Developmentally Programmed DNA Rearrangements


Developmentally programmed deoxyribonucleic acid (DNA) rearrangements are structural reorganisations of the genome that occur reproducibly during the development of a variety of organisms. In the majority of cases, programmed DNA rearrangements function to alter gene expression. V(D)J recombination is a DNA rearrangement that occurs during the development of the human immune system to assemble functional genes encoding antibodies. Some human pathogens use programmed DNA rearrangements to evade the immune system by varying the expression of their antigenic surface proteins. However, in some cases, the function of large‐scale developmentally programmed DNA rearrangements remains unknown. In the ciliate protozoan Tetrahymena thermophila, a wide variety of programmed rearrangements occur during the development of the somatic nucleus including chromosome fragmentation and deletion of specific DNA sequences. In a related ciliate Oxytricha trifallax, programmed genome rearrangements are needed to unscramble segments to assemble functional genes.

Key Concepts

  • Programmed DNA rearrangements utilise diverse recombination mechanisms.
  • Human pathogens use programmed DNA rearrangements to vary expression of antigenic surface proteins to avoid the host immune system.
  • V(D)J recombination in human development assembles functional genes encoding antibodies.
  • Chromatin diminution in parasitic nematodes silences germ‐line‐specific gene expression in somatic cells.
  • The ciliate protozoa undergo large‐scale programmed DNA rearrangements during nuclear development.
  • The mechanism of programmed DNA deletion in the ciliate Tetrahymena thermophila involves small noncoding RNAs that direct formation of a specific chromatin structure.
  • The ciliate Oxytricha trifallax unscrambles gene segments during the development of its somatic nucleus.

Keywords: genome structure; Tetrahymena thermophila; transposition; DNA rearrangement; recombination; antigenic variation; chromatin; RNAi; Oxytricha trifallax; V(D)J recombination

Figure 1. (a) Cointegrate transposition. Single‐stranded cuts are made by transposase at both ends of the transposon (black, striped box) in donor DNA (black). The 3′ hydroxyl ends of the transposon are ligated to 5′‐phosphates of transposase‐cleaved target DNA. DNA replication fills single‐stranded gaps, and recombination between duplicated transposon sequences separates the molecules yielding a donor site that retains the transposon and a target site that has acquired the transposon. (b) ‘Cut‐and‐paste’ transposition. Donor DNA (black) is cleaved at both ends of the transposition (striped black box) by transposase. The 3′ hydroxyl of the transposon is ligated to the transposase‐liberated 5′‐phosphate groups of the target DNA (red). The end result is a transposon inserted into target DNA and a double‐strand break (DSB) at the donor locus.
Figure 2. V–J joining. The product of V–J joining is an imprecise coding joint encoding part of an immunoglobulin G (IgG) molecule and a precisely joined signal joint that is eventually degraded. DNA‐PK, DNA‐dependent protein kinase; RSS, recombination signal sequence.
Figure 3. Nonreciprocal gene conversion of an internal VSG gene (D) into an active telomeric expression site. The expressed VSG gene is located downstream of 76‐bp repeats and the eight expression site‐associated genes (ESAGs). The ESAGs are not affected in this case but may be by telomeric recombination and in situ switches. X, 76‐bp repeats; boxes A–E, distinct VSG genes, black stripes in A–E, conserved 3′ region.
Figure 4. (a) Organisation of DNA at the micronuclear and macronuclear loci of the ARP1 gene of Tetrahymena thermophila. The area inside the diagonal lines indicates micronucleus‐specific DNA, whereas outside these lines macronuclear and micronuclear sequences are identical. The 2.9‐kb eliminated sequence between the diagonal lines is named the micronucleus‐specific element (mse2.9). The eliminated sequence is situated within the second intron of ARP1. Exons are marked by clear boxes; introns by shaded boxes. E, EcoRI; H, HindIII; X, XbaI. (b) Model of IES (internal eliminated sequence) deletion in T. thermophila. Red arrows represent DNA cleavage; green arrows indicate junctions created by IES excision. IES excision is initiated by a staggered double‐strand break produced at a site defined by properly situated adenosine residues on either strand. A one‐step transesterification reaction occurs to produce the chromosomal junction on one strand. Processing of the intermediate occurs to yield the mature junction. Reprinted from Saveliev SV, Cox MM. 1995. Transient DNA breaks associated with programmed genomic deletion events in conjugating cells of Tetrahymena thermophila. Genes Dev. 9(2): 248–255.
Figure 5. In the Oxytricha's MIC, the MAC‐destined sequences (MDSs) from the same gene can be scrambled, inverted and divided by internal eliminated sequences (IESs). The macronuclear (MAC) chromosomes develop from the micronuclear (MIC) genome. Through development, the MIC chromosomes are fragmented, and only the MDSs remain. During this process, the newly formed nanochromosomes contain all ordered MDSs of the MIC gene. The MDSs are joined by identical segments called pointers. In addition, the nanochromosomes acquire telomeres. These nanochromosomes will endoreplicate, resulting in a higher abundance.


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Further Reading

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Saettone, Alejandro, Nabeel‐Shah, Syed, and Fillingham, Jeffrey S(Jun 2018) Developmentally Programmed DNA Rearrangements. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000595.pub3]