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oddgenes

A list of weird gene annotations or things that break bioinformatics assumptions

See also https://github.com/cmdcolin/oddbiology/ for more weird bio

Gene structures

1bp length exon

Evidence given for a 1bp length exon in Arabadopsis and different splicing models are discussed

http://www.nature.com/articles/srep18087

Another 1bp exon is discussed here https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177959

Microexons in general are an interesting topic and are "involved in important biological processes in brain development and human cancers" (ref https://www.cell.com/molecular-therapy-family/nucleic-acids/fulltext/S2162-2531(23)00013-6) yet are commonly misannotated (e.g. in plants https://www.nature.com/articles/s41467-022-28449-8)

See also cryptic splicing

0bp length exon

The phenomenon of recursive splicing can remove sequences progressively inside an intron, so there can exist "0bp exons" that are just the splice-site sequences pasted together.

"To identify potential zero nucleotide exon-type ratchet points, we parsed the RNA-Seq alignments to identify novel splice junctions where the reads mapped to an annotated 5' splice site and an unannotated 3' splice site, and the genomic sequence at the 3' splice site junction was AG/GT"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529404/

Very large introns

Satellite DNA study uncovers megabase scale introns https://www.biorxiv.org/content/early/2018/12/11/493254

An example in this paper kl-3 spans 4.3 million bp

In human, an example is Dystrophin. "Dystrophin is coded for by the DMD gene – the largest known human gene, covering 2.4 megabases (0.08% of the human genome) at locus Xp21. The primary transcript in muscle measures about 2,100 kilobases and takes 16 hours to transcribe; the mature mRNA measures 14.0 kilobases" https://en.wikipedia.org/wiki/Dystrophin

Note: these very large introns require very large amounts of DNA to be transcribed into RNA, before just removing most of the transcribed RNA via intron splicing, which is sort of "wasteful" on a molecular level

Small introns

According to wikipedia "a 2015 study suggests that the shortest known metazoan intron length is 30 base pairs (bp) belonging to the human MST1L gene (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675715/). The shortest known introns belong to the heterotrich ciliates, such as Stentor coeruleus, in which most (> 95%) introns are 15 or 16 bp long (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659724/)"

A novel splicing factor may be involved in small introns https://www.news-medical.net/news/20240215/Novel-splicing-mechanism-for-short-introns-discovered.aspx

Backsplicing and circRNAs

The process of "backsplicing" circularizes RNAs. There can be alternative backsplicing too

See https://academic.oup.com/nar/article/48/4/1779/5715065

Very large number of isoforms in Dscam

"Dscam has 24 exons; exon 4 has 12 variants, exon 6 has 48 variants, exon 9 has 33 variants, and exon 17 has two variants. The combination of exons 4, 6, and 9 leads to 19,008 possible isoforms with different extracellular domains (due to differences in Ig2, Ig3 and Ig4). With two different transmembrane domains from exon 17, the total possible protein products could reach 38,016 isoforms"

Ref https://en.wikipedia.org/wiki/DSCAM https://www.wikigenes.org/e/gene/e/35652.html

Translational frameshift/Ribosomal frameshift/Programmed ribosomal frameshift

"The main distinction between frameshifts resulting from mutation and those resulting from ribosomal frameshifting is that the latter are controlled by various mechanisms found in codons...Certain codons take longer to translate, because there are not equal amounts of tRNA of that particular codon in the cytosol..." which leads to ribosomal slippage into an alternative reading frame.

