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Adding TransmittedSingleton annotation and adding quality threshold a… (
#8329) * Adding TransmittedSingleton annotation and adding quality threshold arguments to PossibleDenovo Annotation
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...main/java/org/broadinstitute/hellbender/tools/walkers/annotator/TransmittedSingleton.java
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package org.broadinstitute.hellbender.tools.walkers.annotator; | ||
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import com.google.common.annotations.VisibleForTesting; | ||
import htsjdk.variant.variantcontext.Allele; | ||
import htsjdk.variant.variantcontext.VariantContext; | ||
import htsjdk.variant.vcf.VCFConstants; | ||
import org.apache.logging.log4j.LogManager; | ||
import org.apache.logging.log4j.Logger; | ||
import org.broadinstitute.barclay.argparser.ExperimentalFeature; | ||
import org.broadinstitute.barclay.help.DocumentedFeature; | ||
import org.broadinstitute.hellbender.engine.GATKPath; | ||
import org.broadinstitute.hellbender.engine.ReferenceContext; | ||
import org.broadinstitute.hellbender.utils.Utils; | ||
import org.broadinstitute.hellbender.utils.genotyper.AlleleLikelihoods; | ||
import org.broadinstitute.hellbender.utils.help.HelpConstants; | ||
import org.broadinstitute.hellbender.utils.logging.OneShotLogger; | ||
import org.broadinstitute.hellbender.utils.read.GATKRead; | ||
import org.broadinstitute.hellbender.utils.samples.Trio; | ||
import org.broadinstitute.hellbender.utils.variant.GATKVCFConstants; | ||
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import java.util.*; | ||
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/** | ||
* Existence of a transmitted or non-transmitted singleton in at least one of the given families | ||
* | ||
* <p>This annotation uses the genotype information from individuals in family trios to identify transmitted and non-transmitted singletons and the sample(s) in which they occur. | ||
* Transmitted singletons occur at sites in a cohort where the allele count is two and these two alleles occur in one parent and the child of a trio. A non-transmitted singleton | ||
* are sites with an allele count of one and this one allele occurs in a parent, but not the child of a trio. In both cases the other parent must have a high quality hom ref call. | ||
* | ||
* <h3>Caveats</h3> | ||
* <ul> | ||
* <li>The calculation assumes that the organism is diploid.</li> | ||
* <li>This annotation requires a valid pedigree file.</li> | ||
* <li>This annotation is only valid for trios, not quads or other more complicated family structures.</li> | ||
* <li>Only reports possible singletons for families where each of the three samples has high GQ (>20) and high depth (>20)</li> | ||
* <li>Only reports possible singletons at sites with a Call Rate greater than 90% (meaning less than 10% of the samples at the given site were no-calls)</li> | ||
* </ul> | ||
*/ | ||
@DocumentedFeature(groupName= HelpConstants.DOC_CAT_ANNOTATORS, groupSummary=HelpConstants.DOC_CAT_ANNOTATORS_SUMMARY, summary="Existence of a transmitted (or non-transmitted) singleton in at least one of the given families (transmittedSingleton, nonTransmittedSingleton)") | ||
public final class TransmittedSingleton extends PedigreeAnnotation implements InfoFieldAnnotation { | ||
protected final Logger warning = LogManager.getLogger(this.getClass()); | ||
private final OneShotLogger oneShotLogger = new OneShotLogger(this.getClass()); | ||
private Set<Trio> trios; | ||
private final int HI_GQ_THRESHOLD = 20; | ||
private final int HI_DP_THRESHOLD = 20; | ||
private final double CALL_RATE_THRESHOLD = 0.90; | ||
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@VisibleForTesting | ||
public TransmittedSingleton(final Set<Trio> trios) { | ||
super((Set<String>) null); | ||
this.trios = Collections.unmodifiableSet(new LinkedHashSet<>(trios)); | ||
} | ||
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public TransmittedSingleton(final GATKPath pedigreeFile){ | ||
super(pedigreeFile); | ||
} | ||
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public TransmittedSingleton(){ | ||
super((Set<String>) null); | ||
} | ||
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private Set<Trio> initializeAndGetTrios() { | ||
if (trios == null) { | ||
trios = getTrios(); | ||
} | ||
final long numOfTrios = trios.stream().map(trio -> trio.getMother().getFamilyID()).count(); | ||
if (numOfTrios == 0) { | ||
