A list of weird gene annotations or things that break bioinformatics assumptions
See also https://github.com/cmdcolin/oddbiology/ for more weird bio
Evidence given for a 1bp length exon in Arabidopsis 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
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/
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 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
In human, the TTN (titan) gene has ~364 exons, which is almost double the next most NEB (nebulin) at ~184 exons
https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=7273
"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/)" https://en.wikipedia.org/wiki/Intron#Distribution
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
An algae published about in 2024 encodes a protein PKZILLA-1 that has a mass of 4.7 megadaltons and contains 140 enzyme domains https://cen.acs.org/biological-chemistry/PKZILLA-proteins-smash-protein-size/102/web/2024/08
In human the TITIN gene (in muscle) has almost 4 megadaltons
The DMD gene above, despite being large on the genome, only encodes a 70 kilo-dalton protein (not megadalton!) https://pmc.ncbi.nlm.nih.gov/articles/PMC49288/
The process of "backsplicing" circularizes RNAs. There can be alternative backsplicing too
See https://academic.oup.com/nar/article/48/4/1779/5715065
"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
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 involves ribosomes skipping over large portions of an mRNA without translating them" Ref https://pubmed.ncbi.nlm.nih.gov/24711422/
"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
"Stop codon suppression or translational readthrough occurs when in translation a stop codon is interpreted as a sense codon, that is, when a (standard) amino acid is 'encoded' by the stop codon. Mutated tRNAs can be the cause of readthrough, but also certain nucleotide motifs close to the stop codon. Translational readthrough is very common in viruses and bacteria, and has also been found as a gene regulatory principle in humans, yeasts, bacteria and drosophila.[28][29] This kind of endogenous translational readthrough constitutes a variation of the genetic code, because a stop codon codes for an amino acid. In the case of human malate dehydrogenase, the stop codon is read through with a frequency of about 4%.[30] The amino acid inserted at the stop codon depends on the identity of the stop codon itself: Gln, Tyr, and Lys have been found for the UAA and UAG codons, while Cys, Trp, and Arg for the UGA codon have been identified by mass spectrometry.[31] Extent of readthrough in mammals have widely variable extents, and can broadly diversify the proteome and affect cancer progression.[32] "
https://en.wikipedia.org/wiki/Stop_codon#Translational_readthrough
The amino acid Selenocysteine is coded for by a "opal" (UGA) stop codon (https://en.wikipedia.org/wiki/Selenocysteine)
Is present in all domains of life including humans
As of 2021, 136 human proteins (in 37 families) are known to contain selenocysteine
Selenocysteine can be coded via a SECIS sequence https://en.wikipedia.org/wiki/SECIS_element and resulting products are called (selenoproteins)
Pyrrolysine also is coded for by the "amber" (UAG) stop codon (https://en.wikipedia.org/wiki/Pyrrolysine), not present in humans
"It is encoded in mRNA by the UAG codon, which in most organisms is the 'amber' stop codon. This requires only the presence of the pylT gene, which encodes an unusual transfer RNA (tRNA) with a CUA anticodon, and the pylS gene, which encodes a class II aminoacyl-tRNA synthetase that charges the pylT-derived tRNA with pyrrolysine. "
There are several other stop codon modifications described here https://www.nature.com/articles/nrg3963
as in the case of mammalian apoliprotein B, B100 isoform.
"A posttranscriptional modification of the apoB mRNA by conversion of cytidine into uridine at nucleotide position 6666 changes the genomically encoded glutamine codon CAA at amino acid residue 2153 into a translational stop codon UAA."
https://pubmed.ncbi.nlm.nih.gov/8409768/
There is a stop codon not in the genome, but one is added post-transcriptionally by polyadenylation
Noted in vertebrate mitochondrial section here https://www.ncbi.nlm.nih.gov/Taxonomy/Utils/wprintgc.cgi#SG2
"Flexibility in the nuclear genetic code has been demonstrated in ciliates that reassign standard stop codons to amino acids...Surprisingly, in two of these species, we find efficient translation of all 64 codons as standard amino acids and recognition of either one or all three stop codons"
Termination is therefore "context dependent" rather than a specific 3 letter sequence https://pubmed.ncbi.nlm.nih.gov/27426948/
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
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
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/
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 (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.
