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The deep evolutionary roots of non-coding RNA - a comparative genomics approach
Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics. (Poole)
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Non-coding RNAs (ncRNA) are a diverse group of genes that do not encode proteins but function exclusively on the level of RNA and were originally suggested to be remnants of a pre-DNA stage of life known as the RNA world. More recent work, however, has uncovered a rich repertoire of previously unknown families with possible consequences for our understanding of the origin and evolution of the modern RNA infrastructure. The main goal of this thesis was therefore to re-examine the evolutionary history of RNAs and theories regarding the transition from an RNA world in light of recent advances in molecular and computational biology.

Using comparative genomics approaches and sequence data from all domains of life, my work shows that the majority of known RNAs exhibit a highly domain-specific distribution, compatible with an ongoing emergence rather than deep ancestry. Focusing on small nucleolar RNAs (snoRNA), I find that the eukaryote ancestor possessed a complex snoRNA infrastructure, but that intronic snoRNAs are mobile over larger evolutionary time scales. The latter has consequences for predictions made by the Introns-first hypothesis, a framework to explain the emergence of introns in an RNA world and which we revisited in light of advances in our understanding of the evolutionary dynamics of introns.

A more in-depth analysis of ncRNA mobility across vertebrates found intronic copies of both snoRNAs and miRNAs to be more stable than intergenic ones, suggesting that this arrangement may be a consequence of co-expression. Also, snoRNAs are frequently located in highly expressed genes, in line with their role in ribosome biogenesis. Finally, a closer examination of the genomic distribution of two essential ncRNAs, snoRNA U3 and the spliceosomal RNA U1 shows that both are present in numerous copies across vertebrate genomes. Using next-generation sequencing data, I tested whether this is the result of genetic drift or a requirement for having many copies.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biology and Functional Genomics, Stockholm University , 2011. , 182 p.
Keyword [en]
non-coding RNA, evolution, comparative genomics, RNA world, introns, snoRNA, miRNA
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-56820ISBN: 978-91-7447-306-3 (print)OAI: oai:DiVA.org:su-56820DiVA: diva2:413243
Public defence
2011-06-07, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 14:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Manuscript. Paper 3: Manuscript. Paper 5: Manuscript.Available from: 2011-05-12 Created: 2011-04-28 Last updated: 2011-05-02Bibliographically approved
List of papers
1. Comparative analysis of RNA families reveals distinct repertoires for each domain of life
Open this publication in new window or tab >>Comparative analysis of RNA families reveals distinct repertoires for each domain of life
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Some RNAs may date back to an RNA-rich period in the early evolution of life, butmany RNAs are thought to have more recent evolutionary origins. To chart the broadevolutionary history of known RNA families, we performed comparative genomicanalysis of over 3 million RNA annotations spanning 1446 families from the Rfam 10database. We report that 99% of known RNA families are restricted to a singledomain of life, revealing discrete repertoires for each domain. For the 1% of RNAfamilies/clans present in more than one domain, over half show evidence ofhorizontal gene transfer (HGT), and only six RNAs directly trace to the LastUniversal Common Ancestor (LUCA). These results indicate that cellular RNAinfrastructure evolves in a domain-specific manner.

Keyword
RNA, comparative genomics, tree of life
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:su:diva-56817 (URN)
Available from: 2011-04-28 Created: 2011-04-28 Last updated: 2011-05-02Bibliographically approved
2. An Overview of the Introns-First Theory
Open this publication in new window or tab >>An Overview of the Introns-First Theory
2009 (English)In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 69, 527-540 p.Article in journal (Refereed) Published
Abstract [en]

We review the introns-first hypothesis a decade after it was first proposed. It is that exons emerged from

non-coding regions interspersed between RNA genes in an early RNA world, and is a subcomponent of a more general ‘RNA-continuity’ hypothesis. The latter is that some RNA based systems, especially in RNA processing, are ‘relics’ that can be traced back either to the RNA world that preceded both DNA and encoded protein synthesis or to the later ribonucleoprotein (RNP) world (before DNA took over the main coding role). RNA-continuity is based on independent evidence—in particular, the relative inefficiency of RNA catalysis compared with protein catalysis— and leads to a wide range of predictions, ranging from the origin of the ribosome, the spliceosome, small nucleolar RNAs, RNases P and MRP, and mRNA, and it is consistent with the wide involvement of RNA-processing and regulation of RNA in modern eukaryotes. While there may still

be cause to withhold judgement on intron origins, there is strong evidence against introns being uncommon in the last eukaryotic common ancestor (LECA), and expanding only within extant eukaryotic groups—the ‘very-late’ intron invasion model. Similarly, it is clear that there are selective forces on numbers and positions of introns; their existence may not always be neutral. There is still a range of viable alternatives, including introns first, early, and ‘latish’ (i.e. well established in LECA), and regardless of which is ultimately correct, it pays to separate out various questions and to focus on testing the predictions of sub-theories.

