M.Mar Albà, September 2014
Evolutionary Genomics Group, IMIM-UPF, Barcelona
evolutionarygenomics.imim.es
Antimicrobial peptides (AMPs) are short proteins produced by a wide range of organisms that have the capacity to kill bacteria (Wiesner and Vilcinskas 2010). AMPs are produced both constitutively or induced when the organism (or a certain tissue) is injured or exposed to microbes (Zasloff 2007). AMPs are a promising alternative to classical therapeutic antibiotics, as bacteria have not developed highly effective resistance mechanisms to these natural substances (Peschel and Sahl 2006).
Well-characterized human AMPs include defensins and cathelidicins (Wiesner and Vilcinskas 2010). Despite their importance in the response to infection, many AMPs encoded in the human genome are likely to remain to be characterized. The main reason for this is their short size, typically between 12 and 50 amino acids, which makes them hard to detect by standard gene prediction programs. In addition, many AMPs appear to be restricted to a particular species or lineage, one example being the primate-specific protein dermcidin secreted in the skin (Schittek et al. 2001).
The aim of this project is to discover and characterize new AMPs in the human genome. First we will use deep RNA sequencing (RNA-seq) from different human tissues to perform de novo transcript assembly. Short open reading frames with significant coding potential will be identified using a novel approach we have developed to annotate short peptides (Ruiz-Orera et al., 2014). We will use AMP prediction programs such as AMPA (Torrent, Di Tommaso, et al. 2012) to find putatively new AMPs. Using this program we have already predicted that lacritin, a peptide of unknown function secreted in lacrimal glands, has antimicrobial activity. This result is supported by the fact that lacritin is homologous to dermcidin, both genes diverged after a gene duplication event in an ancestral mammal (Toll-Riera et al., 2009).
Using similar RNA-seq data from other mammals that is available in the lab we will investigate the conservation and evolutionary patterns of the predicted human AMPs. We will search for adaptive substitutions that may have increase the antimicrobial activity over time using maximum likelihood methods and polymorphism data (Gayà-Vidal and Albà, 2014). The function of the most promising candidates is going to be experimentally tested in collaboration with the Human RNases involved in host defense group leaded by Ester Boix (Universitat Autònoma de Barcelona).
Gayà-Vidal M and Albà MM. 2014. Uncovering adaptive evolution in the human lineage. BMC Genomics 15: 599.
Peschel A, Sahl H-G. 2006. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat Rev Micro 4: 529–536.
Schittek B, Hipfel R, Sauer B, Bauer J, Kalbacher H, Stevanovic S, Schirle M, Schroeder K, Blin N, Meier F, et al. 2001. Dermcidin: a novel human antibiotic peptide secreted by sweat glands. Nature immunology 2: 1133–7.
Toll-Riera M, Bosch N, Bellora N, Castelo R, Armengol L, Estivill X, Albà MM. 2009. Origin of primate orphan genes: a comparative genomics approach. Molecular biology and evolution 26: 603–612.
Torrent M, Di Tommaso P, Pulido D, Nogués MV, Notredame C, Boix E, Andreu D. 2012. AMPA: an automated web server for prediction of protein antimicrobial regions. Bioinformatics 28: 130–1.
Ruiz-Orera J, Messeguer X, Subirana JA, Albà MM. 2014. Long non-coding RNAs as a source of new peptides. eLife Sep 16;3.
Wiesner J, Vilcinskas A. 2010. The ancient arm of the human immune system Antimicrobial peptides. Virulence 1: 440–464.
Williams WM, Castellani RJ, Weinberg A, Perry G, Smith M a. 2012. Do β-defensins and other antimicrobial peptides play a role in neuroimmune function and neurodegeneration? TheScientificWorldJournal 2012: 905785.
Zaiou M. 2007. Multifunctional antimicrobial peptides: therapeutic targets in several human diseases. Journal of Molecular Medicine 85: 317–329.
Zasloff M. 2007. Antimicrobial peptides, innate immunity, and the normally sterile urinary tract. Journal of the American Society of Nephrology : JASN 18: 2810–6.
