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Funcotator: Connected the splice site window size to CLI parameters. (#…
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…8463)

* Funcotator: Connected the splice site window size to CLI parameters.

Fixes #8276
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@jonn-smith
jonn-smith authored Aug 11, 2023
1 parent 618f3b1 commit 4212fdf
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Showing 10 changed files with 203 additions and 18 deletions.
8 changes: 8 additions & 0 deletions ...java/org/broadinstitute/hellbender/tools/funcotator/BaseFuncotatorArgumentCollection.java
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Expand Up @@ -123,4 +123,12 @@ public abstract class BaseFuncotatorArgumentCollection implements Serializable {
doc = "TSV File containing custom Variant Classification severity map of the form: VARIANT_CLASSIFICATION\tSEV. VARIANT_CLASSIFICATION must match one of the VariantClassification names (" + GencodeFuncotation.VariantClassification.ALL_VC_NAMES + "). SEV is an unsigned integer, where lower is sorted first. When using this option it is HIGHLY recommended you also use the `BEST_EFFECT` transcript selection mode."
)
public GATKPath customVariantClassificationOrderFile = null;

@Argument(
fullName = FuncotatorArgumentDefinitions.SPLICE_SITE_WINDOW_SIZE,
optional = true,
minValue = 0,
doc = "Number of bases on either side of a splice site for a variant to be classified as a SPLICE_SITE variant (default: " + FuncotatorUtils.DEFAULT_SPLICE_SITE_WINDOW_SIZE + ")."
)
public int spliceSiteWindow = FuncotatorUtils.DEFAULT_SPLICE_SITE_WINDOW_SIZE;
}
3 changes: 2 additions & 1 deletion src/main/java/org/broadinstitute/hellbender/tools/funcotator/FuncotateSegments.java
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Expand Up @@ -146,7 +146,8 @@ public void onTraversalStart() {
funcotatorArgs.lookaheadFeatureCachingInBp,
new FlankSettings(0,0),
true,
funcotatorArgs.minNumBasesForValidSegment
funcotatorArgs.minNumBasesForValidSegment,
funcotatorArgs.spliceSiteWindow
).stream()
.filter(DataSourceFuncotationFactory::isSupportingSegmentFuncotation)
.collect(Collectors.toList());
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3 changes: 2 additions & 1 deletion src/main/java/org/broadinstitute/hellbender/tools/funcotator/Funcotator.java
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Expand Up @@ -793,7 +793,8 @@ public void onTraversalStart() {
funcotatorArgs.lookaheadFeatureCachingInBp,
new FlankSettings(funcotatorArgs.fivePrimeFlankSize, funcotatorArgs.threePrimeFlankSize),
false,
funcotatorArgs.minNumBasesForValidSegment
funcotatorArgs.minNumBasesForValidSegment,
funcotatorArgs.spliceSiteWindow
);

logger.info("Initializing Funcotator Engine...");
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2 changes: 2 additions & 0 deletions ...in/java/org/broadinstitute/hellbender/tools/funcotator/FuncotatorArgumentDefinitions.java
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Expand Up @@ -69,6 +69,8 @@ public class FuncotatorArgumentDefinitions {

public static final String CUSTOM_VARIANT_CLASS_ORDER_FILE = "custom-variant-classification-order";

public static final String SPLICE_SITE_WINDOW_SIZE = "splice-site-window-size";

// ------------------------------------------------------------
// Helper Types:

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5 changes: 5 additions & 0 deletions src/main/java/org/broadinstitute/hellbender/tools/funcotator/FuncotatorUtils.java
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Expand Up @@ -59,6 +59,11 @@ private FuncotatorUtils() {}

public static final int DEFAULT_MIN_NUM_BASES_FOR_VALID_SEGMENT = 150;

/**
* The default window on either side of splice sites to mark variants as {@link org.broadinstitute.hellbender.tools.funcotator.dataSources.gencode.GencodeFuncotation.VariantClassification#SPLICE_SITE}.
*/
public static final int DEFAULT_SPLICE_SITE_WINDOW_SIZE = 2;

