scholarly journals Template switching in DNA replication can create and maintain RNA hairpins

2021 ◽  
Author(s):  
Heli A. M. Mönttinen ◽  
Ari Löytynoja
Keyword(s):  
Dna Replication ◽  
Structural Changes ◽  
Gene Evolution ◽  
Template Switching ◽  
Single Mutation ◽  
Base Pairing ◽  
Random Mutation ◽  
Origin And Evolution ◽  
Reverse Complement ◽  
A Genome

The evolutionary origin of ribonucleic acid (RNA) stem structures (1, 2) and the preservation of their base-pairing under a spontaneous and random mutation process have puzzled theoretical evolutionary biologists (3, 4). DNA replication-related template switching (5, 6) is a mutation mechanism that creates reverse-complement copies of sequence regions within a genome by replicating briefly either along the complementary or nascent DNA strand. Depending on the relative positions and context of the four switch points, this process may produce a reverse-complement repeat capable of forming the stem of a perfect DNA hairpin, or fix the base-pairing of an existing stem (7). Template switching is typically thought to trigger large structural changes (8–10) and its possible role in the origin and evolution of RNA genes has not been studied. Here we show that the reconstructed ancestral history of ribosomal RNA sequences contains compensatory base substitutions that are linked with parallel sequence changes consistent with the DNA replication-related template switching. In addition to compensatory mutations, the mechanism can explain complex changes involving non-Watson-Crick pairing and appearances of novel stem structures, though mutations breaking the structure rarely get fixed in evolution. Our results suggest a solution for the longstanding dilemma of RNA gene evolution (1, 3, 4) and demonstrate how template switching can both create perfect stem structures with a single mutation event and maintain their base pairing over time with matching changes. The mechanism can also generate parallel sequence changes, many inexplicable under the point mutation model (11), and provides an explanation for the asymmetric base-pair frequencies in stem structures (12).

scholarly journals Leishmania naiffi and Leishmania guyanensis reference genomes highlight genome structure and gene evolution in the Viannia subgenus

2018 ◽  
Vol 5 (4) ◽  
pp. 172212 ◽  
Author(s):  
Simone Coughlan ◽  
Ali Shirley Taylor ◽  
Eoghan Feane ◽  
Mandy Sanders ◽  
Gabriele Schonian ◽  
...  
Keyword(s):  
Copy Number ◽  
Structural Changes ◽  
Gene Evolution ◽  
Genome Structure ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Individual Species ◽  
Short Sequence ◽  
Origin And Evolution ◽  
Reference Genomes

The unicellular protozoan parasite Leishmania causes the neglected tropical disease leishmaniasis, affecting 12 million people in 98 countries. In South America, where the Viannia subgenus predominates, so far only L. ( Viannia ) braziliensis and L. ( V. ) panamensis have been sequenced, assembled and annotated as reference genomes. Addressing this deficit in molecular information can inform species typing, epidemiological monitoring and clinical treatment. Here, L. ( V. ) naiffi and L. ( V. ) guyanensis genomic DNA was sequenced to assemble these two genomes as draft references from short sequence reads. The methods used were tested using short sequence reads for L. braziliensis M2904 against its published reference as a comparison. This assembly and annotation pipeline identified 70 additional genes not annotated on the original M2904 reference. Phylogenetic and evolutionary comparisons of L. guyanensis and L. naiffi with 10 other Viannia genomes revealed four traits common to all Viannia : aneuploidy, 22 orthologous groups of genes absent in other Leishmania subgenera, elevated TATE transposon copies and a high NADH-dependent fumarate reductase gene copy number. Within the Viannia , there were limited structural changes in genome architecture specific to individual species: a 45 Kb amplification on chromosome 34 was present in all bar L. lainsoni , L. naiffi had a higher copy number of the virulence factor leishmanolysin, and laboratory isolate L. shawi M8408 had a possible minichromosome derived from the 3’ end of chromosome 34 . This combination of genome assembly, phylogenetics and comparative analysis across an extended panel of diverse Viannia has uncovered new insights into the origin and evolution of this subgenus and can help improve diagnostics for leishmaniasis surveillance.

scholarly journals Leishmania naiffi and Leishmania guyanensis reference genomes highlight genome structure and gene evolution in the Viannia subgenus

2017 ◽  
Author(s):  
Simone Coughlan ◽  
Ali Shirley Taylor ◽  
Eoghan Feane ◽  
Mandy Sanders ◽  
Gabriele Schonian ◽  
...  
Keyword(s):  
Copy Number ◽  
Structural Changes ◽  
Gene Evolution ◽  
Genome Structure ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Individual Species ◽  
Short Sequence ◽  
Origin And Evolution ◽  
Reference Genomes

