Replication timing

Replication timing refers to the order in which segments of DNA along the length of a chromosome are duplicated.

The temporal order of replication of all the segments in the genome, called its replication-timing program, can now be easily measured in two different ways.

[1] One way simply measures the amount of the different DNA sequences along the length of the chromosome per cell.

However, it is an intriguing cellular mechanism with links to many poorly understood features of the folding of chromosomes inside the cell nucleus.

It was also noticed by Mary Lyon[9] that the inactive X took on a condensed structure in the nucleus called the Barr body[10] (Figure 5) at the same time during development as the genetic inactivation of the chromosome.

Recently developed methods to measure the points where different parts of chromosomes touch each other are almost perfectly aligned to when they replicate.

[18] We do not yet understand the mechanisms behind this link, but it suggests that further research may reveal replication-timing changes as useful biomarkers for such diseases.

The fact that it can now be measured with relative ease indicates that we will soon have a wealth of information about where and when large changes in chromosome folding occur during development and in different diseases.

Figure 1 : Schematic of the cell cycle. outer ring: I = Interphase , M = Mitosis ; inner ring: M = Mitosis , G 1 = Gap 1 , G 2 = Gap 2 , S = Synthesis ; not in ring: G 0 = Gap 0/Resting .
Figure 2 : Replication proceeds via the nearly synchronous firing of clusters of replication origins that replicate segments of chromosomal DNA (“Replication domains”) at defined time periods during S phase.
Figure 3 :Animated sequence of replication.
Figure 4 : A diagrammatic representation of replication timing in a 70-Mb segment of human chromosome 2. The red horizontal line represents time in S-phase, from early (top) to late (bottom). Grey data points each represent a different DNA sequence position along the length of chromosome 2 as indicated on the x axis, with more positive values on the y-axis indicating earlier replication. A smoothed line (blue) is drawn through the data to visualize the domains of different replication timing. Red bands at the top of the image show DNA that has been replicated at the given time in S-phase.
Figure 5 . Nucleus of a female amniotic fluid cell. Top: Both X-chromosome territories are detected by FISH . Shown is a single optical section made with a confocal microscope . Bottom: Same nucleus stained with DAPI and recorded with a CCD camera . The Barr body is indicated by the arrow, it identifies the inactive X (Xi).