SO Definition & Accession No.

GA4GH Definition

“sequence_feature”

Any extent of continuous biological sequence.

SO:0000110

A Sequence is a continuous list of residues (ex. ACTG - nucleotides, ACUG - ribonucleotides, NKMF - amino acids). It has a 0-based start and end coordinate system from which a length can be calculated. A Sequence may contain 1 or more Regions of interest. These Regions may themselves also be Sequences.

Notes:

• A discussion on modeling sequence features as domain entities: https://github.com/ga4gh/va-spec/issues/19 

Discussion:

• Larry Babb on Feb 9, 2021: Is “region of interest” different from “region”?
  
• Larry Babb on Feb 9, 2021: Wouldn’t a region always be a sequence?

• Sean Upchurch on Feb 10, 2021: I believe so. Does anyone have an example of a region that isn’t one?
• Andy Yates on Feb 11, 2021: If a region is plotted against a sequence then it will always be expressible as a sub-sequence, though this maybe discontinuous and the definition of the region might itself be ambiguous i.e. based on a motif or HMM so the subsequence is an instance
  

• Dmitriy Sonkin on Feb 11, 2021: Should we limit residues to nucleotides, ribonucleotides,  amino acids?
  
• Dmitriy Sonkin on Feb 11, 2021: Is it going to be 0 based for AA sequence?
  
• Larry Babb on Dec 1, 2022: I think the most interesting/important thing I want to see in terms of SA growth going forward is some concrete data and use cases of what it does to improve whatever areas need improvement. Based on those cases and arguments for the aim and application of it, whether or not SA needs the same modeling approach as VRS and VA.  I think it does, but I’m not at a place where I could explain it to anyone (could simply be my ignorance and lack of time invested in the problem).  My best understanding of it is that GFF files represent interesting facts about specific spans of genomic sequence (maybe rna and protein sequences too?). These features are not as prolific as sequence variation but they do grow and change and new types are “likely?” to continue emerging. So these “features” much like “Categorical Variation” need a formalized/standardized IM and exchange structure so that we can attach knowledge and annotation to them. It may be interesting to note that in ClinGen we have a Dosage Curation expert group that has been working for many years (came out of the ISCA group). Tristan Nelson has worked in the past with Matt Brush to SEPIOize those dosage statements. Most of them focus on Gene dosage but many of them are based on seemingly random regions of sequence.  And like all good knowledge curators, they want to tie the knowledge and assertions they make about those gene and region, increases and decreases in the genome to cross-build concepts of the genes and regions.  This bridge between physical genome build sequences and the “equivalent” region or feature they represent at a conceptual level (across genome builds) is seemingly the same issue that SA is dealing with. I feel like we are all circling the answer and realization that there’s an important conceptual idea that we have not yet been able to bring ourselves to fully accepting, developing and promoting (because it feels like if we do that we are making things harder - when in fact we are simply frustrating ourselves by trying to play with an incomplete deck).

SO Definition & Accession No.

GA4GH Definition

“region”

A sequence_feature with an extent greater than zero. A nucleotide region is composed of bases and a polypeptide region is composed of amino acids.

SO:0000001

A Region is a portion of a Sequence. It has a start and end coordinate in the coordinate system of the containing Sequence.

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

An Annotation is the group of properties and metadata associated with an Object and describes the content of the Object.

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

The Mapping of a Sequence is the corresponding genomic location of the regions in that Sequence. A Mapping will have a Reference (ex. Chromosome), 0-based start coordinate and if needed a strand identifier. Different regions of a Sequence do not have to map to contiguous regions of the genomic reference. For example, a set of regions representing exons on a Sequence representing a Transcript may be separated by introns when mapped to the host genome despite being contiguous on the Transcript.

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

“transcript”

An RNA synthesized on a DNA or RNA template by an RNA polymerase.

SO:0000673

A Transcript is a Sequence. It is a set of contiguous exons which may have a coding region. Other possible regions on a transcript include the 3' and 5' UTRs.

Notes:

• https://en.wikipedia.org/wiki/RNA 

Discussion:

• Andy Yates on Feb 11, 2021: This is starting to talk about the splicing pattern against the genome. I think it's fair to say a transcript is always located against a region. But transcripts may be broadly coding or non-coding for proteins but will have active products produced.

SO Definition & Accession No.

GA4GH Definition

“gene”

A region (or regions) that includes all of the sequence elements necessary to encode a functional transcript. A gene may include regulatory regions, transcribed regions and/or other functional sequence regions.