Ref https://en.wikipedia.org/wiki/Translational_frameshift

https://www.sciencedirect.com/topics/neuroscience/ribosomal-frameshifting

SARS-CoV-2 uses ribosomal frameshifting and this video shows a 3D animation of the process, showing a 'pseudoknot' in the RNA contributes to it https://www.youtube.com/watch?v=gLcueW61QMU

Another lecture explaining frameshift in viruses https://youtu.be/b5BX5A3dGUQ?t=2980

Ribosome hopping

"Ribosome hopping involves ribosomes skipping over large portions of an mRNA without translating them" Ref https://pubmed.ncbi.nlm.nih.gov/24711422/

Internal Ribosome Entry Sites (IRES)

"Eukaryotic mRNAs are typically monocistronic and translated only a single Open Reading Frame. Some viruses can reinititate translation after translation termination using an IRES" Ref https://en.wikipedia.org/wiki/Internal_ribosome_entry_site

A Stop codon that is not a stop codon

In some cases a stop codon is not interpreted as such. When it is interpreted, it is sometimes called "Stop codon readthrough" and can encode for an amino acid. The amino acid Selenocysteine is coded for by a stop codon (https://en.wikipedia.org/wiki/Selenocysteine) and Pyrrolysine also is coded for by a stop codon (https://en.wikipedia.org/wiki/Pyrrolysine). Both of these lie outside the conventional 20 amino acid code

There are several other stop codon modifications described here https://www.nature.com/articles/nrg3963

Selenocysteine can be coded via a SECIS sequence https://en.wikipedia.org/wiki/SECIS_element and resulting products are called selenoproteins

Pyrolysine is coded through a pyIT tRNA gene that interprets the amber stop codon as pyrolysine

Stop codons can also be removed by RNA editing, as in the case of mammalian apoliprotein B, B100 isoform.

Some bacterial systems are suspected to have no dedicated stop codon but instead all termination is context dependent https://pubmed.ncbi.nlm.nih.gov/27426948/

Readthrough transcription

See also this Ensembl blog on annotating readthrough transcription which joins multiple genes http://www.ensembl.info/2019/02/11/annotating-readthrough-transcription-in-ensembl/

RNA-seq often makes extremely compelling cases for two-or-more different genes to be conjoined by splicing

Some algorithms e.g. mikado https://academic.oup.com/gigascience/article/7/8/giy093/5057872 try to avoid this calling it artifactual fusion/chimera that can be due to some tandem duplication but it does seem to be very prevalent in real data sets

Non-canonical splice sites

The standard splice site recognition sequence is an GU in RNA (or GT in DNA) on the 5' end and AG on the 3' (remember, goes 5' to 3'). This recognition motif accounts for the large majority of splicing. If a different sequence is used it is said that a different spliceosome complex is being used "minor spliceosome"

https://en.wikipedia.org/wiki/Minor_spliceosome

Cryptic splice sites

Some exons harbor internal splice sites (e.g. they get split) that might be unused or underused and are so called "cryptic splice sites"

Review article https://academic.oup.com/nar/article/39/14/5837/1382796

The snaptron project from Ben Langmead analyzed huge amounts of RNA-seq public data and found many types of these cryptic splicing http://snaptron.cs.jhu.edu/

Wobble splicing

NAGNAG, GYNGYN, repeats of the splicing signal cause modified transcriptional behavior

"Another mechanism introducing small variations to protein isoforms is wobble splicing. Here, a GYN repeat at the donor splice site (5’ splice site; Y stands for C or T and N stands for A, C, G, or T) or an NAG repeat at the acceptor splice site (3’ splice site) leads to subtle length variations in the spliced transcripts and finally to alternative isoforms differing in few amino acids." ref https://onlinelibrary.wiley.com/doi/full/10.1002/bies.201900066?af=R

Intron retention

Intron retention (IR) is a phenomenon where intron sequence is preserved, or doesn't get spliced out, in mature RNA

It can occur in both abnormal and normal biological conditions. Transcript with IR often undergo nonsense-mediated decay.

