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GenGenMol > 10 Standardisation - Genomes, Genes and Nomenclature > Flashcards

10 Standardisation - Genomes, Genes and Nomenclature Flashcards

1
Q

What was the specific aim of the human genome project?

A

To sequence the euchromatic human genome: this is the lightly packed chromatin that is enriched in genes. It’s 92% of the genome.

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2
Q

How much of the genome is considered protein coding?

A

25%

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3
Q

How much of the genome is actually protein coding because its in exons?

A

1%

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4
Q

What surprised people about the content of the genome?

A

There’s more segmentally duplicated DNA than expected

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5
Q

What makes up 15% of the genome?

A

Short interspersed Nuclear elements, primarily Alu elements

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6
Q

Who contributed DNA to the human genome project?

A

13 or 30 people… From Buffalo NY. 66% is from one male donor

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7
Q

In 2001 how much of the genome had been sequenced? What was the error rate? And how many gaps were there?

A

90% coverage, high error rate of 1 in 1000, and there were 15,000 gaps in the euchromatic genome

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8
Q

How much of the genome had been sequenced in 2003 with referene Hg16 (NCBI34), what was the error rate, and how many gaps were there?

A

99% coverage, 1 in 10,000 error rate, with 400 gaps in the euchromatic genome

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9
Q

In 2009 Grch37 was published. How many gaps were there, and how many genes still had sequencing error?

A

300 gaps in euchromatic genome in build 37, and 550 genes with sequencing errors

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10
Q

In 2013 what was published?

A

GRCh38

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11
Q

How many gaps were in GRCh38?

A

as few as 89 gaps

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12
Q

When was the Telomere to Telomere (T2T) genome published?

A

2022

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13
Q

Why is it hard to transition from GRCh38 to T2T?

A

Because the MANE project is still of GRCh38. The MANE project is trying to bring about consensus on a defined set of transcripts representative of the expression of the whole genome.

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14
Q

What are patches?

A

Additional sequences with their own identifier, adding info to the reference genome without disrupting it

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15
Q

What are the two types of genome patch?

A

Fix patches and Novel patches

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16
Q

What is a fix patch?

A

They correct gaps or sequence errors

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17
Q

Why are fix patches needed?

A

Because changing the reference genome by incorporating the patch would change downstream position numbers, so it can’t be done directly. A fix patch adds info without altering the number of bases.

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18
Q

What are novel patches?

A

They are designed to provide an alternate structure for a chromosomal region, such as for CYP206 duplication

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19
Q

What happens to fix patches and novel patches when a new genome is released?

A

Fix patches are incorporated, but novel patch scaffolds remain as Alt loci, representation variation

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20
Q

What patches does GRCh38 have?

A

Some missing exons (e.g. SHANK3), some missing genes in patches, and indel errors in a few hundred genes like ABO, a few of which are clinically relevant

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21
Q

Where can the reference genome be downloaded from?

A

UCSC, EBI (Ensembl), or NCBI (RefSeq)

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22
Q

Why is NCBI RefSeq recommended for looking at the reference genome?

A

It has a more conventional numbering system that is used in analyses e.g. Chr1.
Files are an unambigious format.
IDs are uniquely labelled with an accession and version number.

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23
Q

What can you do if you have a reference position in UCSC or Ensembl format and you want it in RefSeq format?

A

RefSeq site has a table for rapid conversion of IDs.

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24
Q

What makes a Transcript Reference Sequence Record different from a Genomic Reference Sequence Record?

A

A Transcript Reference Sequence Record needs to contain functional information, e.g. exon boundaries, transcription start and stop sites etc.

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25
Q

How is functional information stored in a transcript reference sequence record?

A

In Metadata: Sequence ID, CDS start/end, Translation ID/sequence, publications, features

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26
Q

When considering genes from an informatics perspective, what are we really referring to?

A

A collection of transcript reference sequences, and sometimes functional reference sequences, and how they map onto a chromosomal reference sequence

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27
Q

What are General Feature Format files?

A

A simple tab-delimited text file that describes how transcript reference sequences are mapped onto a genomic reference sequence. A single feature per line.