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
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
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 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/)
Pieces of the mitochondrial genome can be inserted into the autosomes in eukaryotes
https://en.wikipedia.org/wiki/Nuclear_mitochondrial_DNA_segment
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/
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 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 post-transcriptional polyadenylation completes the stop codon
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;
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/
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
- The novel EHEC gene asa overlaps the TEGT transporter gene in antisense and is regulated by NaCl and growth phase https://www.ncbi.nlm.nih.gov/m/pubmed/30552341/
- Overlapping genes in natural and engineered genomes https://www.nature.com/articles/s41576-021-00417-w
- Uncovering de novo gene birth in yeast using deep transcriptomics https://www.nature.com/articles/s41467-021-20911-3
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/
"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
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
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/
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
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
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
"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
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
The standard DNA double stranded helix is called B-DNA
"There are also triple-stranded DNA forms and quadruplex forms such as the G-quadruplex and the i-motif. " https://en.wikipedia.org/wiki/Nucleic_acid_double_helix
https://en.wikipedia.org/wiki/Triple-stranded_DNA
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
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
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/
"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)
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]
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/
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 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.
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 can show activity in the zygote (e.g. https://en.wikipedia.org/wiki/Maternal_to_zygotic_transition) which can lead to complex transgenerational 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 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)
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
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
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
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
From another repo https://github.com/molstar/molstar/blob/master/docs/docs/misc/interesting-pdb-entries.md
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
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
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
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
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
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
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)
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"
A child can inherit both copies of the genome from one parent, instead of the "usual" one copy from mom, one from dad
"UPD arises usually from the failure of the two members of a chromosome pair to separate properly into two daughter cells during meiosis in the parent’s germline (nondisjunction). The resulting abnormal gametes contain either two copies of a chromosome (disomic) or no copy of that chromosome (nullisomic), instead of the normal single copy of each chromosome (haploid). This leads to a conception with either three copies of one chromosome (trisomy) or a single copy of a chromosome (monosomy). If a second event occurs by either the loss of one of the extra chromosomes in a trisomy or the duplication of the single chromosome in a monosomy, the karyotypically normal cell may have a growth advantage as compared to the aneuploid cells. UPD results primarily from one of these “rescue” events"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111049/
Older men can have a mosaic loss of the Y chromosome https://en.wikipedia.org/wiki/Mosaic_loss_of_chromosome_Y
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
Similar to the above but for X https://www.cancer.gov/news-events/press-releases/2024/genetic-factors-predict-x-chromosome-loss
In organisms with normally linear chromosomes, circular or "ring" chromosomes can form from aberrant processes https://en.wikipedia.org/wiki/Ring_chromosome
There are also smaller fragments that can be circularized called "supernumerary small ring chromosomes" (sSRC) or their normal linear part, "supernumary small marker chromosomes" (sSMC) https://en.wikipedia.org/wiki/Small_supernumerary_marker_chromosome
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.
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/
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
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/
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)
Just some honorable mentions for largest genome
- Polychaos dubium/Amoeba dubium/Chaos chaos - ~600-1300Gbp (unsequenced, 1968 back of envelope measurement, needs confirmation) https://en.wikipedia.org/wiki/Polychaos_dubium (another ref https://bionumbers.hms.harvard.edu/bionumber.aspx?&id=117342)
- Dinoflagellates - up to 250Gbp (unsequenced, 1987 book referenced in this paper, needs confirmation, has weird chromosome "rod-like" structures) https://www.nature.com/articles/s41588-021-00841-y
- Tmesipteris oblanceolata (fork fern) - ~160Gb (unsequenced) https://www.nature.com/articles/d41586-024-01567-7
- Paris japonica (canopy plant) - ~149Gbp (unsequenced) https://en.wikipedia.org/wiki/Paris_japonica
- Tmesipteris_obliqua (fern) - ~147Gbp (unsequenced) - https://en.wikipedia.org/wiki/Tmesipteris_obliqua
- South American lungfishes (Lepidosiren paradoxa) - ~91Gbp (sequenced) https://www.nature.com/articles/s41586-024-07830-1
- European mistletoe - ~90Gbp (sequenced) https://www.darwintreeoflife.org/news_item/2022-the-year-we-built-the-biggest-genome-in-britain-and-ireland/
- Antarctic krill - ~48Gbp (sequenced) https://www.cell.com/cell/pdf/S0092-8674(23)00107-1.pdf
- Neoceratodus forsteri (Australian lungfish) - ~43Gbp (sequenced) https://www.smithsonianmag.com/smart-news/australian-lungfish-has-biggest-genome-ever-sequenced-180976837/ https://www.ncbi.nlm.nih.gov/genome/?term=Neoceratodus+forsteri
- Ambystoma mexicanum (axolotl) - ~32Gbp (sequenced) https://en.wikipedia.org/wiki/Axolotl https://www.ncbi.nlm.nih.gov/genome/?term=axolotl
- Allium ursinum (wild garlic) - ~30gb https://en.wikipedia.org/wiki/Onion_Test
- Coastal redwood - ~26Gbp (sequenced) https://www.ucdavis.edu/climate/news/coast-redwood-and-sequoia-genome-sequences-completed https://www.ncbi.nlm.nih.gov/genome/?term=redwood
- Loblolly pine - ~22Gbp (sequenced) https://blogs.biomedcentral.com/on-biology/wp-content/uploads/sites/5/2014/03/genomelog030.jpg https://www.ncbi.nlm.nih.gov/genome/?term=loblolly+pine
- Wheat genome - ~17Gbp https://academic.oup.com/gigascience/article/6/11/gix097/4561661 https://www.ncbi.nlm.nih.gov/genome/?term=wheat
Inspired by twitter thread https://twitter.com/PetrovADmitri/status/1506824610360168455
Also see http://www.genomesize.com/statistics.php?stats=entire#stats_top
See also the plant C-value database, which is a measurement you will sometimes see instead of base pair length https://cvalues.science.kew.org/ ("C-value is the amount, in picograms, of DNA contained within a haploid nucleus")
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).
