is really a new one. Otherwise it will result in an exception if it happen to be a reference
* haplotype and this has already be set. This is the case even if the new haplotypes and the current reference
* are equal.
* </p>
*
* @param newHaplotype the new haplotype.
* @throws NullPointerException if {@code newHaplotype} is {@code null}.
* @throws IllegalStateException if there is already a reference haplotype.
*/
private void updateReferenceHaplotype(final Haplotype newHaplotype) {
if (!newHaplotype.isReference()) return;
if (refHaplotype == null)
refHaplotype = newHaplotype;
else // assumes that we have checked wether the haplotype is already in the collection and so is no need to check equality.
throw new IllegalStateException("the assembly-result-set already have a reference haplotype that is different");
}
/**
* Returns a sorted set of variant events that best explain the haplotypes found by the assembly
* across kmerSizes.
*
* <p/>
* The result is sorted incrementally by location.
*
* @return never {@code null}, but perhaps an empty collection.
*/
public TreeSet<VariantContext> getVariationEvents() {
if (variationEvents == null) {
final List<Haplotype> haplotypeList = getHaplotypeList();
EventMap.buildEventMapsForHaplotypes(haplotypeList,fullReferenceWithPadding,paddedReferenceLoc,debug);
variationEvents = EventMap.getAllVariantContexts(haplotypeList);
}
return variationEvents;
}
}