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The genetic signatures of noncoding RNAs.

Mattick JS - PLoS Genet. (2009)

Bottom Line: Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction.The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions.There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses.

View Article: PubMed Central - PubMed

Affiliation: Australian Research Council Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Australia. j.mattick@imb.uq.edu.au

ABSTRACT
The majority of the genome in animals and plants is transcribed in a developmentally regulated manner to produce large numbers of non-protein-coding RNAs (ncRNAs), whose incidence increases with developmental complexity. There is growing evidence that these transcripts are functional, particularly in the regulation of epigenetic processes, leading to the suggestion that they compose a hitherto hidden layer of genomic programming in humans and other complex organisms. However, to date, very few have been identified in genetic screens. Here I show that this is explicable by an historic emphasis, both phenotypically and technically, on mutations in protein-coding sequences, and by presumptions about the nature of regulatory mutations. Most variations in regulatory sequences produce relatively subtle phenotypic changes, in contrast to mutations in protein-coding sequences that frequently cause catastrophic component failure. Until recently, most mapping projects have focused on protein-coding sequences, and the limited number of identified regulatory mutations have been interpreted as affecting conventional cis-acting promoter and enhancer elements, although these regions are often themselves transcribed. Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction. The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions. There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses.

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Related in: MedlinePlus

The contrasting effects of mutations in protein-coding and regulatory sequences.A conceptual diagram of the spectrum of phenotypic effects of mutations in sequences encoding proteins and other analogue components of cells (continuous line) versus variations in non-coding sequences that specify regulatory interactions (dashed line).
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pgen-1000459-g002: The contrasting effects of mutations in protein-coding and regulatory sequences.A conceptual diagram of the spectrum of phenotypic effects of mutations in sequences encoding proteins and other analogue components of cells (continuous line) versus variations in non-coding sequences that specify regulatory interactions (dashed line).

Mentions: There is, of course, a wide spectrum of effects of both coding and noncoding mutations (Figure 2), and there are exceptions to the rule in both directions. Loss-of-function mutations in some protein-coding genes have mild effects [92], as exemplified by as knockouts of the mammalian genes encoding calbindin D9k [93] and C/EBPdelta [94],[95], and the significant number of yeast genes that show no observable phenotype. Reciprocally, knockouts of some highly conserved miRNAs, many of which have multiple targets, give strong phenotypes [96]–[98], even though very few such genes have been identified in genetic screens in Caenorhabditis elegans and Drosophila, and none have been identified in mice, despite the intensity of such screens (see below). Moreover, to date, no naturally arising mutations have been discovered in the Xist gene in either humans or mice, despite the central role that this ncRNA plays in embryogenesis and in X-chromosome dosage control in females [99], possibly because such mutations are lethal.


The genetic signatures of noncoding RNAs.

Mattick JS - PLoS Genet. (2009)

The contrasting effects of mutations in protein-coding and regulatory sequences.A conceptual diagram of the spectrum of phenotypic effects of mutations in sequences encoding proteins and other analogue components of cells (continuous line) versus variations in non-coding sequences that specify regulatory interactions (dashed line).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2667263&req=5

pgen-1000459-g002: The contrasting effects of mutations in protein-coding and regulatory sequences.A conceptual diagram of the spectrum of phenotypic effects of mutations in sequences encoding proteins and other analogue components of cells (continuous line) versus variations in non-coding sequences that specify regulatory interactions (dashed line).
Mentions: There is, of course, a wide spectrum of effects of both coding and noncoding mutations (Figure 2), and there are exceptions to the rule in both directions. Loss-of-function mutations in some protein-coding genes have mild effects [92], as exemplified by as knockouts of the mammalian genes encoding calbindin D9k [93] and C/EBPdelta [94],[95], and the significant number of yeast genes that show no observable phenotype. Reciprocally, knockouts of some highly conserved miRNAs, many of which have multiple targets, give strong phenotypes [96]–[98], even though very few such genes have been identified in genetic screens in Caenorhabditis elegans and Drosophila, and none have been identified in mice, despite the intensity of such screens (see below). Moreover, to date, no naturally arising mutations have been discovered in the Xist gene in either humans or mice, despite the central role that this ncRNA plays in embryogenesis and in X-chromosome dosage control in females [99], possibly because such mutations are lethal.

Bottom Line: Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction.The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions.There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses.

View Article: PubMed Central - PubMed

Affiliation: Australian Research Council Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Australia. j.mattick@imb.uq.edu.au

ABSTRACT
The majority of the genome in animals and plants is transcribed in a developmentally regulated manner to produce large numbers of non-protein-coding RNAs (ncRNAs), whose incidence increases with developmental complexity. There is growing evidence that these transcripts are functional, particularly in the regulation of epigenetic processes, leading to the suggestion that they compose a hitherto hidden layer of genomic programming in humans and other complex organisms. However, to date, very few have been identified in genetic screens. Here I show that this is explicable by an historic emphasis, both phenotypically and technically, on mutations in protein-coding sequences, and by presumptions about the nature of regulatory mutations. Most variations in regulatory sequences produce relatively subtle phenotypic changes, in contrast to mutations in protein-coding sequences that frequently cause catastrophic component failure. Until recently, most mapping projects have focused on protein-coding sequences, and the limited number of identified regulatory mutations have been interpreted as affecting conventional cis-acting promoter and enhancer elements, although these regions are often themselves transcribed. Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction. The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions. There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses.

Show MeSH
Related in: MedlinePlus