Replication timing refers to the order in which segments of DNA along the length of a chromosome are duplicated.
Replication timing refers to the order in which segments of DNA along the length of a chromosome are duplicated.
In eukaryotic cells (cells that package their DNA within a nucleus), chromosomes consist of very long linear double-stranded DNA molecules. During the S-phase of each cell cycle (Figure 1), all of the DNA in a cell is duplicated in order to provide one copy to each of the daughter cells after the next cell division. The process of duplicating DNA is called DNA replication, and it takes place by first unwinding the duplex DNA molecule, starting at many locations called DNA replication origins, followed by an unzipping process that unwinds the DNA as it is being copied. However, replication does not start at all the different origins at once. Rather, there is a defined temporal order in which these origins fire. Frequently a few adjacent origins open up to duplicate a segment of a chromosome, followed some time later by another group of origins opening up in an adjacent segment. Replication does not necessarily start at exactly the same origin sites every time, but the segments appear to replicate in the same temporal sequence regardless of exactly where within each segment replication starts. Figure 2 shows a cartoon of how this is generally envisioned to occur, while Figure 3 shows an animation of when different segments replicate in one type of human cell.
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. Sequences that duplicate first, long before cell division, will be more abundant in each cell than the sequences that replicate last just prior to cell division. The other way is to label newly synthesized DNA with chemically tagged nucleotides that become incorporated into the strands as they are synthesized, and then catch cells at different times during the duplication process and purify the DNA synthesized at each of these times using the chemical tag. In either case, we can measure the amount of the different DNA sequences along the length of the chromosome either directly using a machine that reads how much of each sequence is present or indirectly using a process called microarray hybridization. In any case, the temporal order of replication along the length of each chromosome can be plotted in graphical form to produce a "replication timing profile". Figure 4 shows an example of such a profile across 70,000,000 base pairs of human Chromosome 2. [2]
At present, very little is known about either the mechanisms orchestrating the timing program or its biological significance. However, it is an intriguing cellular mechanism with links to many poorly understood features of the folding of chromosomes inside the cell nucleus. All eukaryotes have a timing program, and this program is similar in related species. [3] [4] [5] [6] [7] This indicates that it is either important itself, or something important influences the program. It is unlikely that replicating DNA in a specific temporal order is necessary simply for the basic purpose of duplicating a DNA molecule. More than likely, it is related to some other chromosomal property or function. Replication timing is correlated with the expression of genes such that the genetic information being utilized in a cell is generally replicated earlier than the information that is not being used. We also know that the replication-timing program changes during development, along with changes in the expression of genes.
For many decades now, it has been known that replication timing is correlated with the structure of chromosomes. For example, female mammals have two X chromosomes. One of these is genetically active, while the other is inactivated early in development. In 1960, J. H. Taylor [8] showed that the active and inactive X chromosomes replicate in a different pattern, with the active X replicating earlier than the inactive X, whereas all the other pairs of chromosomes replicate in the same temporal pattern. 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.
This may not come as too much of a surprise, since the packaging of DNA with proteins and RNA into chromatin takes place immediately after the DNA is synthesized. Therefore, replication timing dictates the time of assembly of chromatin. Less intuitive is the relationship between replication timing and the three-dimensional positioning of chromatin in the nucleus. It is now well-accepted that chromatin is not randomly organized in the cell nucleus, but the positions of each chromosome domain relative to its neighboring domains is characteristic of different cell types, and after this geography is established in each newly formed cell, the chromosome domains do not move appreciably until the next cell division. [11] [12] In all multi-cellular organisms where it has been measured, early replication takes place in the interior of the nucleus and the chromatin around the periphery is replicated later. Recently developed methods to measure the points where different parts of chromosomes touch each other are almost perfectly aligned to when they replicate. [3] In other words, regions that are replicated early versus late are packaged in such a way as to be spatially segregated in the nucleus, with the intervening DNA containing regions of reduced origin activity. [7] [13] One possibility is that these different compartments within the nucleus, established and maintained without the aid of membranes or physical barriers, set thresholds for the initiation of replication so that the more accessible regions are the first to replicate. [14] Another possibility is that the replication timing of a section of DNA contributes to the packaging of that DNA. [15] [16] It has been demonstrated that the protein Rif1 is involved in regulating this process. [17]
Another intriguing aspect of replication timing is that the temporal order of replication is disrupted in most cancers and in many diseases. [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.
Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritance. This is essential for cell division during growth and repair of damaged tissues, while it also ensures that each of the new cells receives its own copy of the DNA. The cell possesses the distinctive property of division, which makes replication of DNA essential.
A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamental subunit of chromatin. Each nucleosome is composed of a little less than two turns of DNA wrapped around a set of eight proteins called histones, which are known as a histone octamer. Each histone octamer is composed of two copies each of the histone proteins H2A, H2B, H3, and H4.
