Alternative splicing

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Schematic representation of alternative splicing using exon skipping .

The alternative splicing (also differential splicing or tissue-specific splicing called) is a special process in the context of transcription in eukaryotes . Even viruses which infect eukaryotes use this mechanism. From the same DNA sequence and, accordingly, one and the same pre-mRNA , several different mature mRNA - molecules and their translation , several different polypeptides or proteins are formed. Around a third of all human genes - some sources even assume up to 59 percent - are subject to alternative splicing. Incorrect regulation here is a common cause of various diseases .

Forms of alternative splicing

Overview of the different forms of alternative splicing (red) compared to constitutive splicing (black)

With alternative splicing, it is only during the splicing process that a decision is made as to which RNA sequences are introns and which are exons . The regulation takes place via splice factors (proteins that recognize signals on the RNA and influence the selection of the splice sites ). Different forms of alternative splicing can be distinguished:

  • Cassette exons ( mutually exclusive exons ),
  • the skipping of exons ( exon skipping ) or
  • using different 5 'or 3' splice sites ( alternative 5 '/ 3' splice sites ), cf. adjacent figure.

Many proteins from just one gene

The discovery of alternative splicing means that the one-gene-one-enzyme hypothesis does not strictly apply to eukaryotes. A DNA sequence, i.e. a gene, can code for different proteins . In this way, e.g. For example, a human cell with around 20,000 genes is able to produce many hundreds of thousands of different proteins - an extremely complex proteome of 500,000 to 1,000,000 protein species is created from relatively few genes . The information density of the DNA is considerably increased by superposition.

An extreme example of this: DSCAM , a gene in Drosophila melanogaster that controls the directional growth of nerve cells , has several cassette exons that can be combined with one another, resulting in a total of 38,016 different proteins from just this one gene. However, only a few of them have actually been detected in the organism. In contrast, the number of genes in this organism appears comparatively small at around 14,000. This underlines impressively that the multitude of proteins in an organism is not primarily determined by the number of its genes, but rather by the alternative splicing of the pre-mRNAs.

Effect on genetics

After sequencing the genome, the number of human genes is now around 20,000, far below the original assumptions. However, since almost every second gene can alternatively be spliced, a much higher variety of proteins can be explained despite the seemingly small number of genes. Understanding alternative splicing is therefore a major challenge when researching human protein diversity and thus understanding many diseases (such as cancer ) and hereditary diseases .

Splicing and Evolution

The alternative splicing represents an evolutionarily particularly important development in eukaryotes :

  • The formation of new proteins can take place much more easily than with prokaryotes , namely by changing the regulation of splicing.
  • The probability that a new protein created by alternative splicing is functional is higher than with a new protein created by mutating the coding DNA sequence. Every protein produced in this way during evolution contains at least several amino acid sequences that already function in other proteins .
  • This facilitates and accelerates the adaptation of eukaryotes to changed living conditions. This could have been a decisive step for the evolution of multicellular organisms with a longer generation duration. While bacteria often pass less than an hour between two generations, this time can grow to several decades in eukaryotes (e.g. humans).

Individual evidence

  1. ↑ Stoss, O. et al .: Misregulation of pre-mRNA splicing that causes human diseases. Concepts and therapeutic strategies . In: Gene Ther Mol Biol . 5, 2000, pp. 9-30.
  2. ↑ Barash, Y. et al .: Deciphering the splicing code . In: Nature . 465, No. 7294, 2010, pp. 53-59. PMID 20445623 .
  3. ↑ Lander, ES et al .: Initial sequencing and analysis of the human genome . In: Nature . 15, No. 409, 2001, pp. 860-921. PMID 11237011 .
  4. ↑ Faustino, NA et al .: Pre-mRNA splicing and human disease . In: Genes & Dev . 17, 2003, pp. 419-437.
  5. ↑ Campbell -Biologiebuch, English edition, S. 362nd

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