Alternative Splicing

2/13/2017 Alternative
splicing Wikipedia
Alternative splicing
From Wikipedia, the free encyclopedia
Alternative splicing, or
differential splicing, is a regulated
process during gene expression that
results in a single gene coding for
multiple proteins. In this process,
particular exons of a gene may be
included within or excluded from
the final, processed messenger RNA
(mRNA) produced from that
gene.[1] Consequently, the proteins
translated from alternatively spliced
mRNAs will contain differences in
their amino acid sequence and, Alternative splicing produces three protein isoforms.
often, in their biological functions
(see Figure). Notably, alternative
splicing allows the human genome to direct the synthesis of many more proteins than would be expected from
its 20,000 proteincoding genes.
Alternative splicing occurs as a normal phenomenon in eukaryotes, where it greatly increases the biodiversity
of proteins that can be encoded by the genome;[1] in humans, ~95% of multiexonic genes are alternatively
spliced.[2] There are numerous modes of alternative splicing observed, of which the most common is exon
skipping. In this mode, a particular exon may be included in mRNAs under some conditions or in particular
tissues, and omitted from the mRNA in others.[1]
The production of alternatively spliced mRNAs is regulated by a system of transacting proteins that bind to
cisacting sites on the primary transcript itself. Such proteins include splicing activators that promote the usage
of a particular splice site, and splicing repressors that reduce the usage of a particular site. Mechanisms of
alternative splicing are highly variable, and new examples are constantly being found, particularly through the
use of highthroughput techniques. Researchers hope to fully elucidate the regulatory systems involved in
splicing, so that alternative splicing products from a given gene under particular conditions ("splicing variants")
could be predicted by a "splicing code".[3][4]
Abnormal variations in splicing are also implicated in disease; a large proportion of human genetic disorders
result from splicing variants.[3] Abnormal splicing variants are also thought to contribute to the development of
cancer,[5][6][7][8] and splicing factor genes are frequently mutated in different types of cancer.[8]
Contents
1 Discovery
2 Modes
3 Alternative splicing mechanisms
3.1 General splicing mechanism
3.2 Regulatory elements and proteins
3.3 Examples
3.3.1 Exon skipping: Drosophila dsx
3.3.2 Alternative acceptor sites: Drosophila Transformer
3.3.3 Exon definition: Fas receptor
3.3.4 Repressoractivator competition: HIV1 tat exon 2
https://en.wikipedia.org/wiki/Alternative_splicing 1/13
2/13/2017 Alternative splicing Wikipedia
4 Adaptive significance
5 Alternative splicing and disease
6 Genomewide analysis of alternative splicing
7 Alternative splicing databases
8 See also
9 References
10 External links
Discovery
Alternative splicing was first observed in 1977.[9][10] The Adenovirus produces five primary transcripts early in
its infectious cycle, prior to viral DNA replication, and an additional one later, after DNA replication begins.
The early primary transcripts continue to be produced after DNA replication begins. The additional primary
transcript produced late in infection is large and comes from 5/6 of the 32kb adenovirus genome. This is much
larger than any of the individual adenovirus mRNAs present in infected cells. Researchers found that the
primary RNA transcript produced by adenovirus type 2 in the late phase was spliced in many different ways,
resulting in mRNAs encoding different viral proteins. In addition, the primary transcript contained multiple
polyadenylation sites, giving different 3’ ends for the processed mRNAs.[11][12][13]
In 1981, the first example of alternative splicing in a transcript from a normal, endogenous gene was
characterized.[11] The gene encoding the thyroid hormone calcitonin was found to be alternatively spliced in
mammalian cells. The primary transcript from this gene contains 6 exons; the calcitonin mRNA contains exons
1–4, and terminates after a polyadenylation site in exon 4. Another mRNA is produced from this premRNA by
skipping exon 4, and includes exons 1–3, 5, and 6. It encodes a protein known as CGRP (calcitonin gene
related peptide).[14][15] Examples of alternative splicing in immunoglobin gene transcripts in mammals were
also observed in the early 1980s.[11][16]
Since then, alternative splicing has been found to be ubiquitous in eukaryotes.[1] The "recordholder" for
alternative splicing is a D. melanogaster gene called Dscam, which could potentially have 38,016 splice
variants.[17]
Modes
Five basic modes of alternative splicing are generally recognized.[1][2][3][18]
Exon skipping or cassette exon: in this case, an exon may be spliced out of the primary transcript or
retained. This is the most common mode in mammalian premRNAs.[18]
Mutually exclusive exons: One of two exons is retained in mRNAs after splicing, but not both.
Alternative donor site: An alternative 5' splice junction (donor site) is used, changing the 3' boundary of
the upstream exon.
Alternative acceptor site: An alternative 3' splice junction (acceptor site) is used, changing the 5'
boundary of the downstream exon.
Intron retention: A sequence may be spliced out as an intron or simply retained. This is distinguished
from exon skipping because the retained sequence is not flanked by introns. If the retained intron is in the
coding region, the intron must encode amino acids in frame with the neighboring exons, or a stop codon
or a shift in the reading frame will cause the protein to be nonfunctional. This is the rarest mode in
mammals.[18]
In addition to these primary modes of alternative splicing, there are two other main mechanisms by which
different mRNAs may be generated from the same gene; multiple promoters and multiple polyadenylation sites.
Use of multiple promoters is properly described as a transcriptional regulation mechanism rather than
alternative splicing; by starting transcription at different points, transcripts with different 5'most exons can be
generated. At the other end,
multiple polyadenylation sites
provide different 3' end points
for the transcript. Both of these
mechanisms are found in
combination with alternative Relative frequencies of types of
splicing and provide additional alternative splicing events differ
variety in mRNAs derived from between humans and fruit flies. [18]
a gene.[1][3]

These modes describe basic
splicing mechanisms, but may
be inadequate to describe
complex splicing events. For
instance, the figure to the right Schematic cutoff from 3 splicing
shows 3 spliceforms from the structures in the murine hyaluronidase
mouse hyaluronidase 3 gene. gene. Directionality of transcription
Comparing the exonic structure from 5' to 3' is shown from left to
shown in the first line (green) right. Exons and introns are not
with the one in the second line drawn to scale.
