A chromatin structure-based model accurately predicts DNA replication timing in human cells

Area of Science:

• Genomics
• Molecular Biology
• Computational Biology

Background:

• Metazoan genome replication occurs in a precise, cell lineage-specific temporal order.
• The molecular mechanisms controlling genome replication timing remain poorly understood.
• No active regulatory mechanisms have been identified for the genome replication firing sequence.

Purpose of the Study:

• To develop a mechanistic model of genome replication.
• To predict the empirical replication timing program in humans.
• To identify the determinants of DNA replication initiation.

Main Methods:

• Developed a mechanistic model of genome replication.
• Incorporated time-stochastic initiation at well-defined sites.
• Utilized DNase-hypersensitive sites as genomic landmarks.

Main Results:

• The model accurately predicts human DNA replication timing.
• DNase-hypersensitive sites are optimal and independent determinants of replication initiation.
• Replication initiation is uncoordinated and time-stochastic.

Conclusions:

• Human DNA replication timing is a robust emergent phenomenon.
• No specific regulatory mechanism is required for replication initiation firing sequence.
• The number of replication forks is a key biological parameter.