Dr. Jack Min will be the seminar speaker this week. His title is "Bioinformatics: Applications in Secretome Prediction and Alternative Splicing Gene Analysis".
I know his is a complex area of study, but he is doing cutting edge stuff. I would encourage all of you to closely listen to his seminar and if you haven't secured a research mentor yet, consider Dr. Min. I can almost guarantee you that with some effort on your part that a publication would be in your future.
Bioinformatics plays an important role in both alternative splicing and secretome ( study of secreted proteins). It provides computational tasks for documenting, managing and retrieving data. Predictions are made based on this information, contributing to the elucidation of a given organism's physiological state and the determination of the specific malfunction in disease states. Dr. Jack highlighted a number of bioinformatics databases and software that are used to analyze the biological meaning of these data, including descriptions of the main functions and limitations of these tools. He also highlighted an article on alternative splicing whose summary I present in addendum.
ReplyDeleteAlternative splicing contributes highly to diversity of protein isoforms in cereals. It modulates protein functions through shuffling of the composition of exons in a transcript or retention of introns. Meaning that numerous different transcripts can be made from the same gene. 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 or some introns may be retained. This recombination creates a diverse array of mRNAs from a single pre-mRNA.
Some of the alternative splicing sub types observed among the four cereal crops considered in this research are exon skipping, alternative donor or accepter site and intron retention. Intron retention predominated especially in maize crop. Complex diversity may also result when these alternative splicing subtypes act in combination. Besides, alternative transcripts may arise as a result of alternative transcript initiation, alternative transcript termination and alternative polyadenylation.
Conserved alternative splicing provides a basis for understanding the evolution of the functional genes and their gene regulation at the transcriptional level.
Question: What are some of the good and bad effects of alternative splicing in both plants, animals and human?
Alternative splicing is a regulated process during gene expression that results in a single gene coding for multiple proteins. First discovered in 1977 from a viral adenovirus. Since then, alternative splicing has been found to be ubiquitous in eukaryotes. The "record-holder" for alternative splicing is a D. melanogaster gene called Dscam, which could potentially have 38,016 splice variants.
ReplyDeleteOne 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.
Overall, vertebrates have higher rates of alternative splicing than invertebrates. There are two commonly recognized hypotheses about why alternative splicing is employed in eukaryotes: proteomic diversity and post-translational regulation. Alternative Splicing is a common feature of plant genomes. Higher plants show evidence of alternative splicing being linked with NMD – similar to mammalian systems. More than 60% of intron-containing genes undergo alternative splicing (AS) in plants. This number will increase when AS in different tissues, developmental stages, and environmental conditions are explored.
Alternative splicing is a form of gene regulation that gives rise the large numbers of different proteins an organism is able to produce. Originally, it was thought that one gene coded for one protein and created a sort of paradox when the genome was sequenced and the number of proteins greatly outnumbered the number of genes. The explanation was that eukaryotic organisms are subject to many forms of genetic regulation like alternative splicing. Once the DNA was transcribed into pre-mRNA, different proteins (termed the spliceosome) would remove parts of the transcript leading to the mRNA and different proteins. It was estimated that about 75% of human genes code for at least 2 protein isoforms. This process is vital to animals and plants alike. There is also believed to be a link between defective splicing and cancer. Cancer can arise from defects in the splicing of genes like signal transduction, growth factors and regulators, apoptosis, or even tumor suppressor genes. If the spliceosome is defective, this can lead to the production of unrecognizable proteins which might result in the cell proliferating out of control (growth regulator) or the cell being unable to destroy itself (apoptosis).
ReplyDeleteMany protein-coding genes are alternatively spliced. Alternative splicing is very important for eukaryotic gene expression which increases coding capacity for human genome, generate mRNAs encoding proteins with different and opposite functions as well as expanding number of examples that clarify choosing of wrong splice section that cause human disease. For instance, mutations in the splicing factors PRPF31/U4-61k and PRP8 cause autosomal dominant forms of retinitis pigmentosa. Since alternative splicing involves many genes, changes in alternative splicing are related with human diseases. Therefore, alternative splicing good for many proteins and bad because there are many opportunities for mistakes because of huge genome.
ReplyDeletehttp://www.sciencedirect.com/science/article/pii/S0925443908001932
http://bitesizebio.com/10148/what-is-alternative-splicing-and-why-is-it-important/
Alternative splicing is less prevalant in plants than it is in mammals. This mechanism is less well known in plants but more research on the model species Arapidopsis thaliana is uncovering more information. Arapidopsis thaliana was estimated to have at least 5% of all their predicted genes alternatively spliced. Studies show that genes associated with stress responses in both animals and plants are prone to be alternatively spliced. Stress response alternative splicing for disease resistance genes as well as abiotic stress responses are known. There are two splicing forms of the Arabidopsis SOS4 (salt overly sensitive 4) gene that is regulated by salt stress. The OsIM gene from rice (Oryza sativa) encodes an alternative oxidase that remove stress-induced reactive oxygen species. This OsIM gene is alternatively spliced under salt stress. The ratio of the two splicing forms, OsIM1 and OsIM2, differs between salt-tolerant and salt-sensitive varieties. The salt-tolerant variety, OsIM1, is maintained in high levels while the salt-sensitive variety, OsIM2, has a decrease in its transcript level after a short exposure to salt stress. There is also a known water-stress and plant defence-associated MAP-kinase gene of rice that is alternatively spliced resulting in two splicing forms.