AbstractThe unicellular protozoan parasite Leishmania causes the neglected tropical disease leishmaniasis, affecting 12 million people in 98 countries. In South America where the Viannia subgenus predominates, so far only L. (Viannia) braziliensis and L. (V.) panamensis have been sequenced, assembled and annotated as reference genomes. Addressing this deficit in molecular information can inform species typing, epidemiological monitoring and clinical treatment. Here, L. (V.) naiffi and L. (V.) guyanensis genomic DNA was sequenced to assemble these two genomes as draft references from short sequence reads. The methods used were tested using short sequence reads for L. braziliensis M2904 against its published reference as a comparison. This assembly and annotation pipeline identified 70 additional genes not annotated on the original M2904 reference. Phylogenetic and evolutionary comparisons of L. guyanensis and L. naiffi with ten other Viannia genomes revealed four traits common to all Viannia: aneuploidy, 22 orthologous groups of genes absent in other Leishmania subgenera, elevated TATE transposon copies, and a high NADH-dependent fumarate reductase gene copy number. Within the Viannia, there were limited structural changes in genome architecture specific to individual species: a 45 Kb amplification on chromosome 34 was present in all bar L. lainsoni, L. naiffi had a higher copy number of the virulence factor leishmanolysin, and laboratory isolate L. shawi M8408 had a possible minichromosome derived from the 3’ end of chromosome 34. This combination of genome assembly, phylogenetics and comparative analysis across an extended panel of diverse Viannia has uncovered new insights into the origin and evolution of this subgenus and can help improve diagnostics for leishmaniasis surveillance.

scholarly journals A genome-wide screen identifies a single β-defensin gene cluster in the chicken: implications for the origin and evolution of mammalian defensins

BMC Genomics ◽  
2004 ◽  
Vol 5 (1) ◽  
Author(s):  
Yanjing Xiao ◽  
Austin L Hughes ◽  
Junko Ando ◽  
Yoichi Matsuda ◽  
Jan-Fang Cheng ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Origin And Evolution ◽  
Defensin Gene ◽  
Genome Wide ◽  
A Genome

scholarly journals DNA Polymerase: Structural Homology, Conformational Dynamics, and the Effects of Carcinogenic DNA Adducts

2010 ◽  
Vol 2010 ◽  
pp. 1-15 ◽  
Author(s):  
Richard G. Federley ◽  
Louis J. Romano
Keyword(s):  
Dna Replication ◽  
Dna Polymerase ◽  
Dna Adducts ◽  
Structural Changes ◽  
Dna Polymerases ◽  
Conformational Dynamics ◽  
Three Dimensional ◽  
Structural Homology ◽  
Human Right ◽  
Selection Of

DNA replication is vital for an organism to proliferate and lying at the heart of this process is the enzyme DNA polymerase. Most DNA polymerases have a similar three dimensional fold, akin to a human right hand, despite differences in sequence homology. This structural homology would predict a relatively unvarying mechanism for DNA synthesis yet various polymerases exhibit markedly different properties on similar substrates, indicative of each type of polymerase being prescribed to a specific role in DNA replication. Several key conformational steps, discrete states, and structural moieties have been identified that contribute to the array of properties the polymerases exhibit. The ability of carcinogenic adducts to interfere with conformational processes by directly interacting with the protein explicates the mutagenic consequences these adducts impose. Recent studies have identified novel states that have been hypothesised to test the fit of the nascent base pair, and have also shown the enzyme to possess a lively quality by continually sampling various conformations. This review focuses on the homologous structural changes that take place in various DNA polymerases, both replicative and those involved in adduct bypass, the role these changes play in selection of a correct substrate, and how the presence of bulky carcinogenic adducts affects these changes.

scholarly journals Origin Replication Complex Binding, Nucleosome Depletion Patterns, and a Primary Sequence Motif Can Predict Origins of Replication in a Genome with Epigenetic Centromeres

mBio ◽  
2014 ◽  
Vol 5 (5) ◽  
Author(s):  
Hung-Ji Tsai ◽  
Joshua A. Baller ◽  
Ivan Liachko ◽  
Amnon Koren ◽  
Laura S. Burrack ◽  
...  
Keyword(s):  
Machine Learning ◽  
Candida Albicans ◽  
Dna Replication ◽  
Content Type ◽  
Replication Complex ◽  
Origins Of Replication ◽  
A Genome ◽  
Bona Fide ◽  
Origin Replication Complex ◽  
Origin Function