private static final Map<String, AminoAcid> tableByCodon;
private static final Map<String, AminoAcid> tableByCode;
private static final Map<String, AminoAcid> tableByLetter;
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15 changes: 11 additions & 4 deletions ...main/java/org/broadinstitute/hellbender/tools/funcotator/dataSources/DataSourceUtils.java
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Expand Up @@ -304,6 +304,8 @@ private static boolean isValidDirectory(final Path p) {
* be annotated with a gencode/transcript datasource.
* Not all datasources support this flag and it is
* ignored for those that don't.
* @param minBasesForValidSegment The minimum number of bases for a segment to be considered valid.
* @param spliceSiteWindowSize The number of bases on either side of a splice site for a variant to be a {@link org.broadinstitute.hellbender.tools.funcotator.dataSources.gencode.GencodeFuncotation.VariantClassification#SPLICE_SITE} variant.
* @return A {@link List} of {@link DataSourceFuncotationFactory} given the data source metadata, overrides, and transcript reporting priority information.
*/
public static List<DataSourceFuncotationFactory> createDataSourceFuncotationFactoriesForDataSources(final Map<Path, Properties> dataSourceMetaData,
Expand All @@ -314,7 +316,8 @@ public static List<DataSourceFuncotationFactory> createDataSourceFuncotationFact
final int lookaheadFeatureCachingInBp,
final FlankSettings flankSettings,
final boolean doAttemptSegmentFuncotationForTranscriptDatasources,
final int minBasesForValidSegment) {
final int minBasesForValidSegment,
final int spliceSiteWindowSize) {
Utils.nonNull(dataSourceMetaData);
Utils.nonNull(annotationOverridesMap);
Utils.nonNull(transcriptSelectionMode);
Expand Down Expand Up @@ -353,7 +356,7 @@ public static List<DataSourceFuncotationFactory> createDataSourceFuncotationFact
case GENCODE:
featureInput = createAndRegisterFeatureInputs(path, properties, gatkToolInstance, lookaheadFeatureCachingInBp, GencodeGtfFeature.class, false);
funcotationFactory = DataSourceUtils.createGencodeDataSource(path, properties, annotationOverridesMap, transcriptSelectionMode,
userTranscriptIdSet, featureInput, flankSettings, doAttemptSegmentFuncotationForTranscriptDatasources, minBasesForValidSegment);
userTranscriptIdSet, featureInput, flankSettings, doAttemptSegmentFuncotationForTranscriptDatasources, minBasesForValidSegment, spliceSiteWindowSize);
break;
case VCF:
featureInput = createAndRegisterFeatureInputs(path, properties, gatkToolInstance, lookaheadFeatureCachingInBp, VariantContext.class, false);
Expand Down Expand Up @@ -557,6 +560,8 @@ private static CosmicFuncotationFactory createCosmicDataSource(final Path dataSo
* @param isSegmentFuncotationEnabled Do we want to allow the output Gencode Funcotation Factory to do segment annotations? If false,
* segments will be funcotated with variant classifications of
* {@link org.broadinstitute.hellbender.tools.funcotator.dataSources.gencode.GencodeFuncotation.VariantClassification#COULD_NOT_DETERMINE}
* @param minBasesForValidSegment The minimum number of bases for a segment to be considered valid.
* @param spliceSiteWindowSize The number of bases on either side of a splice site for a variant to be a {@link org.broadinstitute.hellbender.tools.funcotator.dataSources.gencode.GencodeFuncotation.VariantClassification#SPLICE_SITE} variant.
* @return A new {@link GencodeFuncotationFactory} based on the given data source file information, field overrides map, and transcript information.
*/
private static GencodeFuncotationFactory createGencodeDataSource(final Path dataSourceFile,
Expand All @@ -567,7 +572,8 @@ private static GencodeFuncotationFactory createGencodeDataSource(final Path data
final FeatureInput<? extends Feature> featureInput,
final FlankSettings flankSettings,
final boolean isSegmentFuncotationEnabled,
final int minBasesForValidSegment) {
final int minBasesForValidSegment,
final int spliceSiteWindowSize) {
Utils.nonNull(dataSourceFile);
Utils.nonNull(dataSourceProperties);
Utils.nonNull(annotationOverridesMap);
Expand Down Expand Up @@ -596,7 +602,8 @@ private static GencodeFuncotationFactory createGencodeDataSource(final Path data
isB37,
ncbiBuildVersion,
isSegmentFuncotationEnabled,
minBasesForValidSegment
minBasesForValidSegment,
spliceSiteWindowSize
);
}

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64 changes: 55 additions & 9 deletions ...dinstitute/hellbender/tools/funcotator/dataSources/gencode/GencodeFuncotationFactory.java
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Expand Up @@ -72,11 +72,6 @@ public class GencodeFuncotationFactory extends DataSourceFuncotationFactory {
private static final String LOCAL_GENCODE_TRANSCRIPT_TMP_DIR_PREFIX = "localGencodeTranscriptFastaFolder";
private static final String LOCAL_GENCODE_TRANSCRIPT_FILE_BASE_NAME = "gencodeTranscriptFastaFile";

/**
* The window around splice sites to mark variants as {@link org.broadinstitute.hellbender.tools.funcotator.dataSources.gencode.GencodeFuncotation.VariantClassification#SPLICE_SITE}.
*/
private static final int spliceSiteVariantWindowBases = 2;

