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LOST IN TRANSLATION: BIOINFORMATIC ANALYSIS OF VARIATIONS AFFECTING THE TRANSLATION INITIATION CODON IN THE HUMAN GENOME
Autores:
FRANCISCO ABAD NAVARRO
, MARÍA EUGENIA DE LA MORENA BARRIO,
JAVIER CORRAL DE LA CALLE
,
JESUALDO TOMÁS FERNÁNDEZ BREIS
,
Grupos de investigación:
[GI/IMIB/E170/2011] TECNOLOGÍAS DE MODELADO, PROCESAMIENTO Y GESTIÓN DEL CONOCIMIENTO
[GI/IMIB/C001/2011] HEMATOLOGÍA Y ONCOLOGÍA MÉDICA CLÍNICO-EXPERIMENTAL
Comunicación:
Antecedentes:
Translation of RNA into proteins in eukaryotes begins at the initiation codon “AUG”, which codes for methionine (Met1). Variations affecting this initial codon might have important consequences. Thus, different mutations affecting Met1 have been identified in patients with disorders caused by the lost of function of the affected protein. But also common polymorphisms affecting Met1 of different genes have been described, that affect to this region. However, as far as we know, there is no systematic study that had evaluated all mutations affecting Met1. The objective of this study was to describe the mutations affecting Met1 in the whole genome as well as to define the number of mutations affecting Met1 in a specific individual.
Métodos:
In order to identify all the variations in the human genome affecting initial codons of all available transcripts, a wide search in the Ensembl databases was done by using different bioinformatics tools. Positive findings were extracted with additional information concerning the gene affected, related publications, phenotype, pathogenic predictions (PolyPhen and SIFT), and the frequency of the variation. Moreover, our study also predicted the following Met and the following Met predicted by ATGpr software, as well as the consequence on the reading frame and the conservation of the signal peptide for these alternative Methionines. Variations were separated in two groups: mutations, which have a minor allele frequency (MAF) below 1%, and polymorphisms, with MAF ? 1%. Differences between these groups were evaluated by using appropriate statistic tests. The number and types of mutations affecting Met1 in 5 subjects was determined by the analysis of their whole exome sequence.
Resultados:
There are 35.978 genetic variations, mainly point mutations, overlapping the initial codon of any protein-coding transcript. These variations affect to 9.592 different genes, which is nearly half of the human genome. Analysis of variations with available frequency (3.379) reveals 225 polymorphisms and 3.154 rare mutations, supporting the pathogenic consequences of mutations disturbing the initiation codon. Interestingly, polymorphisms have an alternative initiation codon located closer to the original than mutations, and this alternative Met does not change the frameshift and partially preserves the signal peptide. We therefore propose a new prediction tool to define the pathogenic consequences of mutation affecting Met1, as current predictions (Polyphen and SIFT, based on aminoacid homologies) are not appropriate for these mutations that never cause a missense change. Analysis of individual cases revealed a medium of 11 common polymorphisms affecting Met1.
Conclusiones:
This study is the first one that has evaluated the effects of variations in initiation codons in a global way. These mutations favours the use of alternative initiation codons, with pathogenic consequences depending on the position of these alternative Met.
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