oneShotLogger.warn("Submitted pedigree has no trios. TransmittedSingleton annotation will not be calculated."); | ||
} else if (numOfTrios != trios.stream().map(trio -> trio.getMother().getFamilyID()).distinct().count()) { | ||
oneShotLogger.warn("Submitted pedigree has non-trio families. TransmittedSingleton annotation is only valid for trios. Non-trio families (such as quads) will be ignored."); | ||
} | ||
return trios; | ||
} | ||
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@Override | ||
void validateArguments(Collection<String> founderIds, GATKPath pedigreeFile) { | ||
String warningString = validateArgumentsWhenPedigreeRequired(founderIds, pedigreeFile); | ||
if (warningString != null) { | ||
warning.warn(warningString); | ||
} | ||
} | ||
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@Override | ||
public List<String> getKeyNames() { | ||
return Arrays.asList(GATKVCFConstants.TRANSMITTED_SINGLETON, GATKVCFConstants.NON_TRANSMITTED_SINGLETON); | ||
} | ||
@Override | ||
public Map<String, Object> annotate(final ReferenceContext ref, | ||
final VariantContext vc, | ||
final AlleleLikelihoods<GATKRead, Allele> likelihoods) { | ||
Utils.nonNull(vc); | ||
Set<Trio> trioSet = initializeAndGetTrios(); | ||
if (!vc.isBiallelic() || trioSet.isEmpty()) { | ||
return Collections.emptyMap(); | ||
} | ||
long highQualCalls = vc.getGenotypes().stream().filter(gt -> gt.getGQ() > HI_GQ_THRESHOLD).count(); | ||
if ((double) highQualCalls / vc.getNSamples() < CALL_RATE_THRESHOLD) { | ||
return Collections.emptyMap(); | ||
} | ||
final List<String> transmittedSingletonParent = new ArrayList<>(); | ||
final List<String> nonTransmittedSingletonParent = new ArrayList<>(); | ||
for (final Trio trio : trioSet) { | ||
if (vc.isBiallelic() && | ||
contextHasTrioGQs(vc, trio)) { | ||
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final boolean oneParentHasAllele = (vc.getGenotype(trio.getMaternalID()).isHet() && vc.getGenotype(trio.getPaternalID()).isHomRef()) || (vc.getGenotype(trio.getMaternalID()).isHomRef() && vc.getGenotype(trio.getPaternalID()).isHet()); | ||
final String matchingParentId = vc.getGenotype(trio.getMaternalID()).isHet() ? trio.getMaternalID() : trio.getPaternalID(); | ||
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final boolean momIsHighGQ = vc.getGenotype(trio.getMaternalID()).getGQ() >= HI_GQ_THRESHOLD; | ||
final boolean dadIsHighGQ = vc.getGenotype(trio.getPaternalID()).getGQ() >= HI_GQ_THRESHOLD; | ||
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final boolean childIsHighGQHet = vc.getGenotype(trio.getChildID()).isHet() && vc.getGenotype(trio.getChildID()).getGQ() >= HI_GQ_THRESHOLD; | ||
final boolean childIsHighGQHomRef = vc.getGenotype(trio.getChildID()).isHomRef() && vc.getGenotype(trio.getChildID()).getGQ() >= HI_GQ_THRESHOLD; | ||
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final boolean childIsHighDepth = vc.getGenotype(trio.getChildID()).getDP() >= HI_DP_THRESHOLD; | ||
final boolean momIsHighDepth = vc.getGenotype(trio.getChildID()).getDP() >= HI_DP_THRESHOLD; | ||
final boolean dadIsHighDepth = vc.getGenotype(trio.getChildID()).getDP() >= HI_DP_THRESHOLD; | ||
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//TODO: This only works for trios (not quads or other more complicated family structures that would make the AC>2) | ||
if (childIsHighDepth && momIsHighDepth && dadIsHighDepth && | ||
vc.getAttributeAsInt(VCFConstants.ALLELE_COUNT_KEY, 0) == 2 && | ||
childIsHighGQHet && oneParentHasAllele && momIsHighGQ && dadIsHighGQ) { | ||
transmittedSingletonParent.add(matchingParentId); | ||
} | ||
//TODO: This only works for trios (not quads or other more complicated family structures that would make the AC>1) | ||
if (childIsHighDepth && momIsHighDepth && dadIsHighDepth && | ||
vc.getAttributeAsInt(VCFConstants.ALLELE_COUNT_KEY, 0) == 1 && | ||
childIsHighGQHomRef && momIsHighGQ && dadIsHighGQ) { | ||
nonTransmittedSingletonParent.add(matchingParentId); | ||
} | ||
} | ||
} | ||
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final Map<String, Object> attributeMap = new LinkedHashMap<>(1); | ||
if (!transmittedSingletonParent.isEmpty()) { | ||
attributeMap.put(GATKVCFConstants.TRANSMITTED_SINGLETON, transmittedSingletonParent); | ||
} | ||
if (!nonTransmittedSingletonParent.isEmpty()) { | ||
attributeMap.put(GATKVCFConstants.NON_TRANSMITTED_SINGLETON, nonTransmittedSingletonParent); | ||
} | ||
return attributeMap; | ||
} | ||
} |
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