SO:0000704

A Gene is a Sequence. It may contain one or more Transcripts. A gene containing one or more transcripts will have one or more exons. There are many other regions that a gene may contain.

Notes:

• https://en.wikipedia.org/wiki/Gene
• SO Definition of Gene: http://www.sequenceontology.org/browser/current_release/term/SO:0000704

• A region (or regions) that includes all of the sequence elements necessary to encode a functional transcript. A gene may include regulatory regions, transcribed regions and/or other functional sequence regions.

• VRS Gene: https://vrs.ga4gh.org/en/stable/terms_and_model.html#gene

• Current usage of term by the genetics & bioinformatics communities: A gene is a basic and fundamental unit of heritability. Genes are functional regions of heritable DNA or RNA that include transcript coding regions, regulatory elements, and other functional sequence domains. Because of the complex nature of these many components comprising a gene, the interpretation of a gene depends on context.
• Computational Definition: A reference to a Gene as defined by an authority. For human genes, the use of hgnc as the gene authority is RECOMMENDED.
• Information Model: Some Gene attributes are inherited from Feature.
  
• Implementation guidance:

• Gene symbols (e.g., “BRCA1”) are unreliable keys. Implementations MUST NOT use a gene symbol to define a Gene.
• A gene is specific to a species. Gene orthologs have distinct records in the recommended databases. For example, the BRCA1 gene in humans and the Brca1 gene in mouse are orthologs and have distinct records in the recommended gene databases.
• Implementations MUST use authoritative gene namespaces available from identifiers.org whenever possible. Examples include:

• Hgnc
• Ncbigene
• Ensembl
• Vgnc
• Mgi

• The hgnc namespace is RECOMMENDED for human variation in order to improve interoperability. When using the hgnc namespace, the optional “HGNC:” prefix MUST NOT be used.
• Gene MAY be converted to one or more Locations using external data. The source of such data and mechanism for implementation is not defined by this specification.
• See discussion on Equivalence Between Concepts: https://vrs.ga4gh.org/en/stable/appendices/equivalence.html#equivalence

• VRS allows for the expressive representation of variation concepts. Sometimes this allows for forms that can be reduced from one to another, and sometimes bi-directionally. Examples of this include the bi-directional translation of chromosomal bands to sequence coordinates via a sequence-band mapping, the uni-directional translation of a gene to one or more sequence location(s), and the use of different Sequence Expression instances that would resolve to the same sequence. Similarly, authority-based concepts such as Gene are entirely dependent on the definition of the concept by that authority–we provide no guidance on how to translate or relate such concepts to one another.
• We provide no guidance or mechanism to enforce “equivalence” between these concepts, because the semantics of one representation to another are distinct, even when there exists functions that equate or translate between two distinct concepts. Instead, we encourage communities to adopt policies about how and when to use the various concepts provided by VRS to represent different forms of variation. To assist in that effort, the GA4GH Genomic Knowledge Standards Work Stream is developing a specification for resource-defined Variation Concept Origination Policies (VCOPs). You can learn more about VCOPs in the VRSATILE framework.

• Using Sequence Expressions: When using Sequence Expressions, our general recommendation is to use LiteralSequenceExpression for when the precise sequence state is of importance to the Variation concept; this is the most common use case. When the precise state is not important but instead it is desired to refer to the general sequence derived from a location on a reference sequence, we recommend using a DerivedSequenceExpression; this is typically used when describing large sequences that are approximately reference for use in some large-scale Molecular Variation or Systemic Variation concepts. RepeatedSequenceExpression is typically used for the semantic importance of describing a specific, repeated subsequence by count, such as description of CAG repeats in the ATXN7 gene, where the repeat count is a diagnostic biomarker for severe neurodegenerative disorder spinocerebellar ataxia type 7.

• Bettencourt C, Hensman-Moss D, Flower M, et al. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases. Ann Neurol. 2016;79(6):983-990. doi:10.1002/ana.24656

• Examples: The following examples all refer to the human APOE gene:

{

  'gene_id': 'ncbigene:613',

  'type': 'Gene'

}

• Sources: SequenceOntology: gene (SO:0000704) — A region (or regions) that includes all of the sequence elements necessary to encode a functional transcript. A gene may include regulatory regions, transcribed regions and/or other functional sequence regions.