(yellow) shows intron retention,
Traditional classification of basic whereas the comparison between the second and the third spliceform
types of alternative RNA splicing (yellow vs. blue) exhibits exon skipping. A model nomenclature to
events. uniquely designate all possible splicing patterns has recently been
proposed.[18]
Alternative splicing mechanisms
General splicing mechanism
When the premRNA has been transcribed from the DNA, it includes
several introns and exons. (In nematodes, the mean is 4–5 exons and
introns; in the fruit fly Drosophila there can be more than 100 introns
and exons in one transcribed premRNA.) The exons to be retained in
the mRNA are determined during the splicing process. The regulation
and selection of splice sites are done by transacting splicing activator
and splicing repressor proteins as well as cisacting elements within the
premRNA itself such as exonic splicing enhancers and exonic splicing
silencers.
The typical eukaryotic nuclear intron has consensus sequences defining
important regions. Each intron has GU at its 5' end. Near the 3' end
there is a branch site. The nucleotide at the branchpoint is always an A; Spliceosome A complex defines the 5'
the consensus around this sequence varies somewhat. In humans the and 3' ends of the intron before
branch site consensus sequence is yUnAy.[19] The branch site is removal[3]
followed by a series of pyrimidines the polypyrimidine tract then by
AG at the 3' end.[3]
Splicing of mRNA is performed by an RNA and protein complex known as the spliceosome, containing
snRNPs designated U1, U2, U4, U5, and U6 (U3 is not involved in mRNA splicing).[20] U1 binds to the 5' GU
and U2, with the assistance of the U2AF protein factors, binds to the branchpoint A within the branch site. The
complex at this stage is known as the spliceosome A complex. Formation of the A complex is usually the key
step in determining the ends of the intron to be spliced out, and defining the ends of the exon to be retained.[3]
(The U nomenclature derives from their high uridine content).
The U4,U5,U6 complex binds, and U6 replaces the U1 position. U1 and U4 leave. The remaining complex then
performs two transesterification reactions. In the first transesterification, 5' end of the intron is cleaved from the
upstream exon and joined to the branch site A by a 2',5'phosphodiester linkage. In the second
transesterification, the 3' end of the intron is cleaved from the downstream exon, and the two exons are joined
by a phosphodiester bond. The intron is then released in lariat form and degraded.[1]
Regulatory elements and proteins
Splicing is regulated by transacting proteins (repressors and activators)
and corresponding cisacting regulatory sites (silencers and enhancers)
on the premRNA. However, as part of the complexity of alternative
splicing, it is noted that the effects of a splicing factor are frequently
positiondependent. That is, a splicing factor that serves as a splicing
activator when bound to an intronic enhancer element may serve as a
Splicing repression
repressor when bound to its splicing element in the context of an exon,
and vice versa.[21] The secondary structure of the premRNA transcript
also plays a role in regulating splicing, such as by bringing together splicing elements or by masking a
sequence that would otherwise serve as a binding element for a splicing factor.[22][23] Together, these elements
form a "splicing code" that governs how splicing will occur under different cellular conditions.[24][25]
There are two major types of cisacting RNA sequence elements present in premRNAs and they have
corresponding transacting RNAbinding proteins. Splicing silencers are sites to which splicing repressor
proteins bind, reducing the probability that a nearby site will be used as a splice junction. These can be located
in the intron itself (intronic splicing silencers, ISS) or in a neighboring exon (exonic splicing silencers, ESS).
They vary in sequence, as well as in the types of proteins that bind to them. The majority of splicing repressors
are heterogeneous nuclear ribonucleoproteins (hnRNPs) such as hnRNPA1 and polypyrimidine tract binding
protein (PTB).[3][24] Splicing enhancers are sites to which splicing activator proteins bind, increasing the
probability that a nearby site will be used as a splice junction. These also may occur in the intron (intronic
splicing enhancers, ISE) or exon (exonic splicing enhancers, ESE). Most of the activator proteins that bind to
ISEs and ESEs are members of the SR protein family. Such proteins contain RNA recognition motifs and
arginine and serinerich (RS) domains.[3][24]
In general, the determinants of splicing work in an interdependent
manner that depends on context, so that the rules governing how
splicing is regulated from a splicing code.[25] The presence of a
particular cisacting RNA sequence element may increase the
Splicing activation probability that a nearby site will be spliced in some cases, but decrease
the probability in other cases, depending on context. The context within
which regulatory elements act includes cisacting context that is
established by the presence of other RNA sequence features, and transacting context that is established by
cellular conditions. For example, some cisacting RNA sequence elements influence splicing only if multiple
elements are present in the same region so as to establish context. As another example, a cisacting element can
have opposite effects on splicing, depending on which proteins are expressed in the cell (e.g., neuronal versus
nonneuronal PTB). The adaptive significance of splicing silencers and enhancers is attested by studies
showing that there is strong selection in human genes against mutations that produce new silencers or disrupt
existing enhancers.[26][27]
Examples
Exon skipping: Drosophila dsx
PremRNAs from the D. melanogaster gene dsx contain 6 exons. In
males, exons 1,2,3,5,and 6 are joined to form the mRNA, which
encodes a transcriptional regulatory protein required for male
development. In females, exons 1,2,3, and 4 are joined, and a
polyadenylation signal in exon 4 causes cleavage of the mRNA at that
point. The resulting mRNA is a transcriptional regulatory protein
required for female development.[28]
Alternative splicing of dsx premRNA
This is an example of exon skipping. The intron upstream from exon 4
has a polypyrimidine tract that doesn't match the consensus sequence
well, so that U2AF proteins bind poorly to it without assistance from splicing activators. This 3' splice acceptor
site is therefore not used in males. Females, however, produce the splicing activator Transformer (Tra) (see
below). The SR protein Tra2 is produced in both sexes and binds to an ESE in exon 4; if Tra is present, it binds
to Tra2 and, along with another SR protein, forms a complex that assists U2AF proteins in binding to the weak