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28
Q

Why might you find identical transcripts aligning differently to a given genome build between RS providers?

A

They may have different alignment algorithms

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29
Q

What formats are there for files detailing how transcript RS’s map to genomic RS’s? Which is widely used?

A

GTF and GFF are both types of files suitable, with different file formats. GFF3 is widely used for representing genomic and transcriptomic features including gene annotations, alignments and other features.

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30
Q

What do GFF3 files start with?

A

A header with metadata about the file, beginning with a #

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31
Q

What are some of the columns of feature lines in a GFF3 file?

A

Sequence ID - where the feature is located.
Source - The database or software tool
Type - gene, exon, transcript
Start
End
Score of quality

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32
Q

How is the strand denoted in GFF3 files?

A

+ or -

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33
Q

What is the ‘Phase’ in GFF3 files?

A

It is for coding sequences, either 0, 1 or 2, to denote the phase of the feature, e.g. the reading frame.

34
Q

What are some attribute tags in a GFF3 file?

A

ID; Name; Alias; Parent (e.g. A gene is the parent of an exon)

35
Q

What does LRG stand for?

A

A Locus Reference Genome

36
Q

What are LRGs created for?

A

LRGs are created for clinical reporting, in order to create a stable gene sequence and annotations. They are used for variant reporting and annotation.

37
Q

How are LRGs made?

A

They’re curated by experts and they have the minimal set of transcripts, ideally 1

38
Q

Before GRCh37 the genome sequence was too poor for clinical reporting, what was used instead?

A

GENE reference sequences which transcripts were annotated against.

39
Q

How to LRGs provide stability to genomic references?

A

Because we need unique stable identifiers that are not versioned in an ideal world, LRGs came along to try and establish a coordinate system that is independent of upgrades to the reference genome assembly and will map to present and past assemblies.

40
Q

What do we need to happen to have LRGs be fully useful?

A

A faster convergence between RefSeq and Ensembl. Need multidirectional data exchange between them

41
Q

LRGs are well supported, provide evidence of this

A

They were integrated into different genome browsers for visualisation in genomic context with other existing annotations. And they are compatible with HGVS nomenclature.

42
Q

What is now obsolete in the GRCh38 era?

A

LRGs and GENE reference sequences

43
Q

What are the issues with LRGs?

A

They were too low coverage, and now too old so can’t be aligned to GRCh38

44
Q

What are the take aways from LRGs?

A

They were designed as static reference sequences for standardised clinical practice, from before we had a good reference genome. They are difficult to incorporate new evidence into because they are static, and can’t be updated without creating a new LRG.

45
Q

What does MANE stand for?

A

Matched Annotation between NIH and ENSEMBL.

46
Q

MANE was built on what?

A

The LRG project

47
Q

What was MANE made for?

A

To ensure each gene had at least one identical transcript from end to end, including exon break points, in both the ENSEMBL and RefSeq datasets.

48
Q

What coverage of genes does MANE have compared to LRGs?

A

Much better. 98% compared to 15%. But LRGs did help to inform MANE.

49
Q

MANE ensures transcript IDs are what?

A

Interchangeable between RefSeq and ENSEMBL.

50
Q

LRGs tried to use just one transcript for each gene ideally. But MANE intends to include what?

A

MANE intends to include a comprehensive set of clinical transcripts based on the most up to date scientific and clinical evidence

51
Q

Why do HGVS stress that we must use unique and stable identifiers?

A

Otherwise variant reporting can easily lose track of the reference sequence against which we are describing variants.

52
Q

HGVS numbering states the most ____ position of the variation?

A

The most 3’ position, this is the nucleotide that is arbitrarily described as changed.

53
Q

NM_007298.3 refers to what?

A

A single stable transcript sequence that will never change over time.

54
Q

What would you do if NM_007298.3 needed to have a polyA tail removed?

A

The ID must also change, to NM_007298.4

55
Q

What’s the definition of a variant?

A

A sequence level change between a query sequence in comparison to the aligned position in a reference sequence

56
Q

For correct variant naming, you need to reference sequence to be what?