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
- Tinman - "In mutant or knockout organisms, the loss of tinman results in the lack of heart formation" https://en.wikipedia.org/wiki/Tinman_gene
- Sonic hedgehog (SHH) - SHH mutants have 'spiky' fruit fly embryos https://en.wikipedia.org/wiki/Sonic_hedgehog
- Robotnikin - antagonist of SHH, villain of the sonic hedgehog franchise - https://pmc.ncbi.nlm.nih.gov/articles/PMC2770933/
- Heart of glass (heg) - a zebrafish gene with mutant phenotype "Individual heg myocardial cells are also thinner than wild-type" https://www.ncbi.nlm.nih.gov/pubmed/14680629
- Dracula (drc) - "we isolated a mutation, dracula (drc), which manifested as a light-dependent lysis of red blood cells" https://www.ncbi.nlm.nih.gov/pubmed/10985389 (now renamed https://zfin.org/ZDB-GENE-000928-1)
- Sleeping Beauty transposon system - https://en.wikipedia.org/wiki/Sleeping_Beauty_transposon_system
- Skywalker (sky) - https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=35359
- TIME FOR COFFEE (TIC) - "We characterize the time for coffee (tic) mutant that disrupts circadian gating, photoperiodism, and multiple circadian rhythms, with differential effects among rhythms" https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=821807
- WTF - "Some alleles of the wtf gene family can increase their chances of spreading by using poisons to kill other alleles, and antidotes to save themselves." - https://www.ebi.ac.uk/interpro/entry/IPR004982 https://www.sciencedaily.com/releases/2017/06/170620093209.htm
- Mothers against decapentaplegic - "it was found that a mutation in the gene in the mother repressed the gene decapentaplegic in the embryo. The phrase "Mothers against" was added as a humorous take-off" https://en.wikipedia.org/wiki/Mothers_against_decapentaplegic
- Saxophone (sax) - http://www.sdbonline.org/sites/fly/gene/saxophon.htm
- Beethovan (btv) - http://www.uniprot.org/uniprot/Q0E8P6
- Superman+kryptonite - https://en.wikipedia.org/wiki/Superman_(gene)
- Supervillin (SVIL) - https://www.uniprot.org/uniprot/O95425
- Wishful thinking (wit) - https://www.wikigenes.org/e/gene/e/44096.html
- Doublesex (dsx) - "The gene is expressed in both male and female flies and is subject to alternative splicing, producing the protein isoforms dsx_f in females and the longer dsx_m in males." https://en.wikipedia.org/wiki/Doublesex
- Fruitless (fru) - "Early work refers to the gene as fruity, an apparent pun on both the common name of D. melanogaster, the fruit fly, as well as a slang word for homosexual. As social attitudes towards homosexuality changed, fruity came to be regarded as offensive, or at best, not politically correct. Thus, the gene was re-dubbed fruitless, alluding to the lack of offspring produced by flies with the mutation.[10] However, despite the original name and a continuing history of misleading inferences by the popular media, fruitless mutants primarily show defects in male-female courtship, though certain mutants cause male-male or female-female courtship.[11]" https://en.wikipedia.org/wiki/Fruitless_(gene)
- Transformer (tra) - https://en.wikipedia.org/wiki/Transformer_(gene)
- Gypsy+Flamenco - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1206375/ also described in wiki https://en.wikipedia.org/wiki/Piwi-interacting_RNA#History_and_loci
- Jockey - http://flybase.org/reports/FBgn0015952.html
- Tigger - https://www.omim.org/entry/612972
- Nanog - celtic legend https://www.sciencedaily.com/releases/2003/06/030602024530.htm (source https://twitter.com/EpgntxEinstein/status/1057359656220348417)
- Jerky (jrk) - "A deficit in the Jerky protein in mice causes recurrent seizures" https://www.genecards.org/cgi-bin/carddisp.pl?gene=JRK