The origin of replication is a particular sequence in a genome at which replication is initiated. Propagation of the genetic material between generations requires timely and accurate duplication of DNA by semiconservative replication prior to cell division to ensure each daughter cell receives the full complement of chromosomes. This can either involve the replication of DNA in living organisms such as prokaryotes and eukaryotes, or that of DNA or RNA in viruses, such as double-stranded RNA viruses. Synthesis of daughter strands starts at discrete sites, termed replication origins, and proceeds in a bidirectional manner until all genomic DNA is replicated. Despite the fundamental nature of these events, organisms have evolved surprisingly divergent strategies that control replication onset. Although the specific replication origin organization structure and recognition varies from species to species, some common characteristics are shared.
A pre-replication complex (pre-RC) is a protein complex that forms at the origin of replication during the initiation step of DNA replication. Formation of the pre-RC is required for DNA replication to occur. Complete and faithful replication of the genome ensures that each daughter cell will carry the same genetic information as the parent cell. Accordingly, formation of the pre-RC is a very important part of the cell cycle.
Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. It adheres to Mendelian inheritance, with information coming from two parents, one male and one female—rather than matrilineally as in mitochondrial DNA.
Subtelomeres are segments of DNA between telomeric caps and chromatin.
In biology, the word gene can have several different meanings. The Mendelian gene is a basic unit of heredity and the molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protein-coding genes and noncoding genes.
This glossary of genetics is a list of definitions of terms and concepts commonly used in the study of genetics and related disciplines in biology, including molecular biology, cell biology, and evolutionary biology. It is intended as introductory material for novices; for more specific and technical detail, see the article corresponding to each term. For related terms, see Glossary of evolutionary biology.
NUMT, pronounced "new might," is an acronym for "nuclear mitochondrial DNA" segment coined by evolutionary geneticist, Jose V. Lopez, which describes a transposition of any type of cytoplasmic mitochondrial DNA into the nuclear genome of eukaryotic organisms.
Eukaryotic DNA replication is a conserved mechanism that restricts DNA replication to once per cell cycle. Eukaryotic DNA replication of chromosomal DNA is central for the duplication of a cell and is necessary for the maintenance of the eukaryotic genome.
Ridges are domains of the genome with a high gene expression; the opposite of ridges are antiridges. The term was first used by Caron et al. in 2001. Characteristics of ridges are:
Thomas Cremer, is a German professor of human genetics and anthropology with a main research focus on molecular cytogenetics and 3D/4D analyses of nuclear structure studied by fluorescence microscopy including super-resolution microscopy and live cell imaging. Thomas Cremer is the brother of the German physicist Christoph Cremer and Georg Cremer, Secretary General of the German Caritas Association.
In cell biology, eukaryotes possess a regulatory system that ensures that DNA replication occurs only once per cell cycle.
Chilodonella uncinata is a single-celled organism of the ciliate class of alveoles. As a ciliate, C. uncinata has cilia covering its body and a dual nuclear structure, the micronucleus and macronucleus. Unlike some other ciliates, C. uncinata contains millions of minichromosomes in its macronucleus while its micronucleus is estimated to contain 3 chromosomes. Childonella uncinata is the causative agent of Chilodonelloza, a disease that affects the gills and skin of fresh water fish, and may act as a facultative parasite of mosquito larva.
DNA transposons are DNA sequences, sometimes referred to "jumping genes", that can move and integrate to different locations within the genome. They are class II transposable elements (TEs) that move through a DNA intermediate, as opposed to class I TEs, retrotransposons, that move through an RNA intermediate. DNA transposons can move in the DNA of an organism via a single-or double-stranded DNA intermediate. DNA transposons have been found in both prokaryotic and eukaryotic organisms. They can make up a significant portion of an organism's genome, particularly in eukaryotes. In prokaryotes, TE's can facilitate the horizontal transfer of antibiotic resistance or other genes associated with virulence. After replicating and propagating in a host, all transposon copies become inactivated and are lost unless the transposon passes to a genome by starting a new life cycle with horizontal transfer. It is important to note that DNA transposons do not randomly insert themselves into the genome, but rather show preference for specific sites.
Nuclear organization refers to the spatial distribution of chromatin within a cell nucleus. There are many different levels and scales of nuclear organisation. Chromatin is a higher order structure of DNA.
The genome of most cells of eukaryotes remains mainly constant during life. However, there are cases of genome being altered in specific cells or in different life cycle stages during development. For example, not every human cell has the same genetic content as red blood cells which are devoid of nucleus. One of the best known groups in respect of changes in somatic genome are ciliates. The process resulting in a variation of somatic genome that differs from germline genome is called somatic genome processing.
This glossary of genetics is a list of definitions of terms and concepts commonly used in the study of genetics and related disciplines in biology, including molecular biology, cell biology, and evolutionary biology. It is intended as introductory material for novices; for more specific and technical detail, see the article corresponding to each term. For related terms, see Glossary of evolutionary biology.
This glossary of genetics is a list of definitions of terms and concepts commonly used in the study of genetics and related disciplines in biology, including molecular biology, cell biology, and evolutionary biology. It is split across two articles: