Terminology & Information Model

When biologists define terms in order to describe phenomena and observations, they rely on a background of human experience and intelligence for interpretation. Definitions may be abstract, perhaps correctly reflecting uncertainty of our understanding at the time. Unfortunately, such terms are not readily translatable into an unambiguous representation of knowledge.

For example, “allele” might refer to “an alternative form of a gene or locus” [Wikipedia], “one of two or more forms of the DNA sequence of a particular gene” [ISOGG], or “one of a set of coexisting sequence alleles of a gene” [Sequence Ontology]. Even for human interpretation, these definitions are inconsistent: does the definition precisely describe a specific change on a specific sequence, or, rather, a more general change on an undefined sequence? In addition, all three definitions are inconsistent with the practical need for a way to describe sequence changes outside regions associated with genes.

The computational representation of biological concepts requires translating precise biological definitions into data structures that can be used by implementers. This translation should result in a representation of information that is consistent with conventional biological understanding and, ideally, be able to accommodate future data as well. The resulting computational representation of information should also be cognizant of computational performance, the minimization of opportunities for misunderstanding, and ease of manipulating and transforming data.

Accordingly, for each term we define below, we begin by describing the term as used by biologists (biological definition) as available. When a term has multiple biological definitions, we explicitly choose one of them for the purposes of this specification. We then provide a computer modelling definition (computational definition) that reformulates the biological definition in terms of information content. We then translate each of these computational definitions into precise specifications for the (logical model). Terms are ordered “bottom-up” so that definitions depend only on previously-defined terms.

Note

The keywords “MUST”, “MUST NOT”, “REQUIRED”, “SHALL”, “SHALL NOT”, “SHOULD”, “SHOULD NOT”, “RECOMMENDED”, “MAY”, and “OPTIONAL” in this document are to be interpreted as described in RFC 2119.

Data Model Notes and Principles

  • VR uses snake_case to represent compound words. Although the schema is currently JSON-based (which would typically use camelCase), VR itself is intended to be neutral with respect to languages and database.
  • VR objects are value objects. Two objects are considered equal if and only if their respective attributes are equal. As value objects, VR objects are used as primitive types and SHOULD NOT be used as containers for related data. Instead, related data should be associated with VR objects through identifiers. See Computed Identifiers.
  • Error handling is intentionally unspecified and delegated to implementation. The VR-Spec provides foundational data types that enable significant flexibility. Except where required by this specification, implementations may choose whether and how to validate data. For example, implementations MAY choose to validate that particular combinations of objects are compatible, but such validation is not required.
  • We recognize that a common desire may be to have human-readable identifiers associated with VR objects. We recommend using the _id field (see Optional Attributes below) to create a lookup for any such identifiers (see example usage), and provide reference methods for creating VR identifiers from other common variant formats (see the HGVS translation example).

Optional Attributes

  • VR attributes use a leading underscore to represent optional attributes that are not part of the value object. Such attributes are not considered when evaluating equality or creating computed identifiers. Currently, the only such attribute in the specification is the _id attribute.
  • The _id attribute is available to identifiable objects, and MAY be used by an implementation to store the identifier for a VR object. If used, the stored _id element MUST be a CURIE. If used for creating a Truncated Digest (sha512t24u) for parent objects, the stored element must be a GA4GH Computed Identifier.

Primitive Concepts

CURIE

Biological definition

None.

Computational definition

A CURIE formatted string. A CURIE string has the structure prefix:reference (W3C Terminology).

Implementation guidance

  • All identifiers in VR-Spec MUST be a valid Compact URI (CURIE), regardless of whether the identifier refers to GA4GH VR objects or external data.
  • For GA4GH VR Objects, this specification RECOMMENDS using globally unique Computed Identifiers for use within and between systems.
  • For external data, CURIE-formatted identifiers MUST be used. When an appropriate namespace exists at identifiers.org, that namespace MUST be used. When an appropriate namespace does not exist at identifiers.org, support is implementation-dependent. That is, implementations MAY choose whether and how to support informal or local namespaces.
  • Implemantions MUST use CURIE identifiers verbatim and MUST NOT be modified in any way (e.g., case-folding). Implementations MUST NOT expose partial (parsed) identifiers to any client.

Example

Identifiers for GRCh38 chromosome 19:

ga4gh:SQ.IIB53T8CNeJJdUqzn9V_JnRtQadwWCbl
refseq:NC_000019.10
grch38:19

See Identifier Construction for examples of CURIE-based identifiers for VR objects.

Residue

Biological definition

A residue refers to a specific monomer within the polymeric chain of a protein or nucleic acid (Source: Wikipedia Residue page).

Computational definition

A character representing a specific residue (i.e., molecular species) or groupings of these (“ambiguity codes”), using one-letter IUPAC abbreviations for nucleic acids and amino acids.

Sequence

Biological definition

A contiguous, linear polymer of nucleic acid or amino acid residues.

Computational definition

A character string of Residues that represents a biological sequence using the conventional sequence order (5’-to-3’ for nucleic acid sequences, and amino-to-carboxyl for amino acid sequences). IUPAC ambiguity codes are permitted in Sequences.

Information model

A Sequence is a string, constrained to contain only characters representing IUPAC nucleic acid or amino acid codes.

Implementation guidance

  • Sequences MAY be empty (zero-length) strings. Empty sequences are used as the replacement Sequence for deletion Alleles.
  • Sequences MUST consist of only uppercase IUPAC abbreviations, including ambiguity codes.
  • A Sequence provides a stable coordinate system by which an Allele MAY be located and interpreted.
  • A Sequence MAY have several roles. A “reference sequence” is any Sequence used to define an Allele. A Sequence that replaces another Sequence is called a “replacement sequence”.
  • In some contexts outside the VR specification, “reference sequence” may refer to a member of set of sequences that comprise a genome assembly. In the VR specification, any sequence may be a “reference sequence”, including those in a genome assembly.
  • For the purposes of representing sequence variation, it is not necessary that Sequences be explicitly “typed” (i.e., DNA, RNA, or AA).

Composite Concepts

Interval (Abstract Class)

Biological definition

None.

Computational definition

The Interval abstract class defines a range on a Sequence, possibly with length zero, and specified using Interbase Coordinates. An Interval MAY be a SimpleInterval with a single start and end coordinate. Future Location and Interval types will enable other methods for describing where Variation occurs. Any of these MAY be used as the Interval for Location.

SimpleInterval

Computational definition

An Interval (Abstract Class) with a single start and end coordinate.

Information model

Field Type Limits Description
type string 1..1 Interval type; MUST be set to ‘SimpleInterval
start uint64 1..1 start position
end uint64 1..1 end position

Implementation guidance

  • Implementations MUST enforce values 0 ≤ start ≤ end. In the case of double-stranded DNA, this constraint holds even when a feature is on the complementary strand.

  • VR uses Interbase coordinates because they provide conceptual consistency that is not possible with residue-based systems (see rationale). Implementations will need to convert between interbase and 1-based inclusive residue coordinates familiar to most human users.

  • Interbase coordinates start at 0 (zero).

  • The length of an interval is end - start.

  • An interval in which start == end is a zero width point between two residues.

  • An interval of length == 1 MAY be colloquially referred to as a position.

  • Two intervals are equal if the their start and end coordinates are equal.

  • Two intervals intersect if the start or end coordinate of one is strictly between the start and end coordinates of the other. That is, if:

    • b.start < a.start < b.end OR
    • b.start < a.end < b.end OR
    • a.start < b.start < a.end OR
    • a.start < b.end < a.end
  • Two intervals a and b coincide if they intersect or if they are equal (the equality condition is REQUIRED to handle the case of two identical zero-width Intervals).

  • <start, end>=<0,0> refers to the point with width zero before the first residue.

  • <start, end>=<i,i+1> refers to the i+1th (1-based) residue.

  • <start, end>=<N,N> refers to the position after the last residue for Sequence of length N.

  • See example notebooks in GA4GH VR Python Implementation.