ReplyDeletehttp://www.sciencedirect.com/science/article/pii/S1360138503002115?_rdoc=1&_fmt=high&_origin=gateway&_docanchor=&md5=b8429449ccfc9c30159a5f9aeaa92ffb
Alternative splicing in humans generate a large variety in the proteome, meaning it is important for enhancing protein diversity and regulating gene expression. It is estimated that at >95% of human genes undergo this splicing to produce diverse proteins from even a single gene. This splicing allows organisms’ higher efficiency because of more storage. A negative impact alternative splicing has on the human genome is its role in human pathologies. Any defect during the splicing leads to cell defects, which in turn can cause neurological disease. Alternative splicing has also been implicated in Alzheimer’s disease and cancer (http://www.bioscience-explained.org/ENvol4_1/pdf/spliceeng.pd). Defects caused by alternative splicing are either primary or secondary splicing defects. Primary splicing defects affect sequences on the pre-mRNA while secondary splicing defects mutate a regulatory factory necessary for splicing activity.
ReplyDeleteCompared to higher animals, plants show a variety in their alternative splicing events. Some plants have alternative splicing rates comparable to the rates of animals, while the types of alternative splicing may vary. Comparing different species’ alternative splicing can teach us of the evolution of alternative splicing. Plants benefit from alternative splicing for their environmental fitness and metabolic style and other plant processes. Problems in plants with alternative splicing include various pathogens, affected protein domains (i.e. cold-induced sweetening in potatoes) and longer or shorter circadian periods. Future research will allow new opportunities to modify plant function for improved phenotypes.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1914131/
There are five modes of alternative splicing that are generally recognized:Exon skipping or cassette exon, mutually exclusive exons, alternative donor site, alternative acceptor site, and intron retention.These modes describe basic splicing mechanisms. For example pre-mRNAs 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.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 protein product that is inactive. Another example in humans could be Fas receptor protein. Multiple isoforms of the Fas receptor protein are produced by alternative splicing. Two normally occurring isoforms in humans are produced by an exon-skipping mechanism. 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. It also provides evolutionary flexibility. I think that alternative splicing can have both: positive and negative effects. In one case it can lead to higher efficiency for storing information, since one gene is encoding for multiple proteins, on the other hand if something goes wrong, for example, mis splicing of a transcript, it can lead to dangerous diseases such as cancer.
ReplyDeletehttps://en.wikipedia.org/wiki/Alternative_splicing
Alternative splicing involves a single gene producing many mRNA products through different organizations of exons and introns: in this manner we are able to express many different forms of mRNA with relatively fewer genes. This is a very useful process, as genes can be smaller in size and fit inside the cell much easier. Alternative splicing also makes mistakes creates mutations such as silent, addition or deletion mutations. Alternative splicing occurs as a normal process in Eukaryotes where it will greatly increase the biodiversity of proteins encoded. Exon skipping as well as other additions or deletions add to the creation of new proteins which is necessary for evolution. New proteins that will aid an animal to produce more fertile offspring will stick and in this manner alternative splicing is beneficial. Alternative splicing may also create some proteins that will not increases the fitness of an organism and in this manner alternative splicing is detrimental. Tumors and other genetic diseases are results of alternative splicing gone wrong. Hence alternative splicing is a useful tool used to get multiple products from a single gene and it is also necessary for evolution. It is also responsible for creating genetic diseases and tumors which is a downside but that is nature, that’s how evolution work.
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1914131/
An example of alternative splicing in humans is the retrovirus HIV. It produces a single primary RNA transcript, which is alternatively spliced in multiple ways to produce over 40 different mRNAs. Equilibrium among differentially spliced transcripts provides multiple mRNAs encoding different products that are required for viral multiplication. One of the differentially spliced transcripts contains the tat gene, in which exon 2 may be skipped or included. The inclusion of tat exon 2 in the RNA is regulated by competition between the splicing repressor hnRNP A1 and the SR protein SC35. If A1 repressor protein binds to the exonic splicing silencer sequence (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 exonic splicing enhancer sequence (ESE), it prevents A1 binding and maintains the 5’ donor site in an accessible state for assembly of the spliceosome. The competition between the activator and repressor ensures that both mRNA types are produced.
ReplyDeleteAlternative splicing ultimately results in a single gene coding for multiple proteins. This greatly contributes to the biodiversity within the genome. Recent studies have found that almost 70% of human genes undergo alternative splicing. These events lead to an increase or decrease in the amount of exons. One common advantage of alternative splicing has been found to increase the expression of membrane calcium pumps. This could have both positive and negative effects on the cell. Changes is alternative splicing and it’s regulation has been seen to affect the state of the organism, for instance alternative splicing is under regulation during normal conditions however, it has been observed that during disease states alternative splicing is seen to be less regulated. This was seen when looking at Tcell the CD44 protein involved in Tcell homing is normally seen in high numbers on the surface of activated Tcells. This protein when undergoing alternative splicing has up to 10 isoforms and the expression of certain exons has been associated during different stages in activation.
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