Update Handling of Sequence Variants (Part 3): Protein xml entry #965

trishorts · 2025-10-23T15:55:35Z

Added a new parameter: LocationSequenceId that allows sequence variations to be targeted/limited to specific isoforms.
New method PruneOutOfRangeSequenceVariants that prevent sequence variants from the XML to be added if their locations are beyond the bounds of the sequence.
Added code to handling proper handling of modifications and sequence variants and coordinates

… isoform

Copilot

Pull Request Overview

This PR enhances sequence variant handling in protein XML parsing by introducing isoform-specific targeting, coordinate validation, and improved modification handling. The changes replace SequenceVariantDescription with the more robust VariantCallFormat class and add safeguards against out-of-range variants.

Key changes:

Added LocationSequenceId parameter to restrict sequence variants to specific protein isoforms
Implemented PruneOutOfRangeSequenceVariants() to validate variant coordinates against sequence length
Replaced SequenceVariantDescription with comprehensive VariantCallFormat class featuring enhanced VCF parsing and zygosity classification

Reviewed Changes

Copilot reviewed 10 out of 11 changed files in this pull request and generated 7 comments.

Show a summary per file

File	Description
ProteinXmlEntry.cs	Added isoform filtering via `LocationSequenceId`, coordinate validation with `PruneOutOfRangeSequenceVariants()`, improved documentation, and reorganized modification parsing
ProteinDbLoader.cs	Added automatic conversion of nucleotide substitution modifications to sequence variants during protein loading
VariantCallFormat.cs	New comprehensive VCF parser with proper tab handling, zygosity classification, and multi-sample genotype support
SequenceVariation.cs	Updated to use `VariantCallFormat` instead of deprecated `SequenceVariantDescription`
SequenceVariantDescription.cs	Removed deprecated class replaced by `VariantCallFormat`
TestDbLoader.cs	Removed extraneous blank line
Test.csproj	Added comprehensive VCF test file to build output
vcf_comprehensive_examples.vcf	New test file with 8 VCF examples covering various genotype patterns
VariantTests.cs	New test suite validating VCF parsing, coordinate validation, and nucleotide substitution conversion
TestVariantProtein.cs	Updated test to use `VariantCallFormat` instead of `SequenceVariantDescription`

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mzLib/UsefulProteomicsDatabases/ProteinXmlEntry.cs

Copilot · 2025-10-23T16:02:47Z

mzLib/UsefulProteomicsDatabases/ProteinXmlEntry.cs

                Sequence = ProteinDbLoader.SanitizeAminoAcidSequence(Sequence, 'X');

                ParseAnnotatedMods(OneBasedModifications, modTypesToExclude, unknownModifications, AnnotatedMods);
+                //prune any sequence variants whose coordinates exceed the known sequence length


The comment on line 444 should use proper capitalization and punctuation: 'Prune any sequence variants whose coordinates exceed the known sequence length.' Comments should follow standard sentence structure for consistency.

Suggested change

//prune any sequence variants whose coordinates exceed the known sequence length

// Prune any sequence variants whose coordinates exceed the known sequence length.

mzLib/UsefulProteomicsDatabases/ProteinXmlEntry.cs

mzLib/Omics/BioPolymer/VariantCallFormat.cs

codecov · 2025-10-23T16:04:55Z

Codecov Report

❌ Patch coverage is 86.86869% with 13 lines in your changes missing coverage. Please review.
✅ Project coverage is 80.98%. Comparing base (57f1327) to head (9bdc949).

Files with missing lines	Patch %	Lines
mzLib/UsefulProteomicsDatabases/ProteinXmlEntry.cs	88.29%	7 Missing and 4 partials ⚠️
mzLib/Omics/BioPolymer/SequenceVariation.cs	0.00%	2 Missing ⚠️

Additional details and impacted files

@@            Coverage Diff             @@
##           master     #965      +/-   ##
==========================================
- Coverage   81.00%   80.98%   -0.02%     
==========================================
  Files         269      269              
  Lines       38826    38869      +43     
  Branches     4241     4248       +7     
==========================================
+ Hits        31450    31478      +28     
- Misses       6640     6651      +11     
- Partials      736      740       +4

Files with missing lines	Coverage Δ
mzLib/Omics/BioPolymer/VariantCallFormat.cs	`86.95% <100.00%> (ø)`
mzLib/Omics/BioPolymer/SequenceVariation.cs	`83.05% <0.00%> (-2.92%)`	⬇️
mzLib/UsefulProteomicsDatabases/ProteinXmlEntry.cs	`96.77% <88.29%> (-2.76%)`	⬇️

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Copilot

Pull Request Overview

Copilot reviewed 4 out of 4 changed files in this pull request and generated 4 comments.