Example

{
  "end": 44908822,
  "start": 44908821,
  "type": "SimpleInterval"
}

Location (Abstract Class)

Biological definition

As used by biologists, the precision of “location” (or “locus”) varies widely, ranging from precise start and end numerical coordinates defining a Location, to bounded regions of a sequence, to conceptual references to named genomic features (e.g., chromosomal bands, genes, exons) as proxies for the Locations on an implied reference sequence.

Computational definition

The Location abstract class refers to position of a contiguous segment of a biological sequence. The most common and concrete Location is a SequenceLocation, i.e., a Location based on a named sequence and an Interval on that sequence. Additional Intervals and Locations may also be conceptual or symbolic locations, such as a cytoband region or a gene. Any of these may be used as the Location for Variation.

Implementation Guidance

  • Location refers to a position. Although it MAY imply a sequence, the two concepts are not interchangable, especially when the location is non-specific (e.g., a range) or symbolic (a gene).

SequenceLocation

Biological definition

None

Computational definition

A Location subclass for describing a defined Interval (Abstract Class) over a named Sequence.

Information model

Field Type Limits Description
_id CURIE 0..1 Location Id; MUST be unique within document
type string 1..1 Location type; MUST be set to ‘SequenceLocation
sequence_id CURIE 1..1 An id mapping to the Computed Identifiers of the external database Sequence containing the sequence to be located.
interval Interval (Abstract Class) 1..1 Position of feature on reference sequence specified by sequence_id.

Implementation guidance

  • For a Sequence of length n:
    • 0 ≤ interval.startinterval.endn
    • interbase coordinate 0 refers to the point before the start of the Sequence
    • interbase coordinate n refers to the point after the end of the Sequence.
  • Coordinates MUST refer to a valid Sequence. VR does not support referring to intronic positions within a transcript sequence, extrapolations beyond the ends of sequences, or other implied sequence.

Important

HGVS permits variants that refer to non-existent sequence. Examples include coordinates extrapolated beyond the bounds of a transcript and intronic sequence. Such variants are not representable using VR and MUST be projected to a genomic reference in order to be represented.

Example

{
  "interval": {
    "end": 44908822,
    "start": 44908821,
    "type": "SimpleInterval"
  },
  "sequence_id": "ga4gh:SQ.IIB53T8CNeJJdUqzn9V_JnRtQadwWCbl",
  "type": "SequenceLocation"
}

State (Abstract Class)

Biological definition

None.

Computational definition

State objects are one of two primary components specifying a VR Allele (in addition to Location (Abstract Class)), and the designated components for representing change (or non-change) of the features indicated by the Allele Location. As an abstract class, State may encompass concrete Sequence changes (see SequenceState), complex translocations, copy number changes, expression variation, rule-based variation, and more (see State Classes).

SequenceState

Biological definition

None.

Computational definition

The SequenceState class specifically captures a Sequence as a State (Abstract Class). This is the State class to use for representing “ref-alt” style variation, including SNVs, MNVs, del, ins, and delins.

Information model

Field Type Limits Description
type string 1..1 State type; MUST be set to ‘SequenceState
sequence string 1..1 The string of sequence residues that is to be used as the state for other types.

Example

{
  "sequence": "T",
  "type": "SequenceState"
}

Variation

Biological definition

In biology, variation is often used to mean genetic variation, describing the differences observed in DNA among individuals.

Computational definition

The Variation abstract class is the top-level object in the VR Schema Diagram and represents the concept of a molecular state. The representation and types of molecular states are widely varied, and there are several Variation Classes currently under consideration to capture this diversity. The primary Variation subclass defined by the VR 1.0 specification is the Allele, with the Text subclass for capturing other Variations that are not yet covered.

Allele

Biological definition

One of a number of alternative forms of the same gene or same genetic locus. In the context of biological sequences, “allele” refers to one of a set of specific changes within a Sequence. In the context of VR, Allele refers to a Sequence or Sequence change with respect to a reference sequence, without regard to genes or other features.

