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Stochastic noise in splicing machinery.

Melamud E, Moult J - Nucleic Acids Res. (2009)

Bottom Line: In this paper, we propose that most alternative splicing events are the result of noise in the splicing process.The results strongly support the hypothesis that most alternative splicing is a consequence of stochastic noise in the splicing machinery, and has no functional significance.The results are also consistent with error rates tuned to ensure that an adequate level of functional product is produced and to reduce the toxic effect of accumulation of misfolding proteins.

View Article: PubMed Central - PubMed

Affiliation: Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, USA. melamud@umbi.umd.edu

ABSTRACT
The number of known alternative human isoforms has been increasing steadily with the amount of available transcription data. To date, over 100 000 isoforms have been detected in EST libraries, and at least 75% of human genes have at least one alternative isoform. In this paper, we propose that most alternative splicing events are the result of noise in the splicing process. We show that the number of isoforms and their abundance can be predicted by a simple stochastic noise model that takes into account two factors: the number of introns in a gene and the expression level of a gene. The results strongly support the hypothesis that most alternative splicing is a consequence of stochastic noise in the splicing machinery, and has no functional significance. The results are also consistent with error rates tuned to ensure that an adequate level of functional product is produced and to reduce the toxic effect of accumulation of misfolding proteins. Based on simulation of sampling of virtual cDNA libraries, we estimate that error rates range from 1 to 10% depending on the number of introns and the expression level of a gene.

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Example analysis of EST sequences. In this hypothetical example, the major isoform of a gene has six introns and seven ESTs have been observed in a library. Three of the ESTs sequences (EST3, EST4, EST5) contain alternative introns—introns that differ at the 3′ and/or 5′ end from corresponding intron in the major isoform. The fractional abundance of alternative transcripts is 42% (3 out of 7). The number of isoforms for this gene is 3 (major isoform, EST3 isoform and EST5 isoforms). EST4 is not counted as an additional isoform because it has the same pattern as EST3. There are a total of 13 detected splicing reactions (count of all introns from all ESTs) and 3 of these splicing reactions are classified as alternative. The implied error rate for this gene is 0.23 (3 out of 13 splicing reactions).
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Figure 1: Example analysis of EST sequences. In this hypothetical example, the major isoform of a gene has six introns and seven ESTs have been observed in a library. Three of the ESTs sequences (EST3, EST4, EST5) contain alternative introns—introns that differ at the 3′ and/or 5′ end from corresponding intron in the major isoform. The fractional abundance of alternative transcripts is 42% (3 out of 7). The number of isoforms for this gene is 3 (major isoform, EST3 isoform and EST5 isoforms). EST4 is not counted as an additional isoform because it has the same pattern as EST3. There are a total of 13 detected splicing reactions (count of all introns from all ESTs) and 3 of these splicing reactions are classified as alternative. The implied error rate for this gene is 0.23 (3 out of 13 splicing reactions).

Mentions: For each gene, we compare the intron structure of the major isoform with the intron structure of each EST sequence. If an EST sequence contains at least one intron that differs from the corresponding major isoform intron at the 5′ or 3′ splice site, that EST is counted as an alternative transcript. The total number of alternative transcripts is defined as the total number of ESTs containing alternative splicing. The fraction of alternative transcripts is defined as the number of ESTs with alternative splicing divided by the total number of ESTs for a gene. The number of isoforms for a gene is defined as the number of unique intron patterns discovered in the EST libraries. We also defined the number of detected splicing reactions as the total number of introns observed in all EST sequences of a gene (illustrated in Figure 1).Figure 1.


Stochastic noise in splicing machinery.

Melamud E, Moult J - Nucleic Acids Res. (2009)

Example analysis of EST sequences. In this hypothetical example, the major isoform of a gene has six introns and seven ESTs have been observed in a library. Three of the ESTs sequences (EST3, EST4, EST5) contain alternative introns—introns that differ at the 3′ and/or 5′ end from corresponding intron in the major isoform. The fractional abundance of alternative transcripts is 42% (3 out of 7). The number of isoforms for this gene is 3 (major isoform, EST3 isoform and EST5 isoforms). EST4 is not counted as an additional isoform because it has the same pattern as EST3. There are a total of 13 detected splicing reactions (count of all introns from all ESTs) and 3 of these splicing reactions are classified as alternative. The implied error rate for this gene is 0.23 (3 out of 13 splicing reactions).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724286&req=5

Figure 1: Example analysis of EST sequences. In this hypothetical example, the major isoform of a gene has six introns and seven ESTs have been observed in a library. Three of the ESTs sequences (EST3, EST4, EST5) contain alternative introns—introns that differ at the 3′ and/or 5′ end from corresponding intron in the major isoform. The fractional abundance of alternative transcripts is 42% (3 out of 7). The number of isoforms for this gene is 3 (major isoform, EST3 isoform and EST5 isoforms). EST4 is not counted as an additional isoform because it has the same pattern as EST3. There are a total of 13 detected splicing reactions (count of all introns from all ESTs) and 3 of these splicing reactions are classified as alternative. The implied error rate for this gene is 0.23 (3 out of 13 splicing reactions).
Mentions: For each gene, we compare the intron structure of the major isoform with the intron structure of each EST sequence. If an EST sequence contains at least one intron that differs from the corresponding major isoform intron at the 5′ or 3′ splice site, that EST is counted as an alternative transcript. The total number of alternative transcripts is defined as the total number of ESTs containing alternative splicing. The fraction of alternative transcripts is defined as the number of ESTs with alternative splicing divided by the total number of ESTs for a gene. The number of isoforms for a gene is defined as the number of unique intron patterns discovered in the EST libraries. We also defined the number of detected splicing reactions as the total number of introns observed in all EST sequences of a gene (illustrated in Figure 1).Figure 1.

Bottom Line: In this paper, we propose that most alternative splicing events are the result of noise in the splicing process.The results strongly support the hypothesis that most alternative splicing is a consequence of stochastic noise in the splicing machinery, and has no functional significance.The results are also consistent with error rates tuned to ensure that an adequate level of functional product is produced and to reduce the toxic effect of accumulation of misfolding proteins.

View Article: PubMed Central - PubMed

Affiliation: Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, USA. melamud@umbi.umd.edu

ABSTRACT
The number of known alternative human isoforms has been increasing steadily with the amount of available transcription data. To date, over 100 000 isoforms have been detected in EST libraries, and at least 75% of human genes have at least one alternative isoform. In this paper, we propose that most alternative splicing events are the result of noise in the splicing process. We show that the number of isoforms and their abundance can be predicted by a simple stochastic noise model that takes into account two factors: the number of introns in a gene and the expression level of a gene. The results strongly support the hypothesis that most alternative splicing is a consequence of stochastic noise in the splicing machinery, and has no functional significance. The results are also consistent with error rates tuned to ensure that an adequate level of functional product is produced and to reduce the toxic effect of accumulation of misfolding proteins. Based on simulation of sampling of virtual cDNA libraries, we estimate that error rates range from 1 to 10% depending on the number of introns and the expression level of a gene.

Show MeSH
Related in: MedlinePlus