Evolution of Replication Origins in Vertebrate Genomes: Rapid Turnover Despite Selective Constraints

BackgroundThe replication programme of vertebrate genomes is driven by the chro-mosomal distribution and timing of activation of tens of thousands of replication origins. Genome-wide studies have shown the frequent association of origins with promoters and CpG islands, and their enrichment in G-quadruplex sequence motifs (G4). However, the genetic determinants driving their activity remain poorly understood. To gain insight on the functional constraints operating on replication origins and their spatial distribution, we conducted the first evolutionary comparison of genome-wide origins maps across vertebrates.ResultsWe generated a high resolution genome-wide map of chicken replication origins (the first of a bird genome), and performed an extensive comparison with human and mouse maps. The analysis of intra-species polymorphism revealed a strong depletion of genetic diversity on an ~ 40 bp region centred on the replication initiation loci. Surprisingly, this depletion in genetic diversity was not linked to the presence of G4 motifs, nor to the association with promoters or CpG islands. In contrast, we also showed that origins experienced a rapid turnover during vertebrates evolution, since pairwise comparisons of origin maps revealed that only 4 to 24% of them were conserved between any two species.ConclusionsThis study unravels the existence of a novel genetic determinant of replication origins, the precise functional role of which remains to be determined. Despite the importance of replication initiation activity for the fitness of organisms, the distribution of replication origins along vertebrate chromosomes is highly flexible.

Download Full-text

Multiple replication origins with diverse control mechanisms in Haloarcula hispanica

Nucleic Acids Research ◽

10.1093/nar/gkt1214 ◽

2013 ◽

Vol 42 (4) ◽

pp. 2282-2294 ◽

Cited By ~ 21

Author(s):

Zhenfang Wu ◽

Jingfang Liu ◽

Haibo Yang ◽

Hailong Liu ◽

Hua Xiang

Keyword(s):

Replication Initiation ◽

Control Mechanisms ◽

Replication Origins ◽

Dna Mutation ◽

Genome Wide ◽

Marker Frequency ◽

Haloarcula Hispanica ◽

Specific Control ◽

Main Chromosome ◽

Multiple Replication

Abstract The use of multiple replication origins in archaea is not well understood. In particular, little is known about their specific control mechanisms. Here, we investigated the active replication origins in the three replicons of a halophilic archaeon, Haloarcula hispanica, by extensive gene deletion, DNA mutation and genome-wide marker frequency analyses. We revealed that individual origins are specifically dependent on their co-located cdc6 genes, and a single active origin/cdc6 pairing is essential and sufficient for each replicon. Notably, we demonstrated that the activities of oriC1 and oriC2, the two origins on the main chromosome, are differently controlled. A G-rich inverted repeat located in the internal region between the two inverted origin recognition boxes (ORBs) plays as an enhancer for oriC1, whereas the replication initiation at oriC2 is negatively regulated by an ORB-rich region located downstream of oriC2-cdc6E, likely via Cdc6E-titrating. The oriC2 placed on a plasmid is incompatible with the wild-type (but not the ΔoriC2) host strain, further indicating that strict control of the oriC2 activity is important for the cell. This is the first report revealing diverse control mechanisms of origins in haloarchaea, which has provided novel insights into the use and coordination of multiple replication origins in the domain of Archaea.

Download Full-text

Tuberculosis Genetic Epidemiology: A Latin American Perspective

Genes ◽

10.3390/genes10010053 ◽

2019 ◽

Vol 10 (1) ◽

pp. 53 ◽

Cited By ~ 2

Author(s):

Marc Woodman ◽

Ilsa Haeusler ◽

Louis Grandjean

Keyword(s):

Genetic Diversity ◽

Latin America ◽

Latin American ◽

Genetic Epidemiology ◽

Genetic Determinants ◽

Sequencing Technology ◽

Clinical Phenotypes ◽

Evolutionary Origins ◽

American Perspective ◽

Genome Wide

There are an estimated 10 million new cases of tuberculosis worldwide annually, with 282,000 new or relapsed cases each year reported from the Americas. With improvements in genome sequencing technology, it is now possible to study the genetic diversity of tuberculosis with much greater resolution. Although tuberculosis bacteria do not engage in horizontal gene transfer, the genome is far more variable than previously thought. The study of genome-wide variation in tuberculosis has improved our understanding of the evolutionary origins of tuberculosis, the arrival of tuberculosis in Latin America, the genetic determinants of drug resistance, and lineage-specific associations with important clinical phenotypes. This article reviews what is known about the arrival of tuberculosis in Latin America, the genetic diversity of tuberculosis in Latin America, and the genotypic determinants of clinical phenotypes.

Download Full-text

Genome-wide Analysis of Re-replication Reveals Inhibitory Controls That Target Multiple Stages of Replication Initiation

Molecular Biology of the Cell ◽

10.1091/mbc.e05-11-1037 ◽

2006 ◽

Vol 17 (5) ◽

pp. 2415-2423 ◽

Cited By ~ 22

Author(s):

Robyn E. Tanny ◽

David M. MacAlpine ◽

Hannah G. Blitzblau ◽

Stephen P. Bell

Keyword(s):

Cell Cycle ◽

Dna Microarrays ◽

Model Organism ◽

Replication Initiation ◽

Replication Origins ◽

Genome Maintenance ◽

Yeast Saccharomyces Cerevisiae ◽

Genome Wide Analysis ◽

Genome Wide ◽

Translocation Experiments

DNA replication must be tightly controlled during each cell cycle to prevent unscheduled replication and ensure proper genome maintenance. The currently known controls that prevent re-replication act redundantly to inhibit pre-replicative complex (pre-RC) assembly outside of the G1-phase of the cell cycle. The yeast Saccharomyces cerevisiae has been a useful model organism to study how eukaryotic cells prevent replication origins from reinitiating during a single cell cycle. Using a re-replication-sensitive strain and DNA microarrays, we map sites across the S. cerevisiae genome that are re-replicated as well as sites of pre-RC formation during re-replication. Only a fraction of the genome is re-replicated by a subset of origins, some of which are capable of multiple reinitiation events. Translocation experiments demonstrate that origin-proximal sequences are sufficient to predispose an origin to re-replication. Origins that reinitiate are largely limited to those that can recruit Mcm2-7 under re-replicating conditions; however, the formation of a pre-RC is not sufficient for reinitiation. Our findings allow us to categorize origins with respect to their propensity to reinitiate and demonstrate that pre-RC formation is not the only target for the mechanisms that prevent genomic re-replication.

Download Full-text