/**
* Number of bases to the left and right of a variant in which to calculate the GC content.
*/
Expand Down Expand Up @@ -222,6 +217,11 @@ public class GencodeFuncotationFactory extends DataSourceFuncotationFactory {
*/
private String ncbiBuildVersion = null;

/**
* The window on either side of splice sites to mark variants as {@link org.broadinstitute.hellbender.tools.funcotator.dataSources.gencode.GencodeFuncotation.VariantClassification#SPLICE_SITE}.
*/
private int spliceSiteVariantWindowBases = FuncotatorUtils.DEFAULT_SPLICE_SITE_WINDOW_SIZE;

/**
* Comparator to be used when sorting {@link Funcotation}s created by this {@link GencodeFuncotationFactory}.
* Will be either {@link TranscriptSelectionMode.BestEffectGencodeFuncotationComparator} or {@link TranscriptSelectionMode.CanonicalGencodeFuncotationComparator}.
Expand Down Expand Up @@ -352,6 +352,41 @@ public GencodeFuncotationFactory(final Path gencodeTranscriptFastaFilePath,
final boolean isSegmentFuncotationEnabled,
final int minBasesForValidSegment) {

this(gencodeTranscriptFastaFilePath, version, name, transcriptSelectionMode, userRequestedTranscripts,
annotationOverrides, mainFeatureInput, flankSettings, isDataSourceB37, ncbiBuildVersion,
isSegmentFuncotationEnabled, minBasesForValidSegment, FuncotatorUtils.DEFAULT_SPLICE_SITE_WINDOW_SIZE);
}

/**
* Create a {@link GencodeFuncotationFactory}.
*
* @param gencodeTranscriptFastaFilePath {@link Path} to the FASTA file containing the sequences of all transcripts in the Gencode data source.
* @param version The version {@link String} of Gencode from which {@link Funcotation}s will be made.
* @param name A {@link String} containing the name of this {@link GencodeFuncotationFactory}.
* @param transcriptSelectionMode The {@link TranscriptSelectionMode} by which representative/verbose transcripts will be chosen for overlapping variants.
* @param userRequestedTranscripts A {@link Set<String>} containing Gencode TranscriptIDs that the user requests to be annotated with priority over all other transcripts for overlapping variants.
* @param annotationOverrides A {@link LinkedHashMap<String,String>} containing user-specified overrides for specific {@link Funcotation}s.
* @param mainFeatureInput The backing {@link FeatureInput} for this {@link GencodeFuncotationFactory}, from which all {@link Funcotation}s will be created.
* @param flankSettings Settings object containing our 5'/3' flank sizes
* @param isDataSourceB37 If {@code true}, indicates that the data source behind this {@link GencodeFuncotationFactory} contains B37 data.
* @param ncbiBuildVersion The NCBI build version for this {@link GencodeFuncotationFactory} (can be found in the datasource config file)
* @param minBasesForValidSegment The minimum number of bases for a segment to be considered valid.
* @param spliceSiteWindowSize The number of bases on either side of a splice site for a variant to be a {@link org.broadinstitute.hellbender.tools.funcotator.dataSources.gencode.GencodeFuncotation.VariantClassification#SPLICE_SITE} variant.
*/
public GencodeFuncotationFactory(final Path gencodeTranscriptFastaFilePath,
final String version,
final String name,
final TranscriptSelectionMode transcriptSelectionMode,
final Set<String> userRequestedTranscripts,
final LinkedHashMap<String, String> annotationOverrides,
final FeatureInput<? extends Feature> mainFeatureInput,
final FlankSettings flankSettings,
final boolean isDataSourceB37,
final String ncbiBuildVersion,
final boolean isSegmentFuncotationEnabled,
final int minBasesForValidSegment,
final int spliceSiteWindowSize) {

super(mainFeatureInput, minBasesForValidSegment);

// Set up our local transcript fasta file.
Expand All @@ -375,6 +410,8 @@ public GencodeFuncotationFactory(final Path gencodeTranscriptFastaFilePath,

this.isSegmentFuncotationEnabled = isSegmentFuncotationEnabled;

this.spliceSiteVariantWindowBases = spliceSiteWindowSize;

// Go through each requested transcript and remove the version numbers from them if they exist:
this.userRequestedTranscripts = new HashSet<>();
for ( final String transcript : userRequestedTranscripts ) {
Expand Down Expand Up @@ -1270,7 +1307,9 @@ private GencodeFuncotation createCodingRegionFuncotationForProteinCodingFeature(
.setProteinChange(proteinChange);