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Copilot · 2025-10-24T22:25:34Z

mzLib/UsefulProteomicsDatabases/ProteinXmlEntry.cs

+        /// Finalizes the parsing of a protein XML entry and constructs a <see cref="Protein"/> object.
+        /// This method is called when the end of an &lt;entry&gt; element is reached during XML parsing.
+        /// It sanitizes the sequence, prunes out-of-range sequence variants, resolves and attaches modifications,
+        /// and aggregates all parsed data (such as gene names, proteolysis products, sequence variations, disulfide bonds, and splice sites)
+        /// into a new <see cref="Protein"/> instance.
+        /// After construction, the internal state is cleared to prepare for the next entry.
        /// </summary>
+        /// <param name="xml">The <see cref="XmlReader"/> positioned at the end of the &lt;entry&gt; element.</param>
+        /// <param name="isContaminant">Indicates whether the protein is a contaminant.</param>
+        /// <param name="proteinDbLocation">The file path or identifier of the protein database source.</param>
+        /// <param name="modTypesToExclude">A collection of modification types to exclude from the protein.</param>
+        /// <param name="unknownModifications">A dictionary to collect modifications that could not be resolved.</param>
+        /// <param name="decoyIdentifier">A string used to identify decoy proteins (default: "DECOY").</param>
+        /// <returns>
+        /// A constructed <see cref="Protein"/> object containing all parsed and resolved information,
+        /// or <c>null</c> if the entry is incomplete.
+        /// </returns>


The XML documentation on lines 60-76 describes method behavior but is placed above ParseElement() at line 77, which accepts only elementName and xml parameters. This documentation appears to belong to a different method, likely ParseEntryEndElement() at line 433, which has matching parameters.

Copilot · 2025-10-24T22:25:34Z

mzLib/UsefulProteomicsDatabases/ProteinXmlEntry.cs

+        /// Handles the end of an XML element during protein database parsing, updating the internal state or finalizing objects as needed.
+        /// Depending on the element name, this method processes and stores feature, subfeature, database reference, gene, and organism information,
+        /// or, if the end of an &lt;entry&gt; element is reached, constructs and returns a fully populated <see cref="Protein"/> object.
+        /// For &lt;feature&gt; and &lt;subfeature&gt; elements, it attaches modifications or proteolytic products.
+        /// For &lt;dbReference&gt;, it records database cross-references.
+        /// For &lt;gene&gt; and &lt;organism&gt;, it updates parsing state flags.
+        /// For &lt;entry&gt;, it aggregates all parsed data, resolves modifications, and returns a new <see cref="Protein"/> instance,
+        /// clearing the internal state for the next entry.


The documentation states that for <entry> elements the method 'returns a new Protein instance', but ParseEndElement() at line 326 has return type Protein, not a description of processing different element types. This documentation appears to duplicate or misrepresent the method's actual behavior, which delegates to ParseEntryEndElement() for entry processing.

Suggested change

/// Handles the end of an XML element during protein database parsing, updating the internal state or finalizing objects as needed.

/// Depending on the element name, this method processes and stores feature, subfeature, database reference, gene, and organism information,

/// or, if the end of an <entry> element is reached, constructs and returns a fully populated <see cref="Protein"/> object.

/// For <feature> and <subfeature> elements, it attaches modifications or proteolytic products.

/// For <dbReference>, it records database cross-references.

/// For <gene> and <organism>, it updates parsing state flags.

/// For <entry>, it aggregates all parsed data, resolves modifications, and returns a new <see cref="Protein"/> instance,

/// clearing the internal state for the next entry.

/// Handles the end of an XML element during protein database parsing by dispatching processing based on the element name.

/// For <feature> and <subfeature> elements, this method updates internal state and attaches modifications or proteolytic products.

/// For <dbReference>, it records database cross-references.