Self-splicing RNA

Normally RNA is spliced by a specialized protein complex called a spliceosome. There is also self-splicing RNA where the splicing is done itself with RNA

The Group 1 intron type mentioned above is a "self splicing" function of RNA not requiring external spliceosome https://en.wikipedia.org/wiki/Group_I_catalytic_intron

Group 2 and group 3 with similar but different mechanisms also exist

Bulge helix bulge introns (archael tRNA)

There are some small intron types called "bulge-helix-bulge" in archaea (and other organisms)

From https://www.embopress.org/doi/full/10.1038/embor.2008.101

The figure above shows that the orange part is excised as an intron for the tRNA

Twintron

A twintron is essentially an intron-within-an-intron, and has similar qualities to the 0bp splicing mentioned above. A twintron may be defined as one where the internal intron has to be spliced first before the outer one is (may be referred to as a nested intron if internal is not necessary to be spliced out before the next)

See https://en.wikipedia.org/wiki/Twintron

Figure from https://doi.org/10.1080/15476286.2015.1103427 showing twintron conformations with a) spliceosome type introns (the spliceosome is a protein complex that performs splicing) b) ribosomal type introns (e.g. self splicing RNA) and c) tRNA/bulge helix bulge type introns

Introns in viruses

Introns were actually first discovered in viruses before eukaryotes, and the wikipedia article on introns details this

https://en.wikipedia.org/wiki/Intron#Discovery_and_etymology (see also https://www.proquest.com/docview/303935681/)

Codon tables

Many eukaryotes use the "standard genetic code" for changing codons to amino acids but frequent changes occur across the domains of life. The NCBI "genetic code" table lists several of these and contains recent additions for particular species

https://www.ncbi.nlm.nih.gov/Taxonomy/Utils/wprintgc.cgi#SG31

One article explains how alternative genetic codes work https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207430/

Untranslated regions

The 5' and 3' UTR (un-translated region) is a part of the pre-mRNA at the start and end of the gene respectively that is spliced away in the mature RNA

This blog post by Ensembl shows how they annotate UTR and 19kb 3' UTR in Grin2b http://www.ensembl.info/2018/08/17/ensembl-insights-how-are-utrs-annotated/

They have many important functionality and are often targets of miRNA binding which leads to degradation.

Polyadenylation

Polyadenylation is the addition of a string of "A"s to the pre-mRNA on the 3' end of the transcript (the "A"s are not part of the genome). There is a "poly-A signal" in the genome that is recognized by the "RNA cleavage complex" and after it is cleaved, the poly-A tail is added https://en.wikipedia.org/wiki/Polyadenylation

A survey of poly-A using Oxford Nanopore found a transcript isoform with a 450bp poly-A tail ENST00000581230, with intron retention being a possible correlate of having a longer poly-A tails https://www.biorxiv.org/content/early/2018/11/09/459529.article-info

"Intronic polyadenylation" can also occur, which leads to different isoforms (the wording intronic polyadenylation is maybe a bit odd, but my understanding is that the "transcription stops" at a poly-A site inside an intron essentially)

Figure showing "intronic polyadenylation" (IpA) creating a different isoform from https://www.nature.com/articles/s41467-018-04112-z

In mammalian mitochondria, some messages are polyadenylated after a U residue which is the U in a UAA stop codon -- the polyadenylation completes the stop codon

Circular chromosomes

Circularized chromosomes should be unsurprising to anyone working with plasmids and many prokaryotic genomes but for gene annotation formats which use linear coordinates, representing anything wrapping around the origin is challenging.

Many genomic viewers do not do this well. For GFF format this is done by making the end go past the end of the genome. Below, the genome is 6407 bp in length, but the CDS feature extends past this and sets Is_circular=true

##gff-version 3.2.1
# organism Enterobacteria phage f1
# Note Bacteriophage f1, complete genome.
J02448  GenBank region  1      6407    .       +       .       ID=J02448;Name=J02448;Is_circular=true;
J02448  GenBank CDS     6006   7238    .       +       0       ID=geneII;Name=II;Note=protein II;

Dynamic DNA structures in vivo

The replication of the 2 micron plasmid found in Saccharomyces cerevisiae relies on a programmed DNA rearrangement; in any population of cells two different states of the 2 micron plasmid can be expected and these will interconvert in later generations. Reference: https://pubmed.ncbi.nlm.nih.gov/23541845/

