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A study identifies functional repetitive motifs in human proteins

A new study comparing the human genome with the genomes of other vertebrate species to determine which of the repetitive motifs found in human proteins are important for the proper functioning of the body and which could correspond to the so-called “junk” fraction of the genome has just been published in the online journal Genome Research. The study was carried out entirely by the research group in Evolutionary Genomics, within the Computational Genomics group of GRIB at the University of Pompeu Fabra in Barcelona and was led by Mar Albà, ICREA researcher.

4 june 2010

Repetitive motifs are structures in which a single amino acid is repeated several times in a row. They are found in approximately 20% of human proteins. Until recently it was thought that they were not functional, hence the name of “junk”, but recent studies have shown that some of these repeated fragments have an important role. For example, in some cases it has been observed that when mutated, these repeated fragments cause developmental and neurodegenerative diseases like Huntington's disease.

This makes it even more important to identify which repetitive motifs are functional, as they may be involved in diseases for which there is no known genetic origin.

The functional repetitive motifs have been selected through evolution

The most original element of this study was to compare the degree of conservation of repetitive motifs found in human proteins that we do not know are functional or “junk” with the degree of conservation of a collection of repeat motifs that are known to be basically “junk.” These latter motifs have been identified based on their location in the genome, outside the regions that code for proteins.

Albà explained that: “we have observed that if the motif is in an area that codes for a protein, it is also often present in many other species. However, if the motif is in a region that does not code for a protein, it is not functional. This implies that the majority of repetitive motifs in human proteins may play a functional role, given that we observed a strong imprint of natural selection.”

The study used the genomes of 11 species of vertebrates, including species closely related to humans, such as the mouse or cow, and more distant species like fish. If one repetitive motif in a human protein has been more highly conserved by evolution than the “junk” motifs, it can be concluded that natural selection has played a role in its preservation. The study estimated that approximately 90% of repetitive structures in human proteins that are conserved in other mammalian species have been maintained due to natural selection. Finding that one motif is well conserved in mammals is therefore sufficient reason to suspect that it is functional.

Among the repetitive structures analyzed, the study selected a group of 92 that, from their length and significant level of conservation in different species of vertebrates, have a very high probability of playing an important functional role in the cell.

This group of repetitive structures includes two motifs of alanine in the HOXD13 and PHOX2B genes that, when mutated and extended, cause polydactyly and congenital central hypoventilation syndrome, respectively. It also includes two histidine motifs of the DYRK1A and FAM76B proteins, which are important for proper protein localization in the cell. Mutations in the other motifs on the list of 92 could also result in significant changes and should be investigated.

Albà’s research team was made up of Loris Mularoni, currently at John Hopkins University in the U.S., Alice Ledda and Macarena Toll-Riera, who are currently both finishing their doctorate.

Reference article:
Mularoni, L., Ledda, A., Toll-Riera, M., Albà, M.M. (2010) Natural selection drives the accumulation of amino acid tandem repeats in human proteins, Genome Research, Advanced Online Publication, March 24th 2010.

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