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On the path to genetic novelties: insights from programmed DNA elimination and RNA splicing

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Understanding how genetic novelties arise is a central goal of evolutionary biology. To this end, programmed DNA elimination and RNA splicing deserve special consideration. While programmed DNA elimination reshapes genomes by eliminating chromatin during organismal development, RNA splicing rearranges genetic messages by removing intronic regions during transcription. Small RNAs help to mediate this class of sequence reorganization, which is not error‐free. It is this imperfection that makes programmed DNA elimination and RNA splicing excellent candidates for generating evolutionary novelties. Leveraging a number of these two processes' mechanistic and evolutionary properties, which have been uncovered over the past years, we present recently proposed models and empirical evidence for how splicing can shape the structure of protein‐coding genes in eukaryotes. We also chronicle a number of intriguing similarities between the processes of programmed DNA elimination and RNA splicing, and highlight the role that the variation in the population‐genetic environment may play in shaping their target sequences. WIREs RNA 2015, 6:547–561. doi: 10.1002/wrna.1293 This article is categorized under: RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing
Proposed mechanism for the origin of genetic novelties in Paramecium. In Paramecium programmed DNA elimination occurs when the germline (zygotic) DNA regenerates the polyploid somatic DNA. During this process of germline‐to‐soma differentiation, the germline DNA is fragmented and amplified and thousands of germline noncoding DNA regions (denoted by the yellow segments in germline DNA) are excised. These excised regions are called internal eliminated sequences (IESs). IESs may be occasionally retained in the somatic DNA (denoted by yellow segments in somatic DNA). Additionally, the DNA splicing machinery may erroneously recognize and excise non‐germline specific sequences that are flanked by sequences resembling IES excision signals (as represented by vertical red segments in somatic DNA). Splicing‐weakening or ‐disrupting mutations, in tandem with epigenetic maternal effects, are proposed to modulate the frequency of imperfectly excised sequences. After a number of sexual generations, germline‐specific (somatic) sequences can convert into somatic (germline‐specific) sequences, a heritable change. Novel DNA variants, when nonlethal, have a nonzero probability of spreading through a population and to reach fixation.
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Overview of the proposed mechanism of intronization. A gene acquires a premature in‐frame stop codon either at its 5′ end or at its 3′ end. This stop codon may or may not be removed from the corresponding pre‐mRNA via RNA splicing provided that it is flanked by latent splicing signals. If accidental splicing takes place, and the excised sequence falls between codons and contains a number of nucleotides that is a multiple of 3 (3n), then the resulting mature mRNA will be invisible to nonsense‐mediated decay (NMD) and the translation product will be identical to the original protein, except for an internal deletion. Accidental splicing is more likely to take place in proximity of pre‐mRNA structures/sequences that enhance the recruitment of splicing factors on site, e.g., the cap‐binding complex at the gene 5′ end. If splicing does not take place, NMD will produce a relatively pure pool of stop‐free mRNAs when the stop codon resides at the gene 5′ end—at this location NMD degradation of aberrant transcripts is most efficient. In contrast, truncated and potentially harmful translational products are produced when mRNAs contain premature in‐frame stops at their 3′ end. As a consequence of the expected fitness effects that are associated with these dynamics, intronization is more likely to occur at the gene 5′ end compared to the gene 3′ end.
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Process of exonization and cellular strategies for diminishing their negative impact. From top to bottom: transposed Short INterspersed Elements (SINEs, red line) are actively transcribed from their own internal polymerase III promoter (green line). Transcription can be downregulated by the methyl‐CpG‐binding domain (MBD) that binds specifically to methyl CpG pairs. SINE transcripts (TC) are frequently attacked and destroyed by RNA interference (RNAi). Other polyadenylated transcripts are substrates of the reverse transcriptase (RT)‐ and integrase (IN)‐containing retropositional system delivered in trans from active autonomous elements such as LINE1. Random antisense intronic integrations provide an intrinsic polypyrimidine tract (Tn) and frequently also a specific cryptic 3′‐AG splice site. Subsequent acquisition of a 5′ GT splice site (in this example located in the flanking intronic region, black box) leads to a composed exonized sequence. To be stably inherited in a species any genomic innovation requires germline fixation, a process that takes millions of years. Alternative splicing of an exonized sequence is regulated by the competitive activity of the heterogeneous nuclear ribonucleoprotein C (HNRNPC) that functions as a repressor and the U2 auxiliary factor (U2AF65) that actively processes cryptic splice sites occurring in newly exonized sequences. Nonfunctional mRNAs with premature termination codons introduced by exonized sequences (red and black boxes) will be recognized and destroyed in the nonsense‐mediated decay (NMD) pathway during translation (TL).
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RNA Processing > Splicing Regulation/Alternative Splicing

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