Overlapping genes

It is possible for gene sequences to overlap, on different strands (sense-antisense) or same strand, possibly in alternate coding frames

https://en.wikipedia.org/wiki/Overlapping_gene

Some articles

Flybase

Chimeric genes

The gene Jingwei is a chimera (or fusion) of two genes, alcohol dehydrogenage and yellow emperor. Many chimeras are damaging but this has been selected for

http://www.pnas.org/content/101/46/16246

Two Cytochrome P450 genes that don't confer any insecticide resistance on their own but a chimeric P450 does https://pubmed.ncbi.nlm.nih.gov/22949643/

Wormbase

Adding leader sequence to mRNA

"About 70% of C. elegans mRNAs are trans-spliced to one of two 22 nucleotide spliced leaders. SL1 is used to trim off the 5' ends of pre-mRNAs and replace them with the SL1 sequence. This processing event is very closely related to cis-splicing, or intron removal."

The region that is spliced out is called an outron

http://www.wormbook.org/chapters/www_transsplicingoperons/transsplicingoperons.html

Polycistronic transcripts/operons

Although prevalent in bacteria, operons are not common in eukaryotes. However, they are common in C. elegans specifically. "A characteristic feature of the worm genome is the existence of genes organized into operons. These polycistronic gene clusters contain two or more closely spaced genes, which are oriented in a head to tail direction. They are transcribed as a single polycistronic mRNA and separated into individual mRNAs by the process of trans-splicing"

http://www.wormbook.org/chapters/www_overviewgenestructure.2/genestructure.html

Trans-splicing of exons on different strands

A pre-mRNA from both strands of DNA eri6 and eri7 are combined to create eri-6/7

Source http://forums.wormbase.org/index.php?topic=1225.0 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756026/

Exon shared across different genes

An example from drosophila, C. elegans, and rat shows a gene with a 5' exon being shared between two genes

Source http://forums.wormbase.org/index.php?topic=1225.0 https://www.fasebj.org/doi/full/10.1096/fj.00-0313rev

An example here shows 5'UTR exons shared across different olfactory receptor genes ("Some OR genes share 5'UTR exons")

https://www.biorxiv.org/content/biorxiv/early/2019/09/19/774612.full.pdf

Evolution

Possible adaptive bacteria->eukaryote HGT

A possible horizontal gene transfer from bacteria to eukaryotes is found in an insect that feeds on coffee beans. Changes that the gene had to undergo are covered (added poly-A tail, shine-dalgarno sequence deleted)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306691/

also https://www.cell.com/cell/fulltext/S0092-8674(19)30097-2

Transgenerational epigenetic inheritance

This phenomena of epigenetic modifications being passed down across generations garners a lot of media attention and scientific attention. The idea of it being influenced by what "one does in life" such as experiencing famine is also very interesting.

https://en.wikipedia.org/wiki/Transgenerational_epigenetic_inheritance

There are skeptics also http://www.wiringthebrain.com/2018/07/calibrating-scientific-skepticism-wider.html but the science is hopefully what speaks for itself

Codon usage

Alternative start codons

"The most common start codons for known Escherichia coli genes are AUG (83% of genes), GUG (14%) and UUG (3%)"

"Here, we systematically quantified translation initiation of green fluorescent protein (GFP) from all 64 codons and nanoluciferase from 12 codons on plasmids designed to interrogate a range of translation initiation conditions."

https://www.sciencedaily.com/releases/2017/02/170221080506.htm

Testing in eukaryotes has also revealed alternative starts being viable https://en.wikipedia.org/wiki/Start_codon#Eukaryotes

Molecular

4-base/quaternary/quadruplet codons

3-base codon system is assumed by many, but engineered tRNAs can decode 4-base codons with potential applications for using amino acids outside the 20 canonical ones

review https://elifesciences.org/articles/78869

evolving improved 4-base efficiency https://www.nature.com/articles/s41467-021-25948-y