ABSTRACTOrigins of DNA replication are key genetic elements, yet their identification remains elusive in most organisms. In previous work, we found that centromeres contain origins of replication (ORIs) that are determined epigenetically in the pathogenic yeastCandida albicans. In this study, we used origin recognition complex (ORC) binding and nucleosome occupancy patterns inSaccharomyces cerevisiaeandKluyveromyces lactisto train a machine learning algorithm to predict the position of active arm (noncentromeric) origins in theC. albicansgenome. The model identified bona fide active origins as determined by the presence of replication intermediates on nondenaturing two-dimensional (2D) gels. Importantly, these origins function at their native chromosomal loci and also as autonomously replicating sequences (ARSs) on a linear plasmid. A “mini-ARS screen” identified at least one and often two ARS regions of ≥100 bp within each bona fide origin. Furthermore, a 15-bp AC-rich consensus motif was associated with the predicted origins and conferred autonomous replicating activity to the mini-ARSs. Thus, while centromeres and the origins associated with them are epigenetic, arm origins are dependent upon critical DNA features, such as a binding site for ORC and a propensity for nucleosome exclusion.IMPORTANCEDNA replication machinery is highly conserved, yet the definition of exactly what specifies a replication origin differs in different species. Here, we utilized computational genomics to predict origin locations inCandida albicansby combining locations of binding sites for the conserved origin replication complex, necessary for replication initiation, together with chromatin organization patterns. We identified predicted sequences that exhibited bona fide origin function and developed a linear plasmid assay to delimit the DNA fragments necessary for origin function. Additionally, we found that a short AC-rich motif, which is enriched in predicted origins, is required for origin function. Thus, we demonstrated a new machine learning paradigm for identification of potential origins from a genome with no prior information. Furthermore, this work suggests thatC. albicanshas two different types of origins: “hard-wired” arm origins that rely upon specific sequence motifs and “epigenetic” centromeric origins that are recruited to kinetochores in a sequence-independent manner.

scholarly journals Identification of novel factors involved in or regulating initiation of DNA replication by a genome-wide phenotypic screen inSaccharomyces cerevisiae

Cell Cycle ◽  
2010 ◽  
Vol 9 (21) ◽  
pp. 4399-4410 ◽  
Author(s):  
Lijuan Ma ◽  
Yuanliang Zhai ◽  
Daorong Feng ◽  
Tsz-choi Chan ◽  
Yongjun Lu ◽  
...  
Keyword(s):  
Dna Replication ◽  
Genome Wide ◽  
Phenotypic Screen ◽  
A Genome ◽  
Initiation Of Dna Replication

scholarly journals Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals

2019 ◽  
Vol 116 (51) ◽  
pp. 25745-25755 ◽  
Author(s):  
Nicholas R. Casewell ◽  
Daniel Petras ◽  
Daren C. Card ◽  
Vivek Suranse ◽  
Alexis M. Mychajliw ◽  
...  
Keyword(s):  
Serine Proteases ◽  
Prey Capture ◽  
Convincing Evidence ◽  
Model Systems ◽  
Ancestral State ◽  
Origin And Evolution ◽  
Physiological Processes ◽  
A Genome ◽  
Taxonomic Groups

Venom systems are key adaptations that have evolved throughout the tree of life and typically facilitate predation or defense. Despite venoms being model systems for studying a variety of evolutionary and physiological processes, many taxonomic groups remain understudied, including venomous mammals. Within the order Eulipotyphla, multiple shrew species and solenodons have oral venom systems. Despite morphological variation of their delivery systems, it remains unclear whether venom represents the ancestral state in this group or is the result of multiple independent origins. We investigated the origin and evolution of venom in eulipotyphlans by characterizing the venom system of the endangered Hispaniolan solenodon (Solenodon paradoxus). We constructed a genome to underpin proteomic identifications of solenodon venom toxins, before undertaking evolutionary analyses of those constituents, and functional assessments of the secreted venom. Our findings show that solenodon venom consists of multiple paralogous kallikrein 1 (KLK1) serine proteases, which cause hypotensive effects in vivo, and seem likely to have evolved to facilitate vertebrate prey capture. Comparative analyses provide convincing evidence that the oral venom systems of solenodons and shrews have evolved convergently, with the 4 independent origins of venom in eulipotyphlans outnumbering all other venom origins in mammals. We find thatKLK1s have been independently coopted into the venom of shrews and solenodons following their divergence during the late Cretaceous, suggesting that evolutionary constraints may be acting on these genes. Consequently, our findings represent a striking example of convergent molecular evolution and demonstrate that distinct structural backgrounds can yield equivalent functions.

scholarly journals Dbf4-Dependent Kinase (DDK)-Mediated Proteolysis of CENP-A Prevents Mislocalization of CENP-A in Saccharomyces cerevisiae

