Neural network and kinetic modelling of human genome replication reveal replication origin locations and strengths.

In human and other metazoans, the determinants of replication origin location and strength are still elusive. Origins are licensed in G1 phase and fired in S phase of the cell cycle, respectively. It is debated which of these two temporally separate steps determines origin efficiency. Experiments can independently profile mean replication timing (MRT) and replication fork directionality (RFD) genome-wide. Such profiles contain information on multiple origins' properties and on fork speed. Due to possible origin inactivation by passive replication, however, observed and intrinsic origin efficiencies can markedly differ. Thus, there is a need for methods to infer intrinsic from observed origin efficiency, which is context-dependent. Here, we show that MRT and RFD data are highly consistent with each other but contain information at different spatial scales. Using neural networks, we infer an origin licensing landscape that, when inserted in an appropriate simulation framework, jointly predicts MRT and RFD data with unprecedented precision and underlies the importance of dispersive origin firing. We furthermore uncover an analytical formula that predicts intrinsic from observed origin efficiency combined with MRT data. Comparison of inferred intrinsic origin efficiencies with experimental profiles of licensed origins (ORC, MCM) and actual initiation events (Bubble-seq, SNS-seq, OK-seq, ORM) show that intrinsic origin efficiency is not solely determined by licensing efficiency. Thus, human replication origin efficiency is set at both the origin licensing and firing steps.

Diversity of Harbinger-like Transposons in Teleost Fish Genomes.

Harbinger elements are DNA transposons that are widespread from plants to vertebrates but absent from mammalian genomes. Among vertebrates, teleost fish are the clade presenting not only the largest number of species but also the highest diversity of transposable elements, both quantitatively and qualitatively, making them a very attractive group to investigate the evolution of mobile sequences. We studied Harbinger DNA transposons and the distantly related ISL2EU elements in fish, focusing on representative teleost species compared to the spotted gar, the coelacanth, the elephant shark and the amphioxus. We observed high variability in the genomic composition of Harbinger-like sequences in teleost fish, as they covered 0.002-0.14% of the genome, when present. While Harbinger transposons might have been present in a common ancestor of all the fish species studied here, with secondary loss in elephant shark, our results suggests that ISL2EU elements were gained by horizontal transfer at the base of teleost fish 200-300 million years ago, and that there was secondary loss in a common ancestor of pufferfishes and stickleback. Harbinger transposons code for a transposase and a Myb-like protein. We reconstructed and compared molecular phylogenies of both proteins to get insights into the evolution of Harbinger transposons in fish. Transposase and Myb-like protein phylogenies showed global congruent evolution, indicating unique origin of the association between both genes and suggesting rare recombination between transposon sublineages. Finally, we report one case of Harbinger horizontal transfer between divergent fish species and the transcriptional activity of both Harbinger and ISL2EU transposons in teleost fish. There was male-biased expression in the gonads of the medaka fish.

Coupling between Sequence-Mediated Nucleosome Organization and Genome Evolution.

The nucleosome is a major modulator of DNA accessibility to other cellular factors. Nucleosome positioning has a critical importance in regulating cell processes such as transcription, replication, recombination or DNA repair. The DNA sequence has an influence on the position of nucleosomes on genomes, although other factors are also implicated, such as ATP-dependent remodelers or competition of the nucleosome with DNA binding proteins. Different sequence motifs can promote or inhibit the nucleosome formation, thus influencing the accessibility to the DNA. Sequence-encoded nucleosome positioning having functional consequences on cell processes can then be selected or counter-selected during evolution. We review the interplay between sequence evolution and nucleosome positioning evolution. We first focus on the different ways to encode nucleosome positions in the DNA sequence, and to which extent these mechanisms are responsible of genome-wide nucleosome positioning in vivo. Then, we discuss the findings about selection of sequences for their nucleosomal properties. Finally, we illustrate how the nucleosome can directly influence sequence evolution through its interactions with DNA damage and repair mechanisms. This review aims to provide an overview of the mutual influence of sequence evolution and nucleosome positioning evolution, possibly leading to complex evolutionary dynamics.