/// For <gene> and <organism>, it updates parsing state flags.

/// For <entry> elements, this method delegates processing to <see cref="ParseEntryEndElement"/>, which constructs and returns a fully populated <see cref="Protein"/> object.

/// In all other cases, this method returns <c>null</c>.

Copilot · 2025-10-24T22:25:35Z

mzLib/Omics/BioPolymer/SequenceVariation.cs

+        public VariantCallFormat? VariantCallFormatData { get; }
+        [Obsolete("Use VariantCallFormatData for structured data or Description/SearchableAnnotation for text.")]
+        public VariantCallFormat? LegacyVariantDescription => VariantCallFormatData;


The property VariantCallFormatData is declared but never initialized in any constructor. All constructors only set Description, leaving VariantCallFormatData always null. Either add initialization logic or remove this unused property.

Suggested change

public VariantCallFormat? VariantCallFormatData { get; }

[Obsolete("Use VariantCallFormatData for structured data or Description/SearchableAnnotation for text.")]

public VariantCallFormat? LegacyVariantDescription => VariantCallFormatData;

Copilot · 2025-10-24T22:25:35Z

mzLib/Omics/BioPolymer/SequenceVariation.cs


+        /// <summary>Optional multi-sample VCF record describing the variant (can be null or collapsed).</summary>
+        public VariantCallFormat? VariantCallFormatData { get; }
+        [Obsolete("Use VariantCallFormatData for structured data or Description/SearchableAnnotation for text.")]


The obsolete message directs users to VariantCallFormatData, but that property is never initialized and will always be null. The obsolete attribute should either reference only Description, or VariantCallFormatData needs proper initialization.

Suggested change

[Obsolete("Use VariantCallFormatData for structured data or Description/SearchableAnnotation for text.")]

[Obsolete("Use Description/SearchableAnnotation for text.")]

nbollis · 2025-10-23T22:18:49Z

mzLib/Omics/BioPolymer/SequenceVariation.cs

+        /// <summary>Optional multi-sample VCF record describing the variant (can be null or collapsed).</summary>
+        public VariantCallFormat? VariantCallFormatData { get; }
+        [Obsolete("Use VariantCallFormatData for structured data or Description/SearchableAnnotation for text.")]
+        public VariantCallFormat? LegacyVariantDescription => VariantCallFormatData;


What is up with this?

trishorts added 14 commits October 22, 2025 15:13

rename sequence variant description as variant call format

d09576c

final unit test

acae84e

undo accidental change of descripton to call format

ed23e20

more vcf tests

1f5587b

comprehensive vcf examples

3e96598

test invalid variant

c0e4433

add line to proteindbloader

65c8729

unit tests

302b804

chasing updates to variant call format

676a892

copilot suggestions

fb1f147

h

0c327b8

added new paramater location to proteinxmlentry to reference specific…

c224908

… isoform

primitive tweaks to SequenceVariation

c20aa20

lets see

5853a1b

trishorts requested a review from Copilot October 23, 2025 16:01

Copilot AI reviewed Oct 23, 2025

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trishorts added the ready for review label Oct 23, 2025

trishorts added 3 commits October 24, 2025 14:21

j

d785580

merge upstream

692e724

copilot

38bf019

trishorts requested review from Alexander-Sol, Copilot and nbollis October 24, 2025 22:24

Copilot AI reviewed Oct 24, 2025

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Alexander-Sol previously approved these changes Oct 24, 2025

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9bdc949

trishorts dismissed Alexander-Sol’s stale review via 9bdc949 October 28, 2025 16:10

nbollis approved these changes Oct 28, 2025

View reviewed changes

	//prune any sequence variants whose coordinates exceed the known sequence length
	// Prune any sequence variants whose coordinates exceed the known sequence length.

	public VariantCallFormat? VariantCallFormatData { get; }
	[Obsolete("Use VariantCallFormatData for structured data or Description/SearchableAnnotation for text.")]
	public VariantCallFormat? LegacyVariantDescription => VariantCallFormatData;

	[Obsolete("Use VariantCallFormatData for structured data or Description/SearchableAnnotation for text.")]
	[Obsolete("Use Description/SearchableAnnotation for text.")]

Update Handling of Sequence Variants (Part 3): Protein xml entry #965

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