polypyrimidine tract. U2 is recruited to the associated branchpoint, and this leads to inclusion of exon 4 in the
mRNA.[28][29]
Alternative acceptor sites: Drosophila Transformer
PremRNAs of the Transformer (Tra) gene of Drosophila melanogaster
undergo alternative splicing via the alternative acceptor site mode. The
gene Tra encodes a protein that is expressed only in females. The
primary transcript of this gene contains an intron with two possible
acceptor sites. In males, the upstream acceptor site is used. This causes
a longer version of exon 2 to be included in the processed transcript,
including an early stop codon. The resulting mRNA encodes a truncated
Alternative splicing of the Drosophila protein product that is inactive. Females produce the master sex
Transformer gene product. determination protein Sex lethal (Sxl). The Sxl protein is a splicing
repressor that binds to an ISS in the RNA of the Tra transcript near the
upstream acceptor site, preventing U2AF protein from binding to the polypyrimidine tract. This prevents the
use of this junction, shifting the spliceosome binding to the downstream acceptor site. Splicing at this point
bypasses the stop codon, which is excised as part of the intron. The resulting mRNA encodes an active Tra
protein, which itself is a regulator of alternative splicing of other sexrelated genes (see dsx above).[1]
Exon definition: Fas receptor
Multiple isoforms of the Fas receptor protein are produced by alternative splicing. Two normally occurring
isoforms in humans are produced by an exonskipping mechanism. An mRNA including exon 6 encodes the
membranebound form of the Fas receptor, which promotes apoptosis, or programmed cell death. Increased
expression of Fas receptor in skin cells chronically exposed to the sun, and absence of expression in skin cancer
cells, suggests that this mechanism may be important in elimination of precancerous cells in humans.[30] If
exon 6 is skipped, the resulting mRNA encodes a soluble Fas protein that does not promote apoptosis. The
inclusion or skipping of the exon depends on two antagonistic proteins, TIA1 and polypyrimidine tractbinding
protein (PTB).
The 5' donor site in the intron downstream from exon 6 in the premRNA has a weak agreement with the
consensus sequence, and is not bound usually by the U1 snRNP. If U1 does not bind, the exon is skipped
(see "a" in accompanying figure).
Binding of TIA1 protein to an intronic splicing enhancer site stabilizes binding of the U1 snRNP.[3] The
resulting 5' donor site complex assists in binding of the splicing factor U2AF to the 3' splice site
upstream of the exon, through a mechanism that is not yet known (see b).[31]
Exon 6 contains a pyrimidinerich exonic splicing silencer, ure6,
where PTB can bind. If PTB binds, it inhibits the effect of the 5'
donor complex on the binding of U2AF to the acceptor site,
resulting in exon skipping (see c).
This mechanism is an example of exon definition in splicing. A
spliceosome assembles on an intron, and the snRNP subunits fold the
RNA so that the 5' and 3' ends of the intron are joined. However,
recently studied examples such as this one show that there are also
interactions between the ends of the exon. In this particular case, these
exon definition interactions are necessary to allow the binding of core
splicing factors prior to assembly of the spliceosomes on the two
flanking introns.[31]
Repressoractivator competition: HIV1 tat exon 2
HIV, the retrovirus that causes
AIDS in humans, produces a
single primary RNA transcript,
which is alternatively spliced in
multiple ways to produce over Alternative splicing of the Fas
40 different mRNAs.[32] receptor premRNA
Equilibrium among differentially
spliced transcripts provides
multiple mRNAs encoding different products that are required for viral
multiplication.[33] One of the differentially spliced transcripts contains
the tat gene, in which exon 2 is a cassette exon that may be skipped or
Alternative splicing of HIV1 tat exon included. The inclusion of tat exon 2 in the RNA is regulated by
2 competition between the splicing repressor hnRNP A1 and the SR
protein SC35. Within exon 2 an exonic splicing silencer sequence (ESS)
and an exonic splicing enhancer sequence (ESE) overlap. If A1 repressor protein binds to the ESS, it initiates
cooperative binding of multiple A1 molecules, extending into the 5’ donor site upstream of exon 2 and
preventing the binding of the core splicing factor U2AF35 to the polypyrimidine tract. If SC35 binds to the
ESE, it prevents A1 binding and maintains the 5’ donor site in an accessible state for assembly of the
spliceosome. Competition between the activator and repressor ensures that both mRNA types (with and without
exon 2) are produced.[32]
Adaptive significance
Alternative splicing is one of several exceptions to the original idea that one DNA sequence codes for one
polypeptide (the One geneone enzyme hypothesis). It might be more correct now to say "One gene – many
polypeptides".[34] External information is needed in order to decide which polypeptide is produced, given a
DNA sequence and premRNA. Since the methods of regulation are inherited, this provides novel ways for
mutations to affect gene expression.[7]
It has been proposed that for eukaryotes alternative splicing was a very important step towards higher
efficiency, because information can be stored much more economically. Several proteins can be encoded by a
single gene, rather than requiring a separate gene for each, and thus allowing a more varied proteome from a
genome of limited size.[1] It also provides evolutionary flexibility. A single point mutation may cause a given
exon to be occasionally excluded or included from a transcript during splicing, allowing production of a new
protein isoform without loss of the original protein.[1] Studies have identified intrinsically disordered regions
(see Intrinsically unstructured proteins) as enriched in the nonconstitutive exons[35] suggesting that protein
isoforms may display functional diversity due to the alteration of functional modules within these regions. Such
functional diversity achieved by isoforms is reflected by their expression patterns and can be predicted by
machine learning approaches.[36][37] Comparative studies indicate that alternative splicing preceded
multicellularity in evolution, and suggest that this mechanism might have been coopted to assist in the
development of multicellular organisms.[38]
Research based on the Human Genome Project and other genome sequencing has shown that humans have only
about 30% more genes than the roundworm Caenorhabditis elegans, and only about twice as many as the fly
Drosophila melanogaster. This finding led to speculation that the perceived greater complexity of humans, or
vertebrates generally, might be due to higher rates of alternative splicing in humans than are found in
invertebrates.[39][40] However, a study on samples of 100,000 ESTs each from human, mouse, rat, cow, fly (D.