• VRS CopyNumber: https://vrs.ga4gh.org/en/stable/terms_and_model.html#copynumber

• Current usage of term by the genetics & bioinformatics communities: Copy Number Variation captures the copies of a molecule within a genome, and can be used to express concepts such as amplification and copy loss. Copy Number Variation has conflated meanings in the genomics community, and can mean either (or both) the notion of copy number in a genome or copy number on a molecule. VRS separates the concerns of these two types of statements; this concept is a type of Systemic Variation and so describes the number of copies in a genome. The related Molecular Variation concept can be expressed as an Allele with a RepeatedSequenceExpression.
• Computational Definition: The absolute count of discrete copies of a Molecular Variation, Feature, Sequence Expression, or a CURIE reference within a system (e.g. genome, cell, etc.).
• Information Model: Some CopyNumber attributes are inherited from Variation.

Discussion:

• Mark Diekhans on Feb 9, 2021: Genes are not generally thought of as sequences, they are collections of transcripts at a minimum, sometimes including regulatory regions. We still don’t agree on exactly what a gene is.
  
• Jean Muller on Feb 9, 2021: Agree with you. With one of my colleague we agreed for teaching purposes on defining a gene as a genomic region used as a matrix for synthesizing a single strand RNA molecule during transcription.
  
• Andy Yates on Feb 11, 2021: This is a difference between the conceptual gene i.e. what knowledge is linked to and something that has a location on a genome, which is exactly as you said Mark comes with all of these caveats. Might be better not to define a gene as something that depends on child definitions i.e. transcripts.
  
• Francis Ouellette on Jul 10, 2021: (my first inclusion in this document :-) If there is no transcript, is there a gene? A gene, in the classical (before molecular biology) era was (if I recall correctly) a segment of our inherited material that would have a phenotype of note if it was mutated. We now know this to be an impractical definition. I am very comfortable about referring to a gene as a segment of DNA. I generally don't like that we are going to assign clear demarcations and that genes and genes (by definitions) should have fuzzy ends, and the genetic region should be at a minimum the coordinates of the longest transcript (even if part of it is trans-spliced) but should also include experimentally validated "regions" that affect the expression of the coding (or non-coding) transcript. So getting back to "do we need a transcript" to be a gene, I would say yes, at least one, otherwise we are dealing with a segment of DNA that is affecting another gene's transcript, and now that segment is part of that gene and not an independent DNA segment without a transcript. But, just because we don't know of a transcript, it doesn't mean it isn't there, so I would agree with ayates@ebi.ac.uk that we don't want to make a transcript absolutely necessary to be present. It will be important to discuss evidence codes ... is that part of this model?

• Mark Diekhans on Jul 10, 2021: I agree transcripts should be required.  They are the real molecule.  In the case of a pseudogene, it is the remains of a transcript.

• Francis Ouellette on Jul 10, 2021: yes, I agree with that i think (a pseudo-gene without a transcript of any kind could still be a pseudogene? an anti-sense sink? a cDNA copy without producing any transcript could still be identified and annotated as a pseudogene
  
• Mark Diekhans on Jul 10, 2021: for pseudogene, I should have said "transcript annotation" not an actually RNA
  
• Francis Ouellette on Jul 10, 2021: Not sure I understand what you mean here? There could be something that from sequence similarity is identified as a pseudogene and that this may produce no transcript, ever.
  
• Bob Freimuth on Aug 18, 2021: It may help to strip away the biological function and think abstractly about the physical molecules and processes. DNA => RNA. Does the possible downstream biological function of the RNA change what it is?  What if it could have multiple functions?  Would what we call it then include all possible functions? The way I've thought about this, the function is a role in a given context, documented as an annotation layer.  A hammer can drive nails, remove nails, and crush rocks.  Clearly defining the entity and its potential functions separately may allow us to define each of those things more clearly, the definitions could be more stable, and the resulting aggregation of concepts (entity+functions) could more elegantly evolve to reflect changes in knowledge (e.g., new functions).
  
• Francis Ouellette on Dec 1, 2022: A gene is part of the hereditary material that is responsible for what you see in an organism. You can only see something is a gene when you change, modify or mutate it, giving you a changed phenotype, different from what you normally see … One paradox of this definition is that you need to break a gene to see that it is a gene. That is to say, this is the old Mandelian definition of a gene. Now we define a gene as a segment of DNA that encodes information. This fits nicely with Larry’s challenge/dosage comment above [note: see conversation under “Sequence”]. The challenge from the DNA sequence annotation point of view is that we don’t describe fuzzy boundaries well. This would be useful for defining genetic regions. In lieu of this, we do use (a lot) the coding sequence (CDS), and the transcripts regions, which we understand at the nucleotide resolution. Regulatory regions (which are critical too) we are less sure about their fuzzy limits, and we do annotate genes from the beginning of the regulatory regions (usually 5', but sometimes 3' as well) and the end of the CDS or the transcript.

SO Definition & Accession No.

GA4GH Definition

“exon”

A region of the transcript sequence within a gene which is not removed from the primary RNA transcript by RNA splicing.

SO:0000147

An Exon is a Sequence. Transcripts and Genes both may have 1 or more regions which are Exons.

Notes:

• https://en.wikipedia.org/wiki/Exon 

Discussion:

• Jean Muller on Feb 9, 2021: Shall we say that one exon may or may not contain regions that will translated into protein sequences or remain untranslated?

• Andy Yates on Feb 11, 2021: Mature or active products might be a better way to talk about this. Since ncRNAs do have mature active products. Just not proteins
• Francis Ouellette on Jul 10, 2021: A mature transcript may contain exons that are partially or fully untranslated parts of a mature mRNA.
  

• Dmitriy Sonkin on Feb 11, 2021: If exon is represented as AA sequence, we probably need a way to handle codon splitting between exons.

• Francis Ouellette on Jul 10, 2021: Exons are annotations on a genomic coordinate system that when assembled together produce a mature mRNA. The AA sequence can be derived from the mRNA coordinates, with the correct genetic code. One can infer, from an accurate coordinate system which exon coordinates would lead to an incomplete triplet or AA codons, but I don't think I would use exon coordinates to carry that information.
  

• Francis Ouellette on Jul 10, 2021: I actually have lots of trouble with exons and introns. They are an interpretation of biological molecules we observe: the segment of the DNA that ends up in a mature transcript is labelled (in the DNA) as an exon, and the part that is transcribed but does not end up as part of the mature transcript is the intron. We never actually (very rarely) measure/see introns and exons. What we see are intermediate (non-mature) transcripts and mature transcripts. And on that, we project back to the genome (and unfortunately, sometimes even the transcriptome) the intron and exon "features". They are just a projection we like to add, whilst, all we need are mapped (good coordinates) transcripts (mature or intermediate) transcripts. That said, I think this is a lost battle for me.

• Bob Freimuth on Aug 18, 2021: Exactly. We have the same issue in the VR space, when "variations" are defined at the protein level (a projection from a DNA-based observation through an assumed transcript and into the protein space) and structural changes are asserted (the variation is described as a change relative to an arbitrary reference sequence, but all that was observed was the result of a hidden process that used an unknown (but assumed) starting sequence.

SO Definition & Accession No.

GA4GH Definition

“intron”

A region of a primary transcript that is transcribed, but removed from within the transcript by splicing together the sequences (exons) on either side of it.

SO:0000188

Introns are the regions of a Gene between Exons. Introns are not objects in this model but their existence and location can be inferred from the Gene and its set of Exons.

Notes:

• https://en.wikipedia.org/wiki/Intron 

Discussion:

• Andy Yates on Feb 11, 2021: [In response to “Introns are the regions of a Gene between Exons.”] I would disagree as introns are a consequence of transcription. A region may or may not be intronic based on the transcripts that intersect that point (or don't intersect) and if you are bound by a transcript's outer bounds.

• Bob Freimuth on Aug 18, 2021: +1. See my point elsewhere about a given residue falling into different annotated regions depending on frame of reference.
  

• Mark Diekhans on Feb 9, 2021: inferring introns is a problem with the current models and something that should be addressed.   Due to imperfect data, gaps exist in transcript annotations that are not actually introns.  I have been in multiple conversations where these are referred to incorrectly as "micro introns".  Software breaks because it doesn't expect gaps.  There are also different types of introns that need to be annotated.

• Andy Yates on Feb 11, 2021: The document's definition is much like the gene definition and defines its own place/meaning with respect to the other entities. I believe we can do a better job of defining them without reference to others. Also agreed Mark.

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

• Francis Ouellette on Jul 15, 2021: For this GA4GH document, do we need to limit the scope to humans (taxon id 9606), including two types of genomes: nuclear + mitochondrial? If so, do we need to define a circular chromosome annotation?

SO Definition & Accession No.

GA4GH Definition

“reference_genome”

A collection of sequences (often chromosomes) taken as the standard for a given organism and genome assembly.

SO:0001505

Notes:

Discussion:

• A coordinate system for all genes

SO Definition & Accession No.

GA4GH Definition

“splice_junction”

The boundary between an intron and an exon.

SO:0001421

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

“splice_enhancer”

Region of a transcript that regulates splicing.