Complex DNA structures

The standard DNA double stranded helix is called B-DNA (https://genome.cshlp.org/content/early/2018/11/06/gr.241257.118.abstract)

Other geometries are possible https://en.wikipedia.org/wiki/Nucleic_acid_double_helix#Helix_geometries

Complex structures such as four stranded quadruplex have been found that could have biological functions

See https://news.cnrs.fr/articles/unlocking-the-secrets-of-four-strand-dna

Polytene chromosome

Some organisms, famously insects in their salivary glands, create many copies of genes through multiple phases of incomplete DNA replication https://en.wikipedia.org/wiki/Polytene_chromosome

Figure source https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768140/

"Polytene chromosomes are produced by endoreplication, in which chromosomal DNA undergoes mitotic replication, but the strands do not separate. Ten rounds of endoreplication produces 2^10 = 1,024 DNA strands, which when arranged alongside of each other produce distinctive banding patterns. Endoreplication occurs in cells of the larval salivary glands of many species of Diptera, and increases production of mRNA for Glue Protein that the larvae use to anchor themselves to the walls of (for example) culture vials." from https://www.mun.ca/biology/scarr/Polytene_Chromosomes.html

Endoreplication

The above section about polytene chromosomes mentions endoreplication but this can also affect many other contexts and was mentioned as an issue in genome assembly of some plants. A talk given about vanilla bean found a lot of endoreplication during their genome assembly which leads to very uneven coverage. They tried to select tissue samples that had the least amount of endoreplication. https://plan.core-apps.com/pag_2023/abstract/e26dbeb1-df8f-4c57-a062-dcaf881b79f4

Endo-(poly)ploidy

Different cells may have different numbers of copies of chromosomes and it also occurs in some human cell types: "polyploid cells can exist in otherwise diploid organisms (endopolyploidy). In humans, polyploid cells are found in critical tissues, such as liver and placenta. A general term often used to describe the generation of polyploid cells is endoreplication, which refers to multiple genome duplications without intervening division/cytokinesis" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442802/

Programmed DNA elimination

"While we commonly assume the genome to be largely identical across different cells of a multicellular organism, a number of species undergo a developmentally regulated elimination process by which the genome in somatic cells is reduced, while the germline genome remains intact. This process, called Programmed DNA Elimination (PDE), affects a number of species including copepod crustaceans, lamprey fish, single-celled ciliates and nematode worms (though not C. elegans!)."

From ISMB2023 video "Deciphering developmentally programmed DNA elimination in Mesorhabditis nematodes" https://www.youtube.com/watch?v=2x6ElKeISRY

See also the term "internal eliminated sequences" (IES)

Range of ploidy

Wikipedia lists this table with examples of organisms with different ploidy https://en.wikipedia.org/wiki/Polyploidy#Types

  • haploid (one set; 1x), for example male European fire ants
  • diploid (two sets; 2x), for example humans
  • triploid (three sets; 3x), for example sterile saffron crocus, or seedless watermelons, also common in the phylum Tardigrada[7]
  • tetraploid (four sets; 4x), for example, Plains viscacha rat, Salmonidae fish,[8] the cotton Gossypium hirsutum[9]
  • pentaploid (five sets; 5x), for example Kenai Birch (Betula kenaica)
  • hexaploid (six sets; 6x), for example some species of wheat,[10] kiwifruit[11]
  • heptaploid or septaploid (seven sets; 7x)
  • octaploid or octoploid, (eight sets; 8x), for example Acipenser (genus of sturgeon fish), dahlias
  • decaploid (ten sets; 10x), for example certain strawberries
  • dodecaploid or duodecaploid (twelve sets; 12x), for example the plants Celosia argentea and Spartina anglica [12] or the amphibian Xenopus ruwenzoriensis.
  • tetratetracontaploid (forty-four sets; 44x), for example black mulberry[13]

DNA modifications

There are many chemical modifications that can happen to DNA, leading to an "extended alphabet" with functional changes.