melanogaster), worm (C. elegans), and the plant Arabidopsis thaliana found no large differences in frequency
of alternatively spliced genes among humans and any of the other animals tested.[41] Another study, however,
proposed that these results were an artifact of the different numbers of ESTs available for the various
organisms. When they compared alternative splicing frequencies in random subsets of genes from each
organism, the authors concluded that vertebrates do have higher rates of alternative splicing than
invertebrates.[42]
Alternative splicing and disease
Changes in the RNA processing machinery may lead to missplicing of multiple transcripts, while single
nucleotide alterations in splice sites or cisacting splicing regulatory sites may lead to differences in splicing of
a single gene, and thus in the mRNA produced from a mutant gene's transcripts. A study in 2005 involving
probabilistic analyses indicated that greater than 60% of human diseasecausing mutations affect splicing rather
than directly affecting coding sequences.[43] A more recent study indicates that onethird of all hereditary
diseases are likely to have a splicing component.[21] Regardless of exact percentage, a number of splicing
related diseases do exist.[44] As described below, a prominent example of splicingrelated diseases is cancer.
Abnormally spliced mRNAs are also found in a high proportion of cancerous cells.[5][6][8] Combined RNASeq
and proteomics analyses have revealed striking differential expression of splice isoforms of key proteins in
important cancer pathways.[45] It is not always clear whether such aberrant patterns of splicing contribute to the
cancerous growth, or are merely consequence of cellular abnormalities associated with cancer. Interestingly, for
certain types of cancer, like in colorectal and prostate, the number of splicing errors per cancer has been shown
to vary greatly between individual cancers, a phenomenon referred to as transcriptome instability.[46][47]
Transcriptome instability has further been shown to correlate grealty with reduced expression level of splicing
factor genes. In fact, there is actually a reduction of alternative splicing in cancerous cells compared to normal
ones, and the types of splicing differ; for instance, cancerous cells show higher levels of intron retention than
normal cells, but lower levels of exon skipping.[48] Some of the differences in splicing in cancerous cells may
be due to the high frequency of somatic mutations in splicing factor genes,[8] and some may result from
changes in phosphorylation of transacting splicing factors.[7] Others may be produced by changes in the
relative amounts of splicing factors produced; for instance, breast cancer cells have been shown to have
increased levels of the splicing factor SF2/ASF.[49] One study found that a relatively small percentage (383 out
of over 26000) of alternative splicing variants were significantly higher in frequency in tumor cells than normal
cells, suggesting that there is a limited set of genes which, when misspliced, contribute to tumor
development.[50] It is believed however that the deleterious effects of misspliced transcripts are usually
safeguarded and eliminated by a cellular posttranscriptional quality control mechanism termed Nonsense
mediated mRNA decay [NMD].[51]
One example of a specific splicing variant associated with cancers is in one of the human DNMT genes. Three
DNMT genes encode enzymes that add methyl groups to DNA, a modification that often has regulatory effects.
Several abnormally spliced DNMT3B mRNAs are found in tumors and cancer cell lines. In two separate
studies, expression of two of these abnormally spliced mRNAs in mammalian cells caused changes in the DNA
methylation patterns in those cells. Cells with one of the abnormal mRNAs also grew twice as fast as control
cells, indicating a direct contribution to tumor development by this product.[7]
Another example is the Ron (MST1R) protooncogene. An important property of cancerous cells is their ability
to move and invade normal tissue. Production of an abnormally spliced transcript of Ron has been found to be
associated with increased levels of the SF2/ASF in breast cancer cells. The abnormal isoform of the Ron
protein encoded by this mRNA leads to cell motility.[49]
Overexpression of a truncated splice variant of the FOSB gene – ΔFosB – in a specific population of neurons in
the nucleus accumbens has been identified as the causal mechanism involved in the induction and maintenance
of an addiction to drugs and natural rewards.[52][53][54][55]
Recent provocative studies point to a key function of chromatin structure and histone modifications in
alternative splicing regulation. These insights suggest that epigenetic regulation determines not only what parts
of the genome are expressed but also how they are spliced.[56]
Genomewide analysis of alternative splicing
Genomewide analysis of alternative splicing is a challenging task. Typically, alternatively spliced transcripts
have been found by comparing EST sequences, but this requires sequencing of very large numbers of ESTs.
Most EST libraries come from a very limited number of tissues, so tissuespecific splice variants are likely to
be missed in any case. Highthroughput approaches to investigate splicing have, however, been developed, such
as: DNA microarraybased analyses, RNAbinding assays, and deep sequencing. These methods can be used to
screen for polymorphisms or mutations in or around splicing elements that affect protein binding. When
combined with splicing assays, including in vivo reporter gene assays, the functional effects of polymorphisms
or mutations on the splicing of premRNA transcripts can then be analyzed.[21][24][57]
In microarray analysis, arrays of DNA fragments representing individual exons (e.g. Affymetrix exon
microarray) or exon/exon boundaries (e.g. arrays from ExonHit or Jivan) have been used. The array is then
probed with labeled cDNA from tissues of interest. The probe cDNAs bind to DNA from the exons that are
included in mRNAs in their tissue of origin, or to DNA from the boundary where two exons have been joined.