// Set the Variant Classification:
final GencodeFuncotation.VariantClassification varClass = createVariantClassification(variant, altAllele, variantType, exon, transcript.getExons().size(), sequenceComparison);
final GencodeFuncotation.VariantClassification varClass = createVariantClassification(
variant, altAllele, variantType, exon, transcript.getExons().size(), sequenceComparison, spliceSiteVariantWindowBases
);
final GencodeFuncotation.VariantClassification secondaryVarClass;
gencodeFuncotationBuilder.setVariantClassification(varClass);
if ( varClass == GencodeFuncotation.VariantClassification.SPLICE_SITE ) {
Expand Down Expand Up @@ -1354,6 +1393,7 @@ else if ( exon.getStopCodon() != null ) {
* @param exon The {@link GencodeGtfExonFeature} in which the given {@code variant} occurs.
* @param numberOfExonsInTranscript The number of exons in the transcript in which the given {@code variant} occurs. (Must be > 0).
* @param sequenceComparison The {@link org.broadinstitute.hellbender.tools.funcotator.SequenceComparison} for the given {@code variant}.
* @param spliceSiteWindowBases The window on either side of splice sites to mark variants as {@link org.broadinstitute.hellbender.tools.funcotator.dataSources.gencode.GencodeFuncotation.VariantClassification#SPLICE_SITE}.
* @return A {@link org.broadinstitute.hellbender.tools.funcotator.dataSources.gencode.GencodeFuncotation.VariantClassification} based on the given {@code allele}, {@code variant}, {@code exon}, and {@code sequenceComparison}.
*/
@VisibleForTesting
Expand All @@ -1362,7 +1402,8 @@ static GencodeFuncotation.VariantClassification createVariantClassification(fina
final GencodeFuncotation.VariantType variantType,
final GencodeGtfExonFeature exon,
final int numberOfExonsInTranscript,
final SequenceComparison sequenceComparison ){
final SequenceComparison sequenceComparison,
final int spliceSiteWindowBases){
Utils.nonNull(variant);
Utils.nonNull(altAllele);
Utils.nonNull(variantType);
Expand Down Expand Up @@ -1422,12 +1463,17 @@ static GencodeFuncotation.VariantClassification createVariantClassification(fina
final int adjustedExonStart = adjustLocusForInsertion(exon.getStart(), variant, altAllele, realVariationInterval);
final int adjustedExonEnd = adjustLocusForInsertion(exon.getEnd(), variant, altAllele, realVariationInterval);

// If we have 0 padding, we want to make sure the variant overlaps the exon start itself,
// not within a base of the exon start, so we have to create this adjustment here so that we can
// not subtract one and create an invalid interval.
final int intervalEndCoordAdjuster = spliceSiteWindowBases > 0 ? 1 : 0;

if ( doLeftOverlapCheck ) {
final SimpleInterval leftSideInterval = new SimpleInterval(exon.getContig(), adjustedExonStart - spliceSiteVariantWindowBases, adjustedExonStart + (spliceSiteVariantWindowBases-1));
final SimpleInterval leftSideInterval = new SimpleInterval(exon.getContig(), adjustedExonStart - spliceSiteWindowBases, adjustedExonStart + (spliceSiteWindowBases-intervalEndCoordAdjuster));
overlapsLeft = leftSideInterval.overlaps(realVariationInterval);
}
if ( doRightOverlapCheck ) {
final SimpleInterval rightSideInterval = new SimpleInterval(exon.getContig(), adjustedExonEnd - spliceSiteVariantWindowBases + 1, adjustedExonEnd + (spliceSiteVariantWindowBases-1) + 1);
final SimpleInterval rightSideInterval = new SimpleInterval(exon.getContig(), adjustedExonEnd - spliceSiteWindowBases + 1, adjustedExonEnd + (spliceSiteWindowBases-intervalEndCoordAdjuster) + 1);
overlapsRight = rightSideInterval.overlaps(realVariationInterval);
}

Expand Down
3 changes: 2 additions & 1 deletion src/test/java/org/broadinstitute/hellbender/tools/funcotator/FuncotatorEngineUnitTest.java
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Original file line number Diff line number Diff line change
Expand Up @@ -64,7 +64,8 @@ public void testGetFuncotationFactoriesAndCreateFuncotationMapForVariant(final F
FuncotatorArgumentDefinitions.LOOKAHEAD_CACHE_IN_BP_DEFAULT_VALUE,
new FlankSettings(0, 0),
false,
FuncotatorUtils.DEFAULT_MIN_NUM_BASES_FOR_VALID_SEGMENT)
FuncotatorUtils.DEFAULT_MIN_NUM_BASES_FOR_VALID_SEGMENT,
FuncotatorUtils.DEFAULT_SPLICE_SITE_WINDOW_SIZE)
);

for (int i = 0; i < entireVcf.getRight().size(); i++) {
Expand Down
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