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Developmental biology - Genes

Predicting How Gene Splicing Errors Impact Disease

RNA "instructions" are sent to cell protein factories that correspond precisely with DNA blueprint encoded in our genes...


No one knows how many times in a day, hour or even in a minute, trillions of cells in our body need to make proteins. But we do know protein making is on going - on a massive scale. We also know every time it happens it takes place in the cell nucleus. The process is called RNA splicing and it makes sure RNA 'instructions' get sent to cell protein factories which correspond precisely with blueprints coded in our genes.
Splicing removes segments called introns from a raw, unedited RNA copy of a gene. This leaves only exons - the protein-coding regions.

There are over 200,000 introns in the human genome. If they are spliced out imprecisely, cells will make faulty proteins. Results can be life-threatening, as about 14% of the single-letter mutations linked to human diseases are thought to occur within the DNA sequences that flag intron positions in the genome.

Gene Intron

Cell splicing machinery seeks "splice sites" to correctly remove introns from a raw RNA message.

Splice sites throughout the genome are similar but not identical, and small changes don't always impair splicing efficiency. When a splice site is at the beginning of an intron - known as its 5' ["five-prime"] splice site, Krainer: "We know that at the first and second [DNA-letter] position, mutations have a very strong impact. Mutations elsewhere in the intron can have dramatic effects or no effect, or something in between." This has made it hard to predict how mutations at splice sites within disease-linked genes will impact patients. For example, mutations in the genes BRCA1 or BRCA2 can increase a woman's risk of breast and ovarian cancer, but not every mutation is harmful.

Researchers led by Adrian Krainer, a Cold Spring Harbor Laboratory (CSHL) Professor along with Assistant Professor Justin Kinney, are teasing out the rules that guide how cells process RNA messages. They want to make better predictions about how specific genetic mutations affect the process of splice site selection. This in turn will help assess how certain mutations affect a person's risk for disease.

In experiments led by first author Mandy Wong, a Krainer lab postdoc, the team created 5' splice sites with every possible combination of DNA letters. They then measured how well an associated intron was removed from a larger piece of RNA. In their experiments, they used introns from just three disease-associated genes - BRCA2 and IKBKAP and SMN1, the last - 2 genes - where mutations cause neurodegenerative diseases.
In one intron of each of the three genes, the team tested over 32,000 5' splice sites. finding specific DNA sequences corresponded with similar splicing efficiency or inefficiency on different introns. This is a step toward making general predictions. But they also found that other features of each gene - the larger context - tended to modify the impact in each specific case. In other words: how a mutation within a given 5' splice site will affect splicing is somewhat predictable, but is also influenced by context beyond the splice site itself.

Krainer believes this new knowledge will help predict the impact of splice-site mutations - but deeper investigation needs to continue. The work appears in Molecular Cell.

Highlights
Comprehensive measurement of 5'ss activity in three gene contexts
A major determinant of 5'ss recognition stems from the nucleotide sequence
Context can have a considerable influence on 5?ss usage
Compiled 5'ss measurements help distinguish pathogenic from benign 5?ss mutations

Summary
Pre-mRNA splicing is an essential step in the expression of most human genes. Mutations at the 5? splice site (5?ss) frequently cause defective splicing and disease due to interference with the initial recognition of the exon-intron boundary by U1 small nuclear ribonucleoprotein (snRNP), a component of the spliceosome. Here, we use a massively parallel splicing assay (MPSA) in human cells to quantify the activity of all 32,768 unique 5?ss sequences (NNN/GYNNNN) in three different gene contexts. Our results reveal that although splicing efficiency is mostly governed by the 5?ss sequence, there are substantial differences in this efficiency across gene contexts. Among other uses, these MPSA measurements facilitate the prediction of 5?ss sequence variants that are likely to cause aberrant splicing. This approach provides a framework to assess potential pathogenic variants in the human genome and streamline the development of splicing-corrective therapies.

Authors: Mandy S. Wong, Justin B. Kinney, Adrian R. Krainer.

About Cold Spring Harbor Laboratory
Founded in 1890, Cold Spring Harbor Laboratory has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. Home to eight Nobel Prize winners, the private, not-for-profit Laboratory employs 1,100 people including 600 scientists, students and technicians. The Meetings & Courses Program annually hosts more than 12,000 scientists. The Laboratory's education arm also includes an academic publishing house, a graduate school and the DNA Learning Center with programs for middle and high school students and teachers. For more information, visit http://www.cshl.edu


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Sep 6, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Cells make proteins based on blueprints encoded in our genes. These blueprints are copied into a raw RNA message, which must be edited, or spliced, to form a mature message that can direct the cellular machinery that synthesizes proteins. CSHL scientists have rigorously analyzed how mutations can alter RNA messages at the start of a splicing site (5-prime splice site). 1 and 2 here indicate those positions in a hypothetical raw RNA message. The aim is to be able to predict how errors at these sites will affect protein synthesis. Some errors lead to serious illnesses. Image Credit: Khan Academy.


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