A common DNA modification is called methylation. The most common is a 5mC modification, a methylation of the letter C, and is mostly found in a CpG (a C followed by a G in the genome)

Many other modifications exist, see https://dnamod.hoffmanlab.org/

RNA world

RNA modifications

https://www.hindawi.com/journals/jna/2011/408053/tab1/

updated link on hindawi should point here http://mods.rna.albany.edu/mods/ (this link now dead too, see maybe http://genesilico.pl/modomics/modifications)

RNA editing

RNA editing is a post-transcriptional modification to the mRNA, which can change what we would see when the RNA is sequenced. A-to-I editing is common in some species, which would make the RNA, when sequenced, appear to have a G instead of an A. If the genome was sequenced, it would not show a SNP but the RNA-seq would appear to have A->G.

RNA editing can be conditional; mammalian apolipoprotein B is synthesized as a 48 kilodalton form or a 100 kilodalton form; the latter is created by editing out a stop codon to enable read through

Other editing occurs also https://en.wikipedia.org/wiki/RNA_editing

Editing in some ciliate mitochondria adds information to messages and can increase the length of the final message by over 2-fold.

Post-Transcriptional Exon Shuffling (PTES)

While the exon structure of most mRNAs follows the linear sequence of the transcribed DNA, there are a few cases where mature mRNAs contain exons in a non-linear order.

Al-Balool and Weber et al (2011) validated several cases of PTES in human genes that are evolutionarily conserved, including MAN1A2, PHC3, TLE4, and CDK13: https://genome.cshlp.org/content/21/11/1788.short

Maternal RNAs being passed down

Maternal RNAs can show activity in the zygote (e.g. https://en.wikipedia.org/wiki/Maternal_to_zygotic_transition) which can lead to complex transgenerational effects

Lowly expressed RNA has large effects

A lncRNA VELUCT almost flies under the radar in a lung cancer screen due to being very lowly expressed such that it is "below the detection limit in total RNA from NCI-H460 cells by RT-qPCR as well as RNA-Seq", however this study confirms it as a factor in experiments

https://www.ncbi.nlm.nih.gov/pubmed/28160600?dopt=Abstract

Note that X inactivation relies on relatively lowly expressed RNA also https://twitter.com/mitchguttman/status/1454256452990734336

X chromosome inactivation

X chromosome inactivation is produced by a non-coding transcript called Xist that is transcribed on the X that is being inactivated. The Xist transcript "coats" the X chromosome with itself. An anti-sense transcript called Tsix regulates Xist

https://en.wikipedia.org/wiki/XIST

https://en.wikipedia.org/wiki/X-inactivation#Xist_and_Tsix_RNAs

https://www.youtube.com/watch?v=y3ST0whbA4k (great series from iBiology on X chromosome inactivation)

Types of RNA

There are many types of RNA some more weird an exotic than others, a large list https://en.wikipedia.org/wiki/List_of_RNAs

Some are named based on where they are expressed or active

Others are uniquely shaped. There are also circular RNA for example https://en.wikipedia.org/wiki/Circular_RNA

Small and long non coding RNAs often fold into important structural shapes

Proteins

Removal of start amino acid in proteins

This is probably obvious to many people who work on proteins but while the genome has almost all genes starting with a start codon which produces methionine, this is often post translationally removed https://en.m.wikipedia.org/wiki/Methionyl_aminopeptidase

Inteins

An intein is like an intron but for a protein, a segment of protein that is spliced out https://en.wikipedia.org/wiki/Intein

See section here https://github.com/The-Sequence-Ontology/Specifications/blob/master/gff3.md#pathological-cases

Polyprotein

Viral sequences can create a polyprotein which is fully transcribed and translated before being cleaved by a protease. In some viruses (such as coronaviruses) their translation involves ribosomal frameshifting.