- Hippo (Hpo) - https://www.wikigenes.org/e/gene/e/37247.html
- Dishevelled (Dsh) - https://en.wikipedia.org/wiki/Dishevelled
- Glass bottom boat (gbb) - "fruit fly larvae with a faulty glass bottom boat gene are transparent" https://www.thenakedscientists.com/articles/interviews/gene-month-glass-bottom-boat http://www.sdbonline.org/sites/fly/dbzhnsky/60a-1.htm
- Makes caterpillars floppy (mcf) - https://www.pnas.org/content/99/16/10742 (source https://twitter.com/JUNIUS_64/status/1081007886560608256)
- Eyeless http://flybase.org/reports/FBgn0005558.html
- Straightjaket (stj) - http://flybase.org/reports/FBgn0261041.html
- Huluwa http://science.sciencemag.org/content/362/6417/eaat1045 ref https://twitter.com/zhouwanding/status/1065960714978897921
- frameshifts or pseudogene? - check sequence - https://www.ncbi.nlm.nih.gov/gene/?term=24562233%5Buid%5D
- Bad response to refrigeration (brr) https://twitter.com/hitenmadhani/status/1149471071675924481?s=20
- Mindbomb (mib1) - https://www.sdbonline.org/sites/fly/hjmuller/mindbomb1.htm
- β'COP http://flybase.org/reports/FBgn0025724.html (https://twitter.com/DarrenObbard/status/1260613447198412800)
- King-tubby https://www.uniprot.org/uniprot/B0XFQ9 see also tubby https://www.uniprot.org/uniprot/P50586
- fucK https://www.uniprot.org/uniprot/?query=fuck&sort=score
- Halloween genes https://en.wikipedia.org/wiki/Halloween_genes
- VANDAL21 https://www.arabidopsis.org/servlets/TairObject?type=transposon_family&id=139
- HotDog domain - superfamily of genes/proteins https://www.wikidata.org/wiki/Q24785143 https://www.ebi.ac.uk/interpro/entry/IPR029069
- Flower/fwe - https://flybase.org/reports/FBgn0261722.html
- Brahma https://www.sdbonline.org/sites/fly/polycomb/brahma.htm
- Pokemon gene - "The Pokémon Company threatened MSKCC with legal action in December 2005 for creating an association between cancer and the media franchise, and as a consequence MSKCC is now referring to it by its gene name Zbtb7" - Pokemon/pikachu/zubat (story https://bsky.app/profile/c0nc0rdance.bsky.social/post/3k6w3gwtell2j)
- Bring lots of money (blom7α) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781463/ https://www.uniprot.org/uniprotkb/Q7Z7F0/entry
- MAGOH - Drosophila flies produce unfit progeny when they have mutations in their mago nashi (Japanese: 孫なし, Hepburn: mago nashi, lit. 'grandchildless') gene. The progeny have defects in germplasm assembly and germline development https://www.uniprot.org/uniprotkb/P61326/entry
- IGL@ - a locus containing many immunoglobulin genes, but why the @ sign? https://en.wikipedia.org/wiki/IGL@
- Spooky toxin - https://en.wikipedia.org/wiki/Ssm_spooky_toxin (https://twitter.com/depthsofwiki/status/1712555421918245242)
- Always early (aly) - http://flybase.org/reports/FBgn0004372.html
- Lonely guy (LOG) - https://onlinelibrary.wiley.com/doi/full/10.1111/pbi.13783
- PKZILLA (very large gene) - https://www-science-org.libproxy.berkeley.edu/doi/10.1126/science.ado3290
- Dachshund (dac) "plays a role in leg development" (in flies) https://en.wikipedia.org/wiki/Dachshund_(gene)
- Blanks ("Loss of Blanks causes complete male sterility") https://www.pnas.org/doi/10.1073/pnas.1009781108
- LUMP (and with a p-element insertion p-lump) https://pmc.ncbi.nlm.nih.gov/articles/PMC3166160/
- loquacious https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=34751
Sometimes it is not the gene, but the allele that is named
- Bad hair day http://www.informatics.jax.org/allele/MGI:3764934
- Samba, chacha, bossa nova http://www.informatics.jax.org/allele/MGI:3708457
- Yoda http://www.informatics.jax.org/allele/MGI:3797584
Ref https://twitter.com/hmdc_mgi/status/1242893531779391496
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/