Keyword
Introns, RNA world, Eukaryote origins, RNP world, Spliceosome, Introns early
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-35378 (URN)10.1007/s00239-009-9279-5 (DOI)000272574100012 ()
Available from: 2010-01-18 Created: 2010-01-18 Last updated: 2011-05-02Bibliographically approved
3. Comparative Genomics of Eukaryotic Small Nucleolar RNAs Reveals Deep Evolutionary Roots Amidst Ongoing Intragenomic Mobility
Open this publication in new window or tab >>Comparative Genomics of Eukaryotic Small Nucleolar RNAs Reveals Deep Evolutionary Roots Amidst Ongoing Intragenomic Mobility
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Small nucleolar (sno)RNAs are required for posttranscriptional processing andmodification of ribosomal, spliceosomal and messenger RNAs. There are two broadclasses (C/D and H/ACA), both of which have been characterized in eukaryotes andarchaea. The association with ribosomal RNA processing and modification has led tothe suggestion that snoRNAs are evolutionarily ancient, and date back to the RNAworld. That numerous snoRNAs have been identified in the introns of ribosomalprotein genes has led to alternate views on the origin of this organization. Oneproposal is that intronic snoRNAs predate their surrounding protein-coding exons,the latter being recruited as messenger RNA following the origin of geneticallyencodedprotein synthesis. Another is that intron position reflects selection forcoexpression of snoRNAs and ribosomal components. To gain a clearer insight intothe antiquity of individual snoRNA families and the stability of their genomic location,we examined the evolutionary history of snoRNA families across 44 eukaryotegenomes. Our analysis reveals that dozens of snoRNA families can be traced backto the Last Eukaryotic Common Ancestor (LECA). However, none of the snoRNA1families placed in the LECA are sufficiently similar to characterized archaeal sno-likeRNAs, for us to confidently place specific snoRNA families in the common ancestorof archaea and eukaryotes. In agreement with earlier studies, we can tracenumerous introns to the LECA. However, snoRNAs housed within such positionallyconserved introns are not themselves orthologs. Morevover, our comparativegenomics analysis argues against evolutionarily-stable association betweensnoRNAs and individual host genes — analysis of host gene expression dataindicates that the primary requirement being for hosting intronic snoRNAs is a broadexpression profile. Consistent with mobility over antiquity, we report a case ofdemonstrable intronic snoRNA gain, where an evolutionarily ancient snoRNA hasmigrated into the intron of a mammalian mitochondrial ribosomal protein gene.Together, these data best fit a model wherein snoRNAs are intragenomically mobile,frequently residing in the introns of broadly-expressed protein-coding genes.

Keyword
snoRNA, comparative genomics, introns-first, eukaryotes, evolution
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:su:diva-56818 (URN)
Available from: 2011-04-28 Created: 2011-04-28 Last updated: 2011-05-02Bibliographically approved
4. Evolutionarily Stable Assiciation of Intronic snoRNAs and microRNAs with Their Host Genes
Open this publication in new window or tab >>Evolutionarily Stable Assiciation of Intronic snoRNAs and microRNAs with Their Host Genes
2009 (English)In: Genome Biology and Evolution, ISSN 1759-6653, Vol. 1, no 1, 420-428 p.Article in journal (Refereed) Published
Abstract [en]

Small nucleolar RNAs (snoRNAs) and microRNAs (miRNAs) are integral to a range of processes, including ribosome biogenesis and gene regulation. Some are intron encoded, and this organization may facilitate coordinated coexpression of host gene and RNA. However, snoRNAs and miRNAs are known to be mobile, so intron-RNA associations may not be evolutionarily stable. We have used genome alignments across 11 mammals plus chicken to examine positional orthology of snoRNAs and miRNAs and report that 21% of annotated snoRNAs and 11% of miRNAs are positionally conserved across mammals. Among RNAs traceable to the bird–mammal common ancestor, 98% of snoRNAs and 76% of miRNAs are intronic. Comparison of the most evolutionarily stable mammalian intronic snoRNAs with those positionally conserved among primates reveals that the former are more overrepresented among host genes involved in translation or ribosome biogenesis and are more broadly and highly expressed. This stability is likely attributable to a requirement for overlap between host gene and intronic snoRNA expression profiles, consistent with an ancestral role in ribosome biogenesis. In contrast, whereas miRNA positional conservation is comparable to that observed for snoRNAs, intronic miRNAs show no obvious association with host genes of a particular functional category, and no statistically significant differences in host gene expression are found between those traceable to mammalian or primate ancestors. Our results indicate evolutionarily stable associations of numerous intronic snoRNAs and miRNAs and their host genes, with probable continued diversification of snoRNA function from an ancestral role in ribosome biogenesis.

Keyword
snoRNA, miRNA, intron, evolution
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-35093 (URN)10.1093/gbe/evp045 (DOI)000275269200041 ()
Available from: 2010-01-14 Created: 2010-01-14 Last updated: 2011-05-02Bibliographically approved
5. Maintenance of redundant small RNA gene copies over evolutionarytimescales via a retrotransposition motor?
Open this publication in new window or tab >>Maintenance of redundant small RNA gene copies over evolutionarytimescales via a retrotransposition motor?
(English)Manuscript (preprint) (Other academic)
Abstract [en]

We analysed the stability of duplicated, essential RNAs on the backdrop of theirexpression profiles to test whether the data is compatible with functional redundancy ordiversification. Under the former model, the expectation is that copies are equallyexpressed across tissues and subject to high turn-over. The latter model, in contrast,predicts that sub- or neofunctionalization following duplication may lead to a range ofcomplementary expression profiles across tissues. By example of the spliceosomal RNAU1 and snoRNA U3, we find that only few loci are stable over the course of vertebrateevolution and that the majority of copies show little or no expression. We conclude thatthese findings are most compatible with the redundancy model. Interestingly, the deepestloci are associated with a testis-expressed gene, suggesting a possible driving forcebehind the ongoing proliferation that we observe.

Keyword
ncRNA, evolution, comparative genomics, expression
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:su:diva-56819 (URN)
Available from: 2011-04-28 Created: 2011-04-28 Last updated: 2011-05-02Bibliographically approved

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