Computational definition

An Allele is a specific, single, and contiguous Sequence at a Location (Abstract Class). Each alternative Sequence may be empty, shorter, longer, or the same length as the interval (e.g., due to one or more indels).

Information model

Field Type Limits Description
_id CURIE 0..1 Variation Id; MUST be unique within document
type string 1..1 Variation type; MUST be set to ‘Allele
location Location (Abstract Class) 1..1 Where Allele is located
state State (Abstract Class) 1..1 State at location

Implementation guidance

  • Implementations MUST enforce values interval.end ≤ sequence_length when the Sequence length is known.

  • Alleles are equal only if the component fields are equal: at the same location and with the same state.

  • Alleles MAY have multiple related representations on the same Sequence type due to normalization differences.

  • Implementations SHOULD normalize Alleles using “justified” normalization whenever possible to facilitate comparisons of variation in regions of representational ambiguity.

  • Implementations MUST normalize Alleles using “justified” normalization when generating a Computed Identifiers.

  • When the alternate Sequence is the same length as the interval, the lengths of the reference Sequence and imputed Sequence are the same. (Here, imputed sequence means the sequence derived by applying the Allele to the reference sequence.) When the replacement Sequence is shorter than the length of the interval, the imputed Sequence is shorter than the reference Sequence, and conversely for replacements that are larger than the interval.

  • When the replacement is “” (the empty string), the Allele refers to a deletion at this location.

  • The Allele entity is based on Sequence and is intended to be used for intragenic and extragenic variation. Alleles are not explicitly associated with genes or other features.

  • Biologically, referring to Alleles is typically meaningful only in the context of empirical alternatives. For modelling purposes, Alleles MAY exist as a result of biological observation or computational simulation, i.e., virtual Alleles.

  • “Single, contiguous” refers the representation of the Allele, not the biological mechanism by which it was created. For instance, two non-adjacent single residue Alleles could be represented by a single contiguous multi-residue Allele.

  • The terms “allele” and “variant” are often used interchangeably, although this use may mask subtle distinctions made by some users.

    • In the genetics community, “allele” may also refer to a haplotype.
    • “Allele” connotes a state whereas “variant” connotes a change between states. This distinction makes it awkward to use variant to refer to the concept of an unchanged position in a Sequence and was one of the factors that influenced the preference of “Allele” over “Variant” as the primary subject of annotations.
    • See Use “Allele” rather than “Variant” for further details.
  • When a trait has a known genetic basis, it is typically represented computationally as an association with an Allele.

  • This specification’s definition of Allele applies to all Sequence types (DNA, RNA, AA).

Example

{
   "location": {
      "interval": {
         "end": 44908822,
         "start": 44908821,
         "type": "SimpleInterval"
      },
      "sequence_id": "ga4gh:SQ.IIB53T8CNeJJdUqzn9V_JnRtQadwWCbl",
      "type": "SequenceLocation"
   },
   "state": {
      "sequence": "T",
      "type": "SequenceState"
   },
   "type": "Allele"
}

Text

Biological definition

None

Computational definition

The Text subclass of Variation is intended to capture textual descriptions of variation that cannot be parsed by other Variation subclasses, but are still treated as variation.

Information model

Field Type Limits Description
_id CURIE 0..1 Variation Id; MUST be unique within document
type string 1..1 Variation type; MUST be set to ‘Text
definition string 1..1 The textual variation representation not parsable by other subclasses of Variation.

Implementation guidance

  • An implementation MUST represent Variation with subclasses other than Text if possible.
  • An implementation SHOULD define or adopt conventions for defining the strings stored in Text.definition.
  • If a future version of VR-Spec is adopted by an implementation and the new version enables defining existing Text objects under a different Variation subclass, the implementation MUST construct a new object under the other Variation subclass. In such a case, an implementation SHOULD persist the original Text object and respond to queries matching the Text object with the new object.
  • Additional Variation subclasses are continually under consideration. Please open a GitHub issue if you would like to propose a Variation subclass to cover a needed variation representation.

Example

{
  "definition": "APOE loss",
  "type": "Text"
}