SO:0000344

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

“exonic_splicing_silencer”

An exonic splicing regulatory element that functions to recruit trans acting splicing factors suppress the transcription of the gene or genes they control.

SO:0002058

Notes:

• https://pubmed.ncbi.nlm.nih.gov/23241926/ 

Discussion:

SO Definition & Accession No.

GA4GH Definition

“intronic_splicing_silencer”

An intronic splicing regulatory element that functions to recruit trans acting splicing factors suppress the transcription of the gene or genes they control.

SO:0002056

Notes:

• https://pubmed.ncbi.nlm.nih.gov/23241926/ 

Discussion:

SO Definition & Accession No.

GA4GH Definition

“CDS”

A contiguous sequence which begins with, and includes, a start codon and ends with, and includes, a stop codon.

SO:0000316

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

“start_codon”

First codon to be translated by a ribosome

SO:0000318

Notes:

• https://en.wikipedia.org/wiki/Start_codon 

Discussion:

SO Definition & Accession No.

GA4GH Definition

“reading_frame”

A nucleic acid sequence that when read as sequential triplets, has the potential of encoding a sequential string of amino acids. It need not contain the start or stop codon.

SO:0000717

Notes:

• https://en.wikipedia.org/wiki/Reading_frame 

Discussion:

SO Definition & Accession No.

GA4GH Definition

“stop_codon”

In mRNA, a set of three nucleotides that indicates the end of information for protein synthesis.

SO:0000319

Notes:

• https://en.wikipedia.org/wiki/Stop_codon 

Discussion:

SO Definition & Accession No.

GA4GH Definition

“five_prime_UTR”

A region at the 5' end of a mature transcript (preceding the initiation codon) that is not translated into a protein.

SO:0000204

Notes:

• https://www.insdc.org/files/feature_table.html 
• https://en.wikipedia.org/wiki/Five_prime_untranslated_region 

Discussion:

SO Definition & Accession No.

GA4GH Definition

“three_prime_UTR”

A region at the 3' end of a mature transcript (following the stop codon) that is not translated into a protein.

SO:0000205

Notes:

• https://www.insdc.org/files/feature_table.html 
• https://en.wikipedia.org/wiki/Three_prime_untranslated_region 

Discussion:

SO Definition & Accession No.

GA4GH Definition

“promoter”

A regulatory_region composed of the TSS(s) and binding sites for TF_complexes of the core transcription machinery. A region (DNA) to which RNA polymerase binds, to begin transcription.

SO:0000167

Notes:

• https://en.wikipedia.org/wiki/Promoter 

Discussion:

SO Definition & Accession No.

GA4GH Definition

“TATA_box”

A conserved AT-rich septamer found about 25-bp before the start point of many eukaryotic RNA polymerase II transcript units; may be involved in positioning the enzyme for correct initiation; consensus=TATA(A|T)A(A|T).

SO:0000174

Notes:

• https://pubmed.ncbi.nlm.nih.gov/16858867/ 
• http://www.insdc.org/files/feature_table.html 
• https://en.wikipedia.org/wiki/TATA_box 

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

• https://pubmed.ncbi.nlm.nih.gov/10878578/ 

Discussion:

SO Definition & Accession No.

GA4GH Definition

“repeat_region”

A region of sequence containing one or more repeat units.

SO:0000657

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

“centromere”

A region of chromosome where the spindle fibers attach during mitosis and meiosis.

SO:0000577

Notes:

• https://en.wikipedia.org/wiki/Centromere 

Discussion:

SO Definition & Accession No.

GA4GH Definition

“telomere”

A specific structure at the end of a linear chromosome, required for the integrity and maintenance of the end.

SO:0000624

Notes:

• https://en.wikipedia.org/wiki/Telomere 

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

SO Definition & Accession No.

GA4GH Definition

Notes:

Discussion:

• Single position
• Span of 2 or more nucleotides or AA residues.

SO Definition & Accession No.

GA4GH Definition

“mRNA”

Messenger RNA is the intermediate molecule between DNA and protein. It includes UTR and coding sequences. It does not contain introns.

SO: 0000234

Notes:

• Historical Review: https://www.cell.com/current-biology/fulltext/S0960-9822(15)00606-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0960982215006065%3Fshowall%3Dtrue 

• (Brenner, et al., 1961) ​​https://pubmed.ncbi.nlm.nih.gov/20446365/ 
• (Gros, et al., 1961) ​​https://pubmed.ncbi.nlm.nih.gov/13708983/ 

Discussion:

• Do we need limitations around the use of the term mRNA to exclude broader uses?

