The biological function of multiple repetitions of single amino acids, or homo-repeats, is largely unknown, but their occurrence in proteins has been associated with more than 20 hereditary diseases. Analysing 122 bacterial and eukaryotic genomes, we observed that the number of proteins containing homo-repeats is significantly larger than expected from theoretical estimates. Analysis of statistical significance indicates that the minimal size of homo-repeats varies with amino acid type and proteome. In an attempt to characterize proteins harbouring long homo-repeats, we found that those containing polar or small amino acids S, P, H, E, D, K, Q and N are enriched in structural disorder as well as protein- and RNA-interactions. We observed that E, S, Q, G, L, P, D, A and H homo-repeats are strongly linked with occurrence in human diseases. Moreover, S, E, P, A, Q, D and T homo-repeats are significantly enriched in neuronal proteins associated with autism and other disorders. We release a webserver for further exploration of homo-repeats occurrence in human pathology at http://bioinfo.protres.ru/hradis/.

This study was supported by the Russian Science Foundation grant number 14-14-00536 for OVG and the programs “Molecular and Cellular Biology” (01201353567) for MYL and IVS. GGT received funding from the European Union Seventh Framework Programme (FP7/2007–2013), through the European Research Council, under grant agreement RIBOMYLOME_309545, and from the Spanish Ministry of Economy and Competitiveness. PK and GGT also acknowledge support from the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013–2017’ (SEV-2012-0208). PK is recipient of a “La Caixa” studentship.