A

Widely available.
Well annotated (TSS, UTRs, Exon boundaries)
Maintained.
Uniquely identifiable.
With the appropriate meta data. (accession numbers, and versions, definitions, organism, related articles, annotations, revision history).

57
Q

What are two terms similar to variant that are now outdated?

A

Mutation (any DNA change in sequence), and Polymorphism (any mutation with a frequency >1%).

58
Q

Who came up with the SNV interpretation guidelines?

A

AMCG and AMP

59
Q

What does a VCF file stand for?

A

Variant call format.

60
Q

What does a VCF file do?

A

Describe genome level variation using a genome coordinate based system. Might be point mutations , indels, deletions, copy gains, translocations.

61
Q

What is the HGVS Nomenclature for a substitution?

A

g.1322G>T

62
Q

What is the HGVS Nomenclature for a deletion?

A

g.3601_3627del

63
Q

What is the HGVS Nomenclature for a inversion?

A

g.495_499.inv

64
Q

What is the HGVS Nomenclature for a duplication?

A

g.3661_3702dup

65
Q

What is the HGVS Nomenclature for a conversion? (Also what is a conversion?)

A

g.333_590con1844_2101
Think it’s a non reciprocal translocation of a region

66
Q

What is the HGVS Nomenclature for an insertion?

A

g.7339_7340insTAGG

67
Q

What is the HGVS Nomenclature for a deletion-insertion (delins)

A

g.112_117delinsTG

68
Q

Variant names should be simple. But to add additional context what can you add?

A

Descriptive terms from Sequence Ontology. These can relate to biological features such as binding_site and exon

69
Q

Sequence Ontology terms can be mutable (can change), so what must you provide when using them with variant names?

A

An SO accession number e.g. transcript_ablation - SO:0001893

70
Q

What is the standard format for describing variants, what’s the name for it?

A

The HUGO HGVS format. It’s due an update in 2024 as they do evolve.

71
Q

What was the first molecular disease identified? And what was the cause?

A

Sickle cell anemia. An abnormal beta globin chain due to Glu>Val / A>T change.

72
Q

If we have seen a genomic change, what do we need to do when we write it as a protein change?

A

Annotate that it is predicted unless it has been confirmed by protein sequencing or RNA sequencing.

73
Q

When annotating/naming a protein amino acid change, what important about the numbering of the amino acid?

A

The Methioinine at position 1 is usually cleaved off during translation, however we include the methioinine in the sequence numbering. So position 7 will actually only be the 6th amino acid in the final protein.

74
Q

Sequences start with N and then another letter. What do these represent?
NC
NG
NM
NP

A

Chromosome level
Gene level
mRNA/transcript level
protein level

75
Q

What letters come after the sequence/transcript reference for these?
NC_000011.3:
NG_003345.2:
NM_000651.3:
NP_000815.7:

A

NC_000011.3:g.
NG_003345.2:g.
NM_000651.3:c.
NP_000815.7:p.

76
Q

Where does numbering start for transcripts? i.e. what is c.1?

A

c.1 is the A of the ATG initiation codon. So it starts at a negative position in the 5’ UTR.

77
Q

What are MANE Select Plus Clinical Transcripts?

A

They are being created as a standardised set of additional clinically relevant reference transcripts for genes that are known to use alternatively spliced transcript isoforms.

78
Q

What is the cause of 90% of cases of the AD disease classic Ehlers-Danlos Syndrome (cEDS)

A

Pathogenic variants in either COL5A1 (typically haploinsufficiency) or COL5A2 (dominant negative - mutant protein interrupts function of wild type protein)

79
Q

Some classic Ehlers-Danlos Syndrome (cEDS) patients show a recessive inheritance pattern from a pathogenic variant in COL5A1. Why is this?

A

COL5A1 encodes two alpha1 chains that along with the third alpha2 chain from COL5A2, form the mature collagen V heterotrimer. COL5A1 produces two alternatively spliced transcript variants using mutually exclusive exons, leading to isoform A (~70% expression) with exon 64a, and isoform B (~30% of expression) with exon 64b. It’s something to do with this, but I don’t actually have an explanation…

80
Q

MANE Select Plus clinical transcripts capture all the what?

A

They are able to capture all pathogenic variant information

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