Transcript Type Attribute

Yes/No/etc.

Citation(s)

Processing Mechanism

Exon

Yes

https://pubmed.ncbi.nlm.nih.gov/18978789/
“We carried out the first analysis of alternative splicing complexity in human tissues using mRNA-Seq data. New splice junctions were detected in ∼20% of multiexon genes, many of which are tissue specific. By combining mRNA-Seq and EST-cDNA sequence data, we estimate that transcripts from ∼95% of multiexon genes undergo alternative splicing and that there are ∼100,000 intermediate- to high-abundance alternative splicing events in major human tissues.” 

Intron

Yes

“

5’ UTR

Yes

https://pubmed.ncbi.nlm.nih.gov/21533221/ 

“Our results show strong correlation between 5' untranslated region (5'UTR) intron presence/absence and sequence features at the beginning of the coding region. They also suggest that genes encoding secretory and mitochondrial proteins share a common regulatory mechanism at the level of mRNA export.”

https://pubmed.ncbi.nlm.nih.gov/22538991/

“The 5′ untranslated region (UTR) is a regulatory region of DNA situated at the 5′ end of all protein-coding genes that is transcribed into mRNA but not translated into protein. 5′UTRs contain various regulatory elements (Fig. 1b) and play a major role in the control of translation initiation.”

3’ UTR

Yes

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431537/ 

“A growing body of work demonstrates the importance of post-transcriptional control, in particular translation initiation, in the overall regulation of gene expression. Here we focus on the contribution of regulatory elements within the 5’ and 3’ untranslated regions of mRNA to gene expression in eukaryotic cells including terminal oligopyrimidine tracts, internal ribosome entry segments, upstream open reading frames and cytoplasmic polyadenylation elements.”

CDS

Yes

https://pubmed.ncbi.nlm.nih.gov/16682450/ 

“Single-stranded mRNA molecules form secondary structures through complementary self-interactions. [...] We also demonstrate that functional domains of the mRNA [5'-untranslated region (5'-UTR), CDS and 3'-UTR] preferentially fold onto themselves, while the start codon and stop codon regions are characterized by relaxed secondary structures, which may facilitate initiation and termination of translation.”

PolyA Site

Yes

https://pubmed.ncbi.nlm.nih.gov/18479511/ 

“The polyadenylation of mRNA is one of the critical processing steps during expression of almost all eukaryotic genes.”

Donor Splice Site

Yes

Acceptor Splice Site

Yes

Primary Transcript

protein_coding_primary_transcript

Processed Transcript

mRNA

MANE Select

Yes

MANE Plus

Yes

MANE Clinical

Yes

Polymerase

II

https://pubmed.ncbi.nlm.nih.gov/10611681/ 

“Some 30 years ago, following the elucidation of transcriptional control in prokaryotes, attention turned to the corresponding problem in eukaryotes: how are so many genes transcribed in a cell-type-specific, developmentally regulated manner? The answer has been found in two modes of regulation, one involving chromatin and the other the chief transcribing enzyme, RNA polymerase II.”

https://pubmed.ncbi.nlm.nih.gov/15145350/

“In addition, it has become increasingly clear that transcription by RNA polymerase II extends beyond RNA synthesis, towards a more active role in mRNA maturation, surveillance and export to the cytoplasm.”

Nonsense Mediated Decay

Yes

https://pubmed.ncbi.nlm.nih.gov/17671086/ 

“Here, we provide an overview of three quality control mechanisms--nonsense-mediated mRNA decay, nonstop mRNA decay, and no-go mRNA decay.”

SO Definition & Accession No.

GA4GH Definition

“rRNA”

rRNA is an RNA component of a ribosome that can provide both structural scaffolding and catalytic activity.

SO:0000252

Notes:

Discussion:

Transcript Type Attribute

Yes/No/etc.

Citation(s)

Processing Mechanism

Exon

Yes

Intron

Yes

5’ UTR

No

3’ UTR

No

CDS

No

PolyA Site

Yes

Donor Splice Site

No

Acceptor Splice Site

No

Primary Transcript

Pre-rRNA

Processed Transcript

rRNA

MANE Select

No

MANE Plus

No

MANE Clinical

No

Polymerase

I

NMD

SO Definition & Accession No.