This can reveal the presence of particular alternatively spliced mRNAs.[58]
CLIP (Crosslinking and immunoprecipitation) uses UV radiation to link proteins to RNA molecules in a tissue
during splicing. A transacting splicing regulatory protein of interest is then precipitated using specific
antibodies. When the RNA attached to that protein is isolated and cloned, it reveals the target sequences for that
protein.[4] Another method for identifying RNAbinding proteins and mapping their binding to premRNA
transcripts is "Microarray Evaluation of Genomic Aptamers by shift (MEGAshift)".net[59] This method
involves an adaptation of the "Systematic Evolution of Ligands by Exponential Enrichment (SELEX)"
method[60] together with a microarraybased readout. Use of the MEGAshift method has provided insights into
the regulation of alternative splicing by allowing for the identification of sequences in premRNA transcripts
surrounding alternatively spliced exons that mediate binding to different splicing factors, such as ASF/SF2 and
PTB.[61] This approach has also been used to aid in determining the relationship between RNA secondary
structure and the binding of splicing factors.[23]
Deep sequencing technologies have been used to conduct genomewide analyses of mRNAs unprocessed and
processed thus providing insights into alternative splicing. For example, results from use of deep sequencing
indicate that, in humans, an estimated 95% of transcripts from multiexon genes undergo alternative splicing,
with a number of premRNA transcripts spliced in a tissuespecific manner.[2] Functional genomics and
computational approaches based on multiple instance learning have also been developed to integrate RNAseq
data to predict functions for alternatively spliced isoforms.[37] Deep sequencing has also aided in the in vivo
detection of the transient lariats that are released during splicing, the determination of branch site sequences,
and the largescale mapping of branchpoints in human premRNA transcripts.[62]
Use of reporter assays makes it possible to find the splicing proteins involved in a specific alternative splicing
event by constructing reporter genes that will express one of two different fluorescent proteins depending on
the splicing reaction that occurs. This method has been used to isolate mutants affecting splicing and thus to
identify novel splicing regulatory proteins inactivated in those mutants.[4]
Alternative splicing databases
There is a collection of alternative splicing databases (http://omictools.com/alternativesplicingcategory).
These databases are useful for finding genes having premRNAs undergoing alternative splicing and alternative
splicing events. Such as, the Plant Alternative Splicing Database (http://proteomics.ysu.edu/altsplice/) contains
alternative splicing information for several major cereal plant species and other plant species.
See also
AspicDB database
Exitron
Polyadenylation § Alternative polyadenylation
References
1. Black, Douglas L. (2003). "Mechanisms of 7. Fackenthal, Jd; Godley, La (2008). "Aberrant RNA
alternative premessenger RNA splicing". Annual splicing and its functional consequences in cancer
Review of Biochemistry. 72 (1): 291–336. cells" (Free full text). Disease models & mechanisms. 1
doi:10.1146/annurev.biochem.72.121801.161720. (1): 37–42. doi:10.1242/dmm.000331. PMC 2561970
PMID 12626338. . PMID 19048051.
2. Pan, Q; Shai O; Lee LJ; Frey BJ; Blencowe BJ (Dec 8. Sveen, A; Kilpinen, S; Ruusulehto, A; Lothe, RA;
2008). "Deep surveying of alternative splicing Skotheim, RI (2015). "Aberrant RNA splicing in
complexity in the human transcriptome by high cancer; expression changes and driver mutations of
throughput sequencing". Nature Genetics. 40 (12): splicing factor genes". Oncogene.
1413–1415. doi:10.1038/ng.259. PMID 18978789. doi:10.1038/onc.2015.318. PMID 26300000.
3. Matlin, AJ; Clark, F; Smith, CWJ (May 2005). 9. Chow, Louise T.; Gelinas, Richard E.; Broker,
"Understanding alternative splicing: towards a cellular Thomas R.; Roberts, Richard J. (1977). "An amazing
code". Nature Reviews. 6 (5): 386–398. sequence arrangement at the 5′ ends of adenovirus 2
doi:10.1038/nrm1645. PMID 15956978. messenger RNA". Cell. 12 (1): 1–8.
4. David, C. J.; Manley, J. L. (2008). "The search for doi:10.1016/00928674(77)901805. PMID 902310.
alternative splicing regulators: new approaches offer a 10. Berget SM, Moore C, Sharp PA (1977). "Spliced
path to a splicing code". Genes & Development. 22 segments at the 5' terminus of adenovirus 2 late
(3): 279–85. doi:10.1101/gad.1643108. PMC 2731647 mRNA". Proc. Natl. Acad. Sci. U.S.A. 74 (8): 3171–
. PMID 18245441. 5. Bibcode:1977PNAS...74.3171B.
5. Skotheim, R I; Nees, M (2007). "Alternative splicing doi:10.1073/pnas.74.8.3171. PMC 431482 .
in cancer: noise, functional, or systematic?". The PMID 269380.
international journal of biochemistry & cell biology. 11. Leff SE, Rosenfeld MG, Evans RM (1986).
39 (78): 1432–49. doi:10.1016/j.biocel.2007.02.016. "Complex transcriptional units: diversity in gene
PMID 17416541. expression by alternative RNA processing". Annu.
6. Bauer, Joseph Alan; He, Chunjiang; Zhou, Fang; Zuo, Rev. Biochem. 55 (1): 1091–117.
Zhixiang; Cheng, Hanhua; Zhou, Rongjia (2009). doi:10.1146/annurev.bi.55.070186.005303.
Bauer, Joseph Alan, ed. "A Global View of Cancer PMID 3017190.
Specific Transcript Variants by Subtractive 12. Chow LT, Broker TR (1978). "The spliced structures
TranscriptomeWide Analysis". PLoS ONE. 4 (3): of adenovirus 2 fiber message and the other late
e4732. Bibcode:2009PLoSO...4.4732H. mRNAs". Cell. 15 (2): 497–510. doi:10.1016/0092
doi:10.1371/journal.pone.0004732. PMC 2648985 . 8674(78)900193. PMID 719751.
PMID 19266097.
13. Nevins JR, Darnell JE (1978). "Steps in the 24. Wang, Z; Burge, Cb (2008). "Splicing regulation:
processing of Ad2 mRNA: poly(A)+ nuclear from a parts list of regulatory elements to an
sequences are conserved and poly(A) addition integrated splicing code" (Free full text). RNA. 14 (5):
precedes splicing". Cell. 15 (4): 1477–93. 802–13. doi:10.1261/rna.876308. PMC 2327353 .
doi:10.1016/00928674(78)900715. PMID 729004. PMID 18369186.
14. Rosenfeld MG, Amara SG, Roos BA, Ong ES, Evans 25. Barash, Y; et al. (2010). "Deciphering the splicing
RM (1981). "Altered expression of the calcitonin code". Nature. 465 (7294): 53–59.
gene associated with RNA polymorphism". Nature. Bibcode:2010Natur.465...53B.
