TY - JOUR
T1 - Testing for natural selection in human exonic splicing regulators associated with evolutionary rate shifts
AU - Ramalho, Rodrigo F.
AU - Gelfman, Sahar
AU - De Souza, Jorge E.
AU - Ast, Gil
AU - De Souza, Sandro J.
AU - Meyer, Diogo
N1 - Funding Information:
We thank Daniel Ohara for technical support, Dr. Pedro Galante for providing the exon database, and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for the PhD Fellowship (2007/59721-8) to RFR and for the grant (2009/09127-8) to DM. SG is a Fellow of the Edmond J. Safra Bioinformatics Program at Tel-Aviv University.
PY - 2013/4
Y1 - 2013/4
N2 - Despite evidence that at the interspecific scale, exonic splicing silencers (ESSs) are under negative selection in constitutive exons, little is known about the effects of slightly deleterious polymorphisms on these splicing regulators. Through the application of a modified version of the McDonald-Kreitman test, we compared the normalized proportions of human polymorphisms and human/rhesus substitutions affecting exonic splicing regulators (ESRs) on sequences of constitutive and alternative exons. Our results show a depletion of substitutions and an enrichment of SNPs associated with ESS gain in constitutive exons. Moreover, we show that this evolutionary pattern is also present in a set of ESRs previously involved in the transition from constitutive to skipped exons in the mammalian lineage. The similarity between these two sets of ESRs suggests that the transition from constitutive to skipped exons in mammals is more frequently associated with the inhibition than with the promotion of splicing signals. This is in accordance with the hypothesis of a constitutive origin of exon skipping and corroborates previous findings about the antagonistic role of certain exonic splicing enhancers.
AB - Despite evidence that at the interspecific scale, exonic splicing silencers (ESSs) are under negative selection in constitutive exons, little is known about the effects of slightly deleterious polymorphisms on these splicing regulators. Through the application of a modified version of the McDonald-Kreitman test, we compared the normalized proportions of human polymorphisms and human/rhesus substitutions affecting exonic splicing regulators (ESRs) on sequences of constitutive and alternative exons. Our results show a depletion of substitutions and an enrichment of SNPs associated with ESS gain in constitutive exons. Moreover, we show that this evolutionary pattern is also present in a set of ESRs previously involved in the transition from constitutive to skipped exons in the mammalian lineage. The similarity between these two sets of ESRs suggests that the transition from constitutive to skipped exons in mammals is more frequently associated with the inhibition than with the promotion of splicing signals. This is in accordance with the hypothesis of a constitutive origin of exon skipping and corroborates previous findings about the antagonistic role of certain exonic splicing enhancers.
KW - Alternative splicing
KW - Exonic splicing regulators
KW - Human polymorphism
KW - MK test
UR - https://www.scopus.com/pages/publications/84877812628
U2 - 10.1007/s00239-013-9555-2
DO - 10.1007/s00239-013-9555-2
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C2 - 23529588
AN - SCOPUS:84877812628
SN - 0022-2844
VL - 76
SP - 228
EP - 239
JO - Journal of Molecular Evolution
JF - Journal of Molecular Evolution
IS - 4
ER -