GA4GH Definition

“tRNA”

Transfer RNA (tRNA) molecules are approximately 80 nucleotides in length. Their secondary structure includes four short double-helical elements and three loops (D, anti-codon, and T loops). Further hydrogen bonds mediate the characteristic L-shaped molecular structure. Transfer RNAs have two regions of fundamental functional importance: the anti-codon, which is responsible for specific mRNA codon recognition, and the 3' end, to which the tRNA's corresponding amino acid is attached (by aminoacyl-tRNA synthetases). Transfer RNAs cope with the degeneracy of the genetic code in two manners: having more than one tRNA (with a specific anti-codon) for a particular amino acid; and 'wobble' base-pairing, i.e. permitting non-standard base-pairing at the 3rd anti-codon position.

SO:0000253

Notes:

• https://www.frontiersin.org/articles/10.3389/fgene.2019.00096/full

Discussion:

• Different splicing/ligation steps across genera.

Transcript Type Attribute

Yes/No/etc.

Citation(s)

Processing Mechanism

Exon

Yes

Intron

Yes

5’ UTR

No

3’ UTR

No

CDS

No

PolyA Site

Yes

Donor Splice Site

Acceptor Splice Site

Primary Transcript

Pre-tRNA

Processed Transcript

tRNA

MANE Select

No

MANE Plus

No

MANE Clinical

No

Polymerase

III

NMD

SO Definition & Accession No.

GA4GH Definition

“miRNA”

Small, ~22-nt, RNA molecule that is the endogenous transcript of a miRNA gene (or the product of other non coding RNA genes. Micro RNAs are produced from precursor molecules (SO:0001244) that can form local hairpin structures, which ordinarily are processed (usually via the Dicer pathway) such that a single miRNA molecule accumulates from one arm of a hairpin precursor molecule. Micro RNAs may trigger the cleavage of their target molecules or act as translational repressors.

SO:0000276

Notes:

• https://www.mirbase.org/ftp.shtml 

Discussion:

• miRbase uses two SO terms: miRNA to represent the mature transcript and miRNA_primary_transcript to represent the pri miRNA in the GFF3 they release. If we get more detailed, there is also a pre-miRNA that is the step before the drosha snipping to the mature miRNA
• There is a small subset - mirtrons that do use the more traditional splicing mechanism "Interestingly, there exists a subset of intronic miRNA, known as "mirtron" (49–52), whose processing appears to be independent of Drosha (Fig. 1). Mirtrons were initially identified in Drosophila and C. elegans (49, 50), but more recently identified in human, macaque, chimpanzee and mouse as well (52). Unlike the pri-miRNAs, the mirtrons lack the lower hairpin and the flanking single-stranded regions that recruit the microprocessor complex. Instead, they contain 5' and 3' splice sites that are presumably recognized by small nuclear RNAs (snRNA). After the debranching of the lariate intron, the spliced introns fold back into a stem-loop structure that obviates the need for the Drosha-mediated microprocessor function. It will not be surprising if refined methods of high-resolution deep-sequencing reveal many more mirtrons in mammalian genomes, including human."  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315687/ miRNAs are transcribed by RNA polymerases II or III as pri-mRNA that are modified with cap structure and polyadenylation.

Transcript Type Attribute

Yes/No/etc.

Citation(s)

Processing Mechanism

Similar to siRNA

Exon

No

Intron

No

5’ UTR

No

3’ UTR

No

CDS

No

PolyA Site

Yes

Donor Splice Site

No

Acceptor Splice Site

No

Primary Transcript

Pre-miRNA

Processed Transcript

miRNA

MANE Select

No

MANE Plus

No

MANE Clinical

No

Polymerase

II

NMD

SO Definition & Accession No.

GA4GH Definition

“piRNA”

A small non coding RNA, part of a silencing system that prevents the spreading of selfish genetic elements.

SO:0001035

Notes:

• https://www.pirnadb.org/
• https://www.tandfonline.com/doi/pdf/10.4161/cc.24989 

Discussion:

Transcript Type Attribute

Yes/No/etc.

Citation(s)

Processing Mechanism

Exon

Yes?

Intron

Yes?

5’ UTR

No

3’ UTR

No

CDS

No

PolyA Site

Yes

Donor Splice Site

No

Acceptor Splice Site

No

Primary Transcript

Primary piRNA

Processed Transcript

piRNA

MANE Select

No

MANE Plus

No

MANE Clinical

No

Polymerase

II

NMD

SO Definition & Accession No.

GA4GH Definition

“siRNA”

A small RNA molecule that is the product of a longer exogenous or endogenous dsRNA, which is either a bimolecular duplex or very long hairpin, processed (via the Dicer pathway) such that numerous siRNAs accumulate from both strands of the dsRNA. siRNAs trigger the cleavage of their target molecules.

