Interplay between coding and exonic splicing regulatory sequences

Abstract

The inclusion of exons during the splicing process depends on the binding of splicing factors to short low-complexity regulatory sequences. The relationship between exonic splicing regulatory sequences and coding sequences is still poorly understood. We demonstrate that exons that are coregulated by any given splicing factor share a similar nucleotide composition bias and preferentially code for amino acids with similar physicochemical properties because of the nonrandomness of the genetic code. Indeed, amino acids sharing similar physicochemical properties correspond to codons that have the same nucleotide composition bias. In particular, we uncover that the TRA2A and TRA2B splicing factors that bind to adenine-rich motifs promote the inclusion of adenine-rich exons coding preferentially for hydrophilic amino acids that correspond to adenine-rich codons. SRSF2 that binds guanine/cytosine-rich motifs promotes the inclusion of GC-rich exons coding preferentially for small amino acids, whereas SRSF3 that binds cytosine-rich motifs promotes the inclusion of exons coding preferentially for uncharged amino acids, like serine and threonine that can be phosphorylated. Finally, coregulated exons encoding amino acids with similar physicochemical properties correspond to specific protein features. In conclusion, the regulation of an exon by a splicing factor that relies on the affinity of this factor for specific nucleotide(s) is tightly interconnected with the exon-encoded physicochemical properties. We therefore uncover an unanticipated bidirectional interplay between the splicing regulatory process and its biological functional outcome.

Characterizing the interplay between gene nucleotide composition bias and splicing

“…As exon recognition also depends on the binding to the pre-mRNAs of splicing factors that interact with compositionally biased sequences, one interesting possibility is that the nature of these splicing factors depends at least in part on the gene nucleotide composition bias. In this setting, we have recently reported that exons regulated by different splicing factors have different nucleotide composition bias [27].…”

Physicochemical Foundations of Life that Direct Evolution: Chance and Natural Selection are not Evolutionary Driving Forces

“…Interestingly, coding exons can share the same nucleotide composition bias as their flanking introns and their hosting genes [79,255]. As a consequence, mRNAs produced from co-regulated genes share the same nucleotide composition bias and are likely regulated by the same set of RNAs binding proteins, that interact with nucleotide composition biased sequences, in agreement with the concept or RNA regulons [50,253,256,257]. Furthermore, since the genetic code is not random, coding sequences sharing the same nucleotide composition bias encode for proteins having the same amino acid composition bias or the same physicochemical properties (see main text).…”

“…Supporting the notion that constraints on the physicochemical properties of one kind of polymer affects composition biases of the cognate polymers are the following observations: (i) Nucleosome positioning leaves a footprint in protein sequences, (ii) splicing sites and splicing factor binding motifs constrain the amino acid composition of peptides encoded by splicing-regulated exons, and (iii) mRNA secondary structures depending on base complementarity have consequences on the secondary structures of the encoded protein [40,[49][50][51]. Conversely, protein secondary structures leave a footprint in the nucleotide composition bias of coding sequences, for example, amino acids that favor alpha-helices and beta-sheets correspond to codons ending with purines and pyrimidines, respectively [52].…”

Congenital nephrotic syndrome in a Hispanic Guatemalan newborn associated with a NPHS1 variant: A case report

“…F����������, � ������ ����� f���� ���� � ������������� f�����'� binding affinity in exons is weak, but improves in the noncoding sequences of DNA (22). It is quite possible that genetic variants may affect exonic splicing regulatory sequences and consequently disrupt pre-mRNA splicing and initiate genetic diseases (23,24).…”