290 (5801): 63–5. Bibcode:1981Natur.290...63R. doi:10.1038/nature09000. PMID 20445623.
doi:10.1038/290063a0. PMID 7207587. 26. Ke S, Zhang XH, Chasin LA (2008). "Positive
15. Rosenfeld MG, Lin CR, Amara SG, et al. (1982). selection acting on splicing motifs reflects
"Calcitonin mRNA polymorphism: peptide switching compensatory evolution". Genome Res. 18 (4): 533–
associated with alternative RNA splicing events". 43. doi:10.1101/gr.070268.107. PMC 2279241 .
Proc. Natl. Acad. Sci. U.S.A. 79 (6): 1717–21. PMID 18204002.
Bibcode:1982PNAS...79.1717R. 27. Fairbrother, WG; Holste, D; Burge, CB; Sharp, PA
doi:10.1073/pnas.79.6.1717. PMC 346051 . (2004). "Single nucleotide polymorphism–based
PMID 6952224. validation of exonic splicing enhancers". PLoS Biol. 2
16. Maki R, Roeder W, Traunecker A, et al. (1981). "The (9): e268. doi:10.1371/journal.pbio.0020268.
role of DNA rearrangement and alternative RNA PMC 514884 . PMID 15340491.
processing in the expression of immunoglobulin delta 28. Lynch KW, Maniatis T (1996). "Assembly of specific
genes". Cell. 24 (2): 353–65. doi:10.1016/0092 SR protein complexes on distinct regulatory elements
8674(81)903251. PMID 6786756. of the Drosophila doublesex splicing enhancer".
17. Schmucker D, Clemens JC, Shu H, Worby CA, Xiao Genes Dev. 10 (16): 2089–101.
J, Muda M, Dixon JE, Zipursky SL (2000). doi:10.1101/gad.10.16.2089. PMID 8769651.
"Drosophila Dscam is an axon guidance receptor 29. Graveley BR, Hertel KJ, Maniatis T (2001). "The
exhibiting extraordinary molecular diversity". Cell. role of U2AF35 and U2AF65 in enhancerdependent
101 (6): 671–84. doi:10.1016/S00928674(00)80878 splicing". RNA. 7 (6): 806–18.
8. PMID 10892653. doi:10.1017/S1355838201010317. PMC 1370132 .
18. Michael Sammeth; Sylvain Foissac; Roderic Guigó PMID 11421359.
(2008). Brent, Michael R., ed. "A general definition 30. Filipowicz, Ewa; Adegboyega, P.; Sanchez, R. L.;
and nomenclature for alternative splicing events". Gatalica, Zoran (2002). "Expression of CD95 (Fas) in
PLoS Comput. Biol. 4 (8): e1000147. sunexposed human skin and cutaneous carcinomas".
Bibcode:2008PLSCB...4E0147S. Cancer. 94 (3): 814–9. doi:10.1002/cncr.10277.
doi:10.1371/journal.pcbi.1000147. PMC 2467475 . PMID 11857317.
PMID 18688268. 31. Izquierdo JM, Majós N, Bonnal S, et al. (2005).
19. Gao, K.; Masuda, A.; Matsuura, T.; Ohno, K. (2008). "Regulation of Fas alternative splicing by antagonistic
"Human branch point consensus sequence is yUnAy". effects of TIA1 and PTB on exon definition". Mol.
Nucleic Acids Research. 36 (7): 2257–67. Cell. 19 (4): 475–84.
doi:10.1093/nar/gkn073. PMC 2367711 . doi:10.1016/j.molcel.2005.06.015. PMID 16109372.
PMID 18285363. 32. Zahler, A. M.; Damgaard, CK; Kjems, J; Caputi, M
20. Clark, David (2005). Molecular biology. Amsterdam: (2003). "SC35 and Heterogeneous Nuclear
Elsevier Academic Press. ISBN 0121755517. Ribonucleoprotein A/B Proteins Bind to a Juxtaposed
21. Lim, KH; Ferraris, L; Filloux, ME; Raphael, BJ; Exonic Splicing Enhancer/Exonic Splicing Silencer
Fairbrother, WG (2011). "Using positional Element to Regulate HIV1 tat Exon 2 Splicing".
distribution to identify splicing elements and predict Journal of Biological Chemistry. 279 (11): 10077–84.
premRNA processing defects in human genes". Proc. doi:10.1074/jbc.M312743200. PMID 14703516.
Natl. Acad. Sci. USA. 108 (27): 11093–11098. 33. Jacquenet, S.; Méreau, A; Bilodeau, PS; Damier, L;
doi:10.1073/pnas.1101135108. PMC 3131313 . Stoltzfus, CM; Branlant, C (2001). "A Second Exon
PMID 21685335. Splicing Silencer within Human Immunodeficiency
22. Warf, MB; Berglund, JA (2010). "Role of RNA Virus Type 1 tat Exon 2 Represses Splicing of Tat
structure in regulating premRNA splicing". Trends mRNA and Binds Protein hnRNP H". Journal of
Biochem. Sci. 35 (3): 169–178. Biological Chemistry. 276 (44): 40464–75.
doi:10.1016/j.tibs.2009.10.004. PMC 2834840 . doi:10.1074/jbc.M104070200. PMID 11526107.
PMID 19959365. 34. "HHMI Bulletin September 2005: Alternative
23. Reid, DC; Chang, BL; Gunderson, SI; Alpert, L; Splicing". www.hhmi.org. Archived from the original
Thompson, WA; Fairbrother, WG (2009). "Next on 22 June 2009. Retrieved 20090526.
generation SELEX identifies sequence and structural
determinants of splicing factor binding in human pre
mRNA sequence". RNA. 15 (12): 2385–2397.
doi:10.1261/rna.1821809. PMC 2779669 .
PMID 19861426.