SO:0000646

Notes:

Discussion:

• Long dsRNA (which can come from hairpin, complementary RNAs, and RNA-dependent RNA polymerases) is cleaved by an endo-ribonuclease called Dicer. Dicer cuts the long dsRNA to form short interfering RNA or siRNA; this is what enables the molecules to form the RNA-Induced Silencing Complex (RISC).

Transcript Type Attribute

Yes/No/etc.

Citation(s)

Processing Mechanism

Similar to miRNA

Exon

No

Intron

No

5’ UTR

No

3’ UTR

No

CDS

No

PolyA Site

In precursor sometimes

Donor Splice Site

No

Acceptor Splice Site

No

Primary Transcript

dsRNA, siRNA precursor

Processed Transcript

siRNA

MANE Select

No

MANE Plus

No

MANE Clinical

No

Polymerase

RNA-dependent RNA polymerases

NMD

SO Definition & Accession No.

GA4GH Definition

“snRNA”

A small nuclear RNA molecule involved in pre-mRNA splicing and processing.

SO:0000274

Notes:

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493778/ 

Discussion:

• They have a relatively uncomplicated gene structure, having no TATA box, no introns and no polyadenylation, which is consistent with the lack of an open reading frame. 3'end is trimmed.

Transcript Type Attribute

Yes/No/etc.

Citation(s)

Processing Mechanism

Exon

Single exon?

Intron

No

5’ UTR

No

3’ UTR

No

CDS

No

PolyA Site

Yes

Donor Splice Site

No

Acceptor Splice Site

No

Primary Transcript

Pre-snRNA

Processed Transcript

snRNA

MANE Select

No

MANE Plus

No

MANE Clinical

No

Polymerase

II

NMD

SO Definition & Accession No.

GA4GH Definition

“snoRNA”

A snoRNA (small nucleolar RNA) is any one of a class of small RNAs that are associated with the eukaryotic nucleus as components of small nucleolar ribonucleoproteins. They participate in the processing or modifications of many RNAs, mostly ribosomal RNAs (rRNAs) though snoRNAs are also known to target other classes of RNA, including spliceosomal RNAs, tRNAs, and mRNAs via a stretch of sequence that is complementary to a sequence in the targeted RNA.

SO:0000275

Notes:

Discussion:

• The precursor loses a hairpin

Transcript Type Attribute

Yes/No/etc.

Citation(s)

Processing Mechanism

Exon

Intron

5’ UTR

No

3’ UTR

No

CDS

No

PolyA Site

Yes

Donor Splice Site

Acceptor Splice Site

Primary Transcript

Precursor snoRNA

Processed Transcript

snoRNA

MANE Select

No

MANE Plus

No

MANE Clinical

No

Polymerase

II (mostly)

NMD

SO Definition & Accession No.

GA4GH Definition

“vault_RNA”

A family of RNAs are found as part of the enigmatic vault ribonucleoprotein complex. The complex consists of a major vault protein (MVP), two minor vault proteins (VPARP and TEP1), and several small untranslated RNA molecules. It has been suggested that the vault complex is involved in drug resistance.

SO:0000404

Notes:

• https://rnacentral.org/ 

Discussion:

Transcript Type Attribute

Yes/No/etc.

Citation(s)

Processing Mechanism

Exon

Intron

5’ UTR

No

3’ UTR

No

CDS

No

PolyA Site

Donor Splice Site

Acceptor Splice Site

Primary Transcript

Processed Transcript

MANE Select

No

MANE Plus

No

MANE Clinical

No

Polymerase

III

NMD

SO Definition & Accession No.

GA4GH Definition

“lncRNA”

A non-coding RNA over 200 nucleotides in length.

SO:0001877

Notes:

• https://www.nature.com/articles/s41580-020-00315-9 

Discussion:

• This includes pseudogenes

Transcript Type Attribute

Yes/No/etc.

Citation(s)

Processing Mechanism

Exon

Yes

Intron

Yes (sometimes but not always) (Rory DBMR Bern Swiss)

5’ UTR

No

3’ UTR

No

CDS

No

PolyA Site

Yes (sometimes but not always) (Rory)

Donor Splice Site

Yes

Acceptor Splice Site

Yes

Primary Transcript

“Pre-lncRNA”? (Rory)

Processed Transcript

lncRNA

MANE Select

No

MANE Plus

No

MANE Clinical

No

Polymerase

II

NMD