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Micro peptides as a new class of bio-active peptides in Eukaryotes

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Abstract
Background : For a long time it was assumed that protein-coding genes were at least 100 AA in length. Besides, algorithms for detection of coding sequence with such very short open reading frame (ORF) length are less reliable since they can be buried in a pile of ‘junk’ ORFs formed by chance. However, over the recent years many of these non-canonical (< 100 AA in length) genes were discovered in different organisms as Arabidopsis, Saccharomyces, and Drosophila. Here, the resulting small peptides (micro-peptides) are translated directly from their small open reading frames (smORFs). Also, recently a first evolutionary conserved micro-peptide (polished rice or tarsal-less, Drosophila) has been functionally characterized, playing its role in early developmental stages. Thanks to advances in sequencing, bioinformatics tools and computing power, it is now possible to scan the genome of different species unceasingly deep, e.g. in a search for this type of small peptides. Methods : Using bio-informatics methods, we performed a systematic search for putatively functional smORFs in both the Drosophila melanogaster and Mus musculus genome. Our search pipeline consists of several steps. We first scan for smORFs with the sORFfinder tool, using a hidden markov model predicting the coding potential of possible open reading frames genome-wide. Secondly, we checked for transcriptional evidence using public or in-house RNA-seq and/or ribosome profiling data of specific embryonic (and larval stages). Thirdly, the pattern of conservation of those detected smORFs was investigated using the UCSC multiple alignments (containing 14 insects for Drosophila melanogaster and 29 vertebrates for Mus musculus). The ratio of synonymous versus non-synonymous mutations, the ORF length and start-stop codon conservation and the number of existing alignments were examined. A customized scoring algorithm, built on all derived properties, allows us to rank these predicted micro-peptides. Results : Based on the aforementioned pipeline, a list of putative micro-peptides with high coding potential was obtained. All predicted micro-peptides are highly conserved on both DNA and AA level, and moreover have a favorable synonymous versus non-synonymous mutation rate. Next, they are supported by experimental evidence by means of (bidirectional) RNAseq, ribosomal profiling data, or Ensembl ncRNA gene annotations. Specific research effort is needed to gather experimental evidence for the translation and functionality of smORFs (e.g. using genetic manipulation and/or ribosome profiling studies). Conclusion : Micro-peptide research is still in its infancy. The combination of the analyses led us to postulate the existence of many new functional smORFs in both fruitfly and mouse. We strongly belief that micro-peptides herald important functions and are, in the same way as microRNAs, an important but long time overlooked class of bio-active molecules.
Keywords
sORFs, Micropeptides, Drosophila melanogaster, genome-wide, small open reading frames, Mus musculus

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Chicago
Crappé, Jeroen, Gerben Menschaert, Geert Trooskens, Joachim De Schrijver, Geert Baggerman, and Wim Van Criekinge. 2011. “Micro Peptides as a New Class of Bio-active Peptides in Eukaryotes.” In Benelux Bioinformatics Conference : Proceedings of BBC11, 77–77.
APA
Crappé, J., Menschaert, G., Trooskens, G., De Schrijver, J., Baggerman, G., & Van Criekinge, W. (2011). Micro peptides as a new class of bio-active peptides in Eukaryotes. Benelux Bioinformatics Conference : proceedings of BBC11 (pp. 77–77). Presented at the 6th Benelux Bioinformatics Conference (BBC  ’11).
Vancouver
1.
Crappé J, Menschaert G, Trooskens G, De Schrijver J, Baggerman G, Van Criekinge W. Micro peptides as a new class of bio-active peptides in Eukaryotes. Benelux Bioinformatics Conference : proceedings of BBC11. 2011. p. 77–77.
MLA
Crappé, Jeroen, Gerben Menschaert, Geert Trooskens, et al. “Micro Peptides as a New Class of Bio-active Peptides in Eukaryotes.” Benelux Bioinformatics Conference : Proceedings of BBC11. 2011. 77–77. Print.
@inproceedings{3038816,
  abstract     = {Background : For a long time it was assumed that protein-coding genes were at least 100 AA in length. Besides, algorithms for detection of coding sequence with such very short open reading frame (ORF) length are less reliable since they can be buried in a pile of {\textquoteleft}junk{\textquoteright} ORFs formed by chance. However, over the recent years many of these non-canonical  ({\textlangle} 100 AA in length) genes were discovered in different organisms as Arabidopsis, Saccharomyces, and Drosophila. Here, the resulting small peptides (micro-peptides) are translated directly from their small open reading frames (smORFs). Also, recently a first evolutionary conserved micro-peptide (polished rice or tarsal-less, Drosophila) has been functionally characterized, playing its role in early developmental stages. Thanks to advances in sequencing, bioinformatics tools and computing power, it is now possible to scan the genome of different species unceasingly deep, e.g. in a search for this type of small peptides.
Methods : Using bio-informatics methods, we performed a systematic search for putatively functional smORFs in both the Drosophila melanogaster and Mus musculus genome. Our search pipeline consists of several steps. We first scan for smORFs with the sORFfinder tool, using a hidden markov model predicting the coding potential of possible open reading frames genome-wide. Secondly, we checked for transcriptional evidence using public or in-house RNA-seq and/or ribosome profiling data of specific embryonic (and larval stages). Thirdly, the pattern of conservation of those detected smORFs was investigated using the UCSC multiple alignments (containing 14 insects for Drosophila melanogaster and 29 vertebrates for Mus musculus). The ratio of synonymous versus non-synonymous mutations, the ORF length and start-stop codon conservation and the number of existing alignments were examined. A customized scoring algorithm, built on all derived properties, allows us to rank these predicted micro-peptides.
Results : Based on the aforementioned pipeline, a list of putative micro-peptides with high coding potential was obtained. All predicted micro-peptides are highly conserved on both DNA and AA level, and moreover have a favorable synonymous versus non-synonymous mutation rate. Next, they are supported by experimental evidence by means of (bidirectional) RNAseq, ribosomal profiling data, or Ensembl ncRNA gene annotations. Specific research effort is needed to gather experimental evidence for the translation and functionality of smORFs (e.g. using genetic manipulation and/or ribosome profiling studies).
Conclusion : Micro-peptide research is still in its infancy. The combination of the analyses led us to postulate the existence of many new functional smORFs in both fruitfly and mouse. We strongly belief that micro-peptides herald important functions and are, in the same way as microRNAs, an important but long time overlooked class of bio-active molecules.},
  articleno    = {abstract B12},
  author       = {Crapp{\'e}, Jeroen and Menschaert, Gerben and Trooskens, Geert and De Schrijver, Joachim and Baggerman, Geert  and Van Criekinge, Wim},
  booktitle    = {Benelux Bioinformatics Conference : proceedings of BBC11},
  language     = {eng},
  location     = {Luxembourg, GD Luxembourg},
  pages        = {abstract B12:77--abstract B12:77},
  title        = {Micro peptides as a new class of bio-active peptides in Eukaryotes},
  url          = {http://www.bbc11.lu/documents/ConferenceProceedingsBBC2011update.pdf},
  year         = {2011},
}