35. Romero, Pedro; Zaidi, Saima; Fang, Ya Yin; Uversky, 46. Sveen, A; Ågesen, TH; Nesbakken, A; Rognum, TO;
Vladimir; Dunker, Keith (2006). "Alternative splicing Lothe, RA; Skotheim, RI (2011). "Transcriptome
in concert with protein intrinsic disorder enables instability in colorectal cancer identified by exon
increased functional diversity in multicellular microarray analyses: Associations with splicing factor
organisms.". Proc Natl Acad Sci U S A. 103: 8390– expression levels and patient survival". Genome
8395. Bibcode:2006PNAS..103.8390R. Medicine. 15: 672. doi:10.1186/1471216415672.
doi:10.1073/pnas.0507916103. PMC 1482503 . PMC 3219073 . PMID 25109687.
PMID 16717195. 47. Sveen, A; Johannessen, B; Teixeira, MR; Lothe, RA;
36. Li, HD; Menon, R; Omenn, GS; Guan, Y (Jun 17, Skotheim, RI (2014). "Transcriptome instability as a
2014). "The emerging era of genomic data integration molecular pancancer characteristic of carcinomas".
for analyzing splice isoform function.". Trends in BMC Genomics. 3: 32. doi:10.1186/gm248.
genetics : TIG. 30 (8): 340–347. PMC 4137096 . PMID 21619627.
doi:10.1016/j.tig.2014.05.005. PMID 24951248. 48. Kim E, Goren A, Ast G (2008). "Insights into the
37. Eksi, R; Li, HD; Menon, R; Wen, Y; Omenn, GS; connection between cancer and alternative splicing".
Kretzler, M; Guan, Y (Nov 2013). "Systematically Trends Genet. 24 (1): 7–10.
differentiating functions for alternatively spliced doi:10.1016/j.tig.2007.10.001. PMID 18054115.
isoforms through integrating RNAseq data.". PLOS 49. Ghigna C, Giordano S, Shen H, et al. (2005). "Cell
Computational Biology. 9 (11): e1003314. motility is controlled by SF2/ASF through alternative
Bibcode:2013PLSCB...9E3314E. splicing of the Ron protooncogene". Mol. Cell. 20
doi:10.1371/journal.pcbi.1003314. PMC 3820534 . (6): 881–90. doi:10.1016/j.molcel.2005.10.026.
PMID 24244129. PMID 16364913.
38. Irimia, Manuel; Rukov, Jakob; Penny, David; Roy, 50. Hui L, Zhang X, Wu X, et al. (2004). "Identification
Scott (2007). "Functional and evolutionary analysis of of alternatively spliced mRNA variants related to
alternatively spliced genes is consistent with an early cancers by genomewide ESTs alignment". Oncogene.
eukaryotic origin of alternative splicing". BMC 23 (17): 3013–23. doi:10.1038/sj.onc.1207362.
Evolutionary Biology. 7: 188. doi:10.1186/14712148 PMID 15048092.
7188. PMC 2082043 . PMID 17916237. 51. Danckwardt S, NeuYilik G, Thermann R, Frede U,
39. Ewing, B; Green P (June 2000). "Analysis of Hentze MW, Kulozik AE (2002). "Abnormally
expressed sequence tags indicates 35,000 human spliced betaglobin mRNAs: a single point mutation
genes". Nature Genetics. 25 (2): 232–234. generates transcripts sensitive and insensitive to
doi:10.1038/76115. PMID 10835644. nonsensemediated mRNA decay". Blood. 99 (5):
40. Crollius, HR; et al. (2000). "Estimate of human gene 1811–6. doi:10.1182/blood.V99.5.1811.
number provided by genomewide analysis using PMID 11861299.
Tetraodon nigroviridis DNA sequence". Nature 52. Nestler EJ (December 2013). "Cellular basis of
Genetics. 25 (2): 235–238. doi:10.1038/76118. memory for addiction". Dialogues Clin. Neurosci. 15
PMID 10835645. (4): 431–443. PMC 3898681 . PMID 24459410.
41. David Brett; Heike Pospisil; Juan Valcárcel; Jens "DESPITE THE IMPORTANCE OF NUMEROUS
Reich; Peer Bork (2002). "Alternative splicing and PSYCHOSOCIAL FACTORS, AT ITS CORE,
genome complexity". Nature Genetics. 30 (1): 29–30. DRUG ADDICTION INVOLVES A BIOLOGICAL
doi:10.1038/ng803. PMID 11743582. PROCESS: the ability of repeated exposure to a drug
42. Kim, E.; Magen, A.; Ast, G. (2006). "Different levels of abuse to induce changes in a vulnerable brain that
of alternative splicing among eukaryotes". Nucleic drive the compulsive seeking and taking of drugs, and
Acids Research. 35 (1): 125–31. loss of control over drug use, that define a state of
doi:10.1093/nar/gkl924. PMC 1802581 . addiction. ... A large body of literature has
PMID 17158149. demonstrated that such ΔFosB induction in D1type
43. LópezBigas, Núria; Audit, Benjamin; Ouzounis, NAc neurons increases an animal's sensitivity to drug
Christos; Parra, Genís; Guigó, Roderic (2005). "Are as well as natural rewards and promotes drug self
splicing mutations the most frequent cause of administration, presumably through a process of
hereditary disease?". FEBS Letters. 579 (9): 1900–3. positive reinforcement"
doi:10.1016/j.febslet.2005.02.047. PMID 15792793.
44. Ward, AJ; Cooper, TA (2010). "The pathobiology of
splicing". J. Pathol. 220 (2): 152–163.
doi:10.1002/path.2649. PMC 2855871 .
PMID 19918805.
45. Omenn, GS; Guan, Y; Menon, R (May 3, 2014). "A
New Class of Protein Cancer Biomarker Candidates:
DifferentiallyExpressed Splice Variants of ERBB2
(HER2/neu) and ERBB1 (EGFR) in Breast Cancer
Cell Lines.". Journal of proteomics. 107C: 103–112.
doi:10.1016/j.jprot.2014.04.012. PMID 24802673.
53. Ruffle JK (November 2014). "Molecular 55. Olsen CM (December 2011). "Natural rewards,
neurobiology of addiction: what's all the (Δ)FosB neuroplasticity, and nondrug addictions".
about?". Am J Drug Alcohol Abuse. 40 (6): 428–437. Neuropharmacology. 61 (7): 1109–1122.
doi:10.3109/00952990.2014.933840. doi:10.1016/j.neuropharm.2011.03.010.
PMID 25083822. "ΔFosB is an essential transcription PMC 3139704 . PMID 21459101.
factor implicated in the molecular and behavioral 56. Luco, RF; Allo, M; Schor, IE; Kornblihtt, AR;
pathways of addiction following repeated drug Misteli, T. (2011). "Epigenetics in alternative pre
exposure. The formation of ΔFosB in multiple brain mRNA splicing". Cell. 144 (1): 16–26.
regions, and the molecular pathway leading to the doi:10.1016/j.cell.2010.11.056. PMC 3038581 .
formation of AP1 complexes is well understood. The PMID 21215366.
establishment of a functional purpose for ΔFosB has 57. Fairbrother, WG; Yeh, RF; Sharp, PA; Burge, CB
allowed further determination as to some of the key (2002). "Predictive identification of exonic splicing
aspects of its molecular cascades, involving effectors enhancers in human genes". Science. 297 (5583):
such as GluR2 (87,88), Cdk5 (93) and NFkB (100). 1007–1013. Bibcode:2002Sci...297.1007F.
Moreover, many of these molecular changes identified doi:10.1126/science.1073774. PMID 12114529.
are now directly linked to the structural, physiological 58. Pan, Qun; Shai, Ofer; Misquitta, Christine; Zhang,
and behavioral changes observed following chronic Wen; Saltzman, Arneet L.; Mohammad, Naveed;
drug exposure (60,95,97,102). New frontiers of Babak, Tomas; Siu, Henry; Hughes, Timothy R.
research investigating the molecular roles of ΔFosB (2004). "Revealing Global Regulatory Features of
have been opened by epigenetic studies, and recent Mammalian Alternative Splicing Using a Quantitative
advances have illustrated the role of ΔFosB acting on Microarray Platform". Molecular Cell. 16 (6): 929–
DNA and histones, truly as a ‘‘molecular switch’’ 41. doi:10.1016/j.molcel.2004.12.004.
(34). As a consequence of our improved PMID 15610736.
understanding of ΔFosB in addiction, it is possible to 59. Watkins, KH; Stewart, A; Fairbrother, WG (2009).
evaluate the addictive potential of current medications "A rapid highthroughput method for mapping
(119), as well as use it as a biomarker for assessing ribonucleoproteins (RNPs) on human premRNA". J.
the efficacy of therapeutic interventions Vis. Exp. 34: 1622. doi:10.3791/1622.
(121,122,124). Some of these proposed interventions 60. Tuerk, C; Gold, L (1990). "Systematic evolution of
have limitations (125) or are in their infancy (75). ligands by exponential enrichment: RNA ligands to
However, it is hoped that some of these preliminary bacteriophage T4 DNA polymerase". Science. 249
findings may lead to innovative treatments, which are (4968): 505–510. Bibcode:1990Sci...249..505T.
much needed in addiction." doi:10.1126/science.2200121. PMID 2200121.
54. Biliński P, Wojtyła A, KapkaSkrzypczak L, 61. Chang, B; Levin, J; Thompson, WA; Fairbrother,
Chwedorowicz R, Cyranka M, Studziński T (2012). WG (2010). "Highthroughput binding analysis
"Epigenetic regulation in drug addiction". Ann. Agric. determines the binding specificity of ASF/SF2 on
Environ. Med. 19 (3): 491–496. PMID 23020045. alternatively spliced human premRNAs". Comb.
"For these reasons, ΔFosB is considered a primary Chem. High Throughput Screen. 13 (3): 242–252.
and causative transcription factor in creating new doi:10.2174/138620710790980522. PMID 20015017.
neural connections in the reward centre, prefrontal 62. Taggart, AJ; DeSimone, AM; Shih, JS; Filloux, ME;
cortex, and other regions of the limbic system. This is Fairbrother, WG (2012). "Largescale mapping of
reflected in the increased, stable and longlasting level branchpoints in human premRNA transcripts in
of sensitivity to cocaine and other drugs, and tendency vivo". Nat. Struct. Mol. Biol. 19 (7): 719–721.
to relapse even after long periods of abstinence. These doi:10.1038/nsmb.2327. PMC 3465671 .
newly constructed networks function very efficiently PMID 22705790.
via new pathways as soon as drugs of abuse are
further taken"
External links
A General Definition and Nomenclature for Alternative Splicing
Wikimedia Commons has
Events (http://scivee.tv/node/6837) at SciVee
media related to Alternative
AStalavista (Alternative Splicing landscape visualization tool), a splicing.
method for the computationally exhaustive classification of
Alternative Splicing Structures (http://genome.imim.es/astalavista/index.html)
IsoPred: computationally predicted isoform functions (http://guanlab.ccmb.med.umich.edu/isoPred)
Stammslab.net: Research Group dealing with alternative Splicing issues and missplicing in human
diseases (http://www.stammslab.net)
Alternative Splicing of ion channels in the brain, connected to mental and neurological diseases (http://w
ww.dip.molmed.eu)
BIPASS: Web Services in Alternative Splicing (http://bip.umiacs.umd.edu:8080/)
Retrieved from "https://en.wikipedia.org/w/index.php?title=Alternative_splicing&oldid=748364088"
Categories: Gene expression Spliceosome RNA splicing
This page was last modified on 7 November 2016, at 21:08.
Text is available under the Creative Commons AttributionShareAlike License; additional terms may
apply. By using this site, you agree to the Terms of Use and Privacy Policy. Wikipedia® is a registered
trademark of the Wikimedia Foundation, Inc., a nonprofit organization.

Alternative Splicing

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Alternative Splicing

Uploaded by

Copyright:

Available Formats

2/13/2017 Alternative

Categories: Gene expression Spliceosome RNA splicing

You might also like