Dengue, HIV, flu, etc. use this

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040172/ https://www.sciencedirect.com/science/article/abs/pii/S0959440X15000597

Interesting PDB entries

From another repo https://github.com/molstar/molstar/blob/master/docs/docs/misc/interesting-pdb-entries.md

Transposons

Cross-species BovB transposon transfers

Or "How a quarter of the cow genome came from snakes" http://phenomena.nationalgeographic.com/2013/01/01/how-a-quarter-of-the-cow-genome-came-from-snakes/

Source http://www.pnas.org/content/110/3/1012.full

LINE1 important for embryonic development

Transposon activity can mutate DNA as it will insert itself into the genome. The genome has functions for keeping transposons inactive. However, evidence shows that the LINE1 is important for embryonic development.

https://www.ucsf.edu/news/2018/06/410781/not-junk-jumping-gene-critical-early-embryo

Immunity

VDJ Recombination

VDJ recombination is a process of somatic recombination that is done in immune cells. It recognizes certain "recombination signal sequences". Different gene segments of class "V", class "D", and class "J" exons (sometimes the exons are referred to as "genes" themselves in literature) are somatically rearranged into coherent genes that are then transcribed to create immune diversity. Splicing at the DNA level is not precise, with terminal transferase adding random nucleotides to further diversify the sequences

https://en.wikipedia.org/wiki/V(D)J_recombination

MHC region

The MHC region is a very polymorphic region of the genome on chr6. I'm not personally familiar with all the intricacies of MHC beyond that it is a unique contributor of some additional hg38 alternative loci/contigs due to it's high diversity

Structural variations

Tandem duplication

A tandem duplication can be seen as a piece of DNA that copied side by side in the genome. But why would this occur?

Some biological factors can include

  • replication slippage
  • retrotransposition
  • unequal crossing over (UCO).
  • imperfect repair of double-strand breaks by nonhomologous end joining (NHEJ) (specifically generates 1-100bp range indels according to article)

Ref https://academic.oup.com/mbe/article/24/5/1190/1038942

Pseudogenes

A pseudogene that can protect against cancer in Elephants

The LIF gene has many copies in Elephant but many are non-functional. One copy can be "turned back on" and play a role in cancer protection. They call this a "zombie gene"

https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31145-8

https://www.sciencealert.com/lif6-pseudogene-elephant-tumour-suppression-solution-petos-paradox

Regulation

Intron mediated enhancement (IME)

It has been shown that some intron sequences can enhance expression similar to how promoter sequences work https://en.wikipedia.org/wiki/Intron-mediated_enhancement

The first intron of the UBQ10 gene in Arabidopsis exhibits IME, and "the sequences responsible for increasing mRNA accumulation are redundant and dispersed throughout the UBQ10 intron" http://www.plantcell.org/content/early/2017/04/03/tpc.17.00020.full.pdf+html

The classic peppered moth phenotype is a intron TE insertion https://www.nature.com/articles/nature17951 (may not be strictly IME, I'm personally not sure)

Bidirectional promoters

Wikipedia https://en.wikipedia.org/wiki/Promoter_(genetics)#Bidirectional_(mammalian)

"Bidirectional promoters are a common feature of mammalian genomes. About 11% of human genes are bidirectionally paired."

"The two genes are often functionally related, and modification of their shared promoter region allows them to be co-regulated and thus co-expressed"

Chromosomal abnormalities

Loss of Y chromosome

Older men can have a mosaic loss of the Y chromosome in blood samples

https://www.karger.com/Article/FullText/508564 (found from https://www.biostars.org/p/9482437/)

may be associated with cardiac issues https://www.science.org/doi/10.1126/science.abn3100

File formats

Non-ACGT letters in fasta files

The latest human genome, for example, downloaded from NCBI, contains a number of Non-ACGT letters in the form of IUPAC codes https://www.bioinformatics.org/sms/iupac.html These represent ambiguous bases.

Here is the incidence of non-ACGTN IUPAC letters in the entire human genome GRCh38.p14 from https://ftp.ncbi.nlm.nih.gov/refseq/H_sapiens/annotation/GRCh38_latest/refseq_identifiers/GRCh38_latest_genomic.fna.gz (same for the "analysis set" files in https://ftp.ncbi.nlm.nih.gov/genomes/all/GCA/000/001/405/GCA_000001405.15_GRCh38/seqs_for_alignment_pipelines.ucsc_ids/)

{
  'B' => 2,
  'K' => 8,
  'Y' => 36,
  'M' => 8,
  'R' => 29,
  'W' => 15,
  'S' => 5
};

Did you expect that in your bioinformatics software? Note that the mouse genome (GRCm38.p5) as far as I could tell does not contain any non-ACGT IUPAC letters

See count_fasta_letters.pl for a script to count this. The UCSC hg38.fa.gz does not have any non-ACGTN letters.

rs SNP identifiers occurring in multiple places

Due to how dbSNP is created (based on alignments), an rs ID can occur in multiple places on the genome https://www.biostars.org/p/2323/

Weird characters in FASTA sequence names

In response to hg38 including a colon in sequence names, which conflicts with commonly used representation of a range as chr1:1-100 for example (note: SAMv1.pdf contains a regex to help resolve this), people analyzed meta-character frequencies in sequence names samtools/hts-specs#291

ENA
#   16927
*   1
,   231
-   122563947
.   521540419
/   236951
\   0
:   30181
;   72892
=   186611
@   3713
|   949

Broad(?)
     12 #
    527 *
    357 ,
1451132 -
1492749 .
  86114 /
 233731 :
   2034 =
     17 @
1735713 |

Reference sequences
 # 203
 % 203
 * 525
 + 1
 , 496
 - 154226
 . 1826561
 : 1577
 = 26
 _ 4961932
 | 1098333

Note that commas in FASTA names is being suggested as an illegal character because of the supplementary alignment tag in SAM/BAM using comma separated values

Humongous chromosomes V1

Genomes such as wheat have large chromosomes averaging 806Mbp but the BAI/TBI file formats are limited to 2^29-1 ~ 536Mbp in size (this is due to the binning strategy, the max bin size is listed as 2^29). The CSI index format was created to help index BAM and tabix files with large chromosomes.

Bonus: I made a web tool to help visualize BAI files to show how the binning index works https://cmdcolin.github.io/bam_index_visualizer/

Humongous chromosomes V2

The axolotl genome has individual chromosomes that are of size 3.14 Gbp https://genome.cshlp.org/content/29/2/317.long (2019) which is almost as big as the entire human genome

The BAM and CRAM formats can only store 2^31-1 (~2.14Gbp) length chromosomes however so bgzip/tabix SAM is used (discussion samtools/hts-specs#655)

Largest genomes

Just some honorable mentions for largest genome

Inspired by twitter thread https://twitter.com/PetrovADmitri/status/1506824610360168455

Also see http://www.genomesize.com/statistics.php?stats=entire#stats_top

Humongous CIGAR strings

The CG tag was invented in order to store CIGAR strings longer than 64k operations, since n_cigar_opt is a uint16 in BAM. The CIGAR string is relevant only for BAM files, CRAM uses a different storage mechanism for CIGAR type data (e.g. the reference based compression).

Interesting gene names

Update Dec 2023

I extracted all the genes from a number of model organism databases here https://cmdcolin.github.io/genes/

Here are some random highlights from earlier work

Allele names

Sometimes it is not the gene, but the allele that is named

Ref https://twitter.com/hmdc_mgi/status/1242893531779391496

More reading

Great illustrations of interesting biology, including information about gene names https://twitter.com/vividbiology

Many of the stories behind fly gene nomenclature is available at https://web.archive.org/web/20110716201703/http://www.flynome.com/cgi-bin/search?source=browse including the famous ForRentApartments dot com gene (just kidding but lol https://web.archive.org/web/20110716202150/http://www.flynome.com/cgi-bin/search?storyID=180)

Musing article: "What is in a (gene) name?" https://web.archive.org/web/20180731060319/https://blogs.plos.org/toothandclaw/2012/06/17/whats-in-a-gene-name/

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