2020 ◽  
Vol 10 (6) ◽  
pp. 2057-2068 ◽  
Author(s):  
Jessica R. Eisenstatt ◽  
Lars Boeckmann ◽  
Wei-Chun Au ◽  
Valerie Garcia ◽  
Levi Bursch ◽  
...  
Keyword(s):  
Dna Replication ◽  
Replication Initiation ◽  
Centromeric Chromatin ◽  
Dna Replication Initiation ◽  
Link Type ◽  
Genome Wide ◽  
A Genome ◽  
Evolutionarily Conserved ◽  
Histone H3 Variant

The evolutionarily conserved centromeric histone H3 variant (Cse4 in budding yeast, CENP-A in humans) is essential for faithful chromosome segregation. Mislocalization of CENP-A to non-centromeric chromatin contributes to chromosomal instability (CIN) in yeast, fly, and human cells and CENP-A is highly expressed and mislocalized in cancers. Defining mechanisms that prevent mislocalization of CENP-A is an area of active investigation. Ubiquitin-mediated proteolysis of overexpressed Cse4 (GALCSE4) by E3 ubiquitin ligases such as Psh1 prevents mislocalization of Cse4, and psh1Δ strains display synthetic dosage lethality (SDL) with GALCSE4. We previously performed a genome-wide screen and identified five alleles of CDC7 and DBF4 that encode the Dbf4-dependent kinase (DDK) complex, which regulates DNA replication initiation, among the top twelve hits that displayed SDL with GALCSE4. We determined that cdc7-7 strains exhibit defects in ubiquitin-mediated proteolysis of Cse4 and show mislocalization of Cse4. Mutation of MCM5 (mcm5-bob1) bypasses the requirement of Cdc7 for replication initiation and rescues replication defects in a cdc7-7 strain. We determined that mcm5-bob1 does not rescue the SDL and defects in proteolysis of GALCSE4 in a cdc7-7 strain, suggesting a DNA replication-independent role for Cdc7 in Cse4 proteolysis. The SDL phenotype, defects in ubiquitin-mediated proteolysis, and the mislocalization pattern of Cse4 in a cdc7-7 psh1Δ strain were similar to that of cdc7-7 and psh1Δ strains, suggesting that Cdc7 regulates Cse4 in a pathway that overlaps with Psh1. Our results define a DNA replication initiation-independent role of DDK as a regulator of Psh1-mediated proteolysis of Cse4 to prevent mislocalization of Cse4.

scholarly journals Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis

2017 ◽  
Vol 114 (22) ◽  
pp. E4442-E4451 ◽  
Author(s):  
Tobias T. Schmidt ◽  
Gloria Reyes ◽  
Kerstin Gries ◽  
Cemile Ümran Ceylan ◽  
Sushma Sharma ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Polymerase ◽  
Cancer Susceptibility ◽  
Dntp Pool ◽  
Dna Mismatch ◽  
Genome Wide ◽  
A Genome ◽  
Damage Response ◽  
Eukaryotic Dna ◽  
Active Site Mutants

Eukaryotic DNA replication fidelity relies on the concerted action of DNA polymerase nucleotide selectivity, proofreading activity, and DNA mismatch repair (MMR). Nucleotide selectivity and proofreading are affected by the balance and concentration of deoxyribonucleotide (dNTP) pools, which are strictly regulated by ribonucleotide reductase (RNR). Mutations preventing DNA polymerase proofreading activity or MMR function cause mutator phenotypes and consequently increased cancer susceptibility. To identify genes not previously linked to high-fidelity DNA replication, we conducted a genome-wide screen in Saccharomyces cerevisiae using DNA polymerase active-site mutants as a “sensitized mutator background.” Among the genes identified in our screen, three metabolism-related genes (GLN3, URA7, and SHM2) have not been previously associated to the suppression of mutations. Loss of either the transcription factor Gln3 or inactivation of the CTP synthetase Ura7 both resulted in the activation of the DNA damage response and imbalanced dNTP pools. Importantly, these dNTP imbalances are strongly mutagenic in genetic backgrounds where DNA polymerase function or MMR activity is partially compromised. Previous reports have shown that dNTP pool imbalances can be caused by mutations altering the allosteric regulation of enzymes involved in dNTP biosynthesis (e.g., RNR or dCMP deaminase). Here, we provide evidence that mutations affecting genes involved in RNR substrate production can cause dNTP imbalances, which cannot be compensated by RNR or other enzymatic activities. Moreover, Gln3 inactivation links nutrient deprivation to increased mutagenesis. Our results suggest that similar genetic interactions could drive mutator phenotypes in cancer cells.

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