Friday, March 13, 2009

Mitotic Recombination

 
It is widely believed that recombination, or crossing over, only occurs at meiosis in diploid eukaryotes. Most textbooks reinforce this belief by associating crossovers with chiasmata, which are only seen at meiosis.

In spite of the textbook claims, most people are well aware of the fact that recombination takes place in somatic cells. After all, it's the basis of most recombinant DNA technology and underlies many of the mechanisms that cause cancer. Furthermore, some developmental processes, such as immunoglobulin gene rearrangements require recombination in somatic cells.

Mitotic recombination has been known to occur since the 1930s when it was used for fate mapping in Drosophila so it's somewhat surprising that crossing over is so intimately connected with meiosis in the textbooks. The frequency of mitotic crossing over may be lower than that seen during meiosis, although the differences may not be great in most species.

In yeast, the frequency of recombination during meiosis can be 10,000 times greater than the frequency of crossing over in somatic cells but that's partly because meiotic recombination is very high in yeast cells. Perhaps they have been selected in vitro for high rates of recombination.

Why does recombination occur in mitotic cells? Probably for the same reason it occurs during meiosis—it's a form of DNA repair.

There's a short review of mitotic recombination in the lastest issue of PLoS Genetics [Mitotic Recombination: Why? When? How? Where?]. Let's try and put an end to the false idea that recombination and crossing over only takes place during meiosis.


8 comments :

  1. See also the sister chromatid exchange assay, a standard of genotoxicity testing for many years.

    The de-emphasis of mitotic crossing-over likely derives from studies of double-strand break repair. The original model from Szostak, Orr-Weaver, Rothstein and Stahl (Cell. 1983 May;33(1):25-35) invokes the formation of a double Holliday junction, with predicted equal yield of crossover and non-crossover products due to random orientation of Holliday junction resolution. However, subsequent experiments in S. cereviseae clearly demonstrated a tremendous bias against the production of crossover mitotic recombination double strand break repair products (Paques & Haber, Mol Cell Biol. 1998 Apr;18(4):2045-54) , and the notion of mitotic crossing over fell into disfavor.

    The current thinking is that the role of recombination in mitotic cells is primarily the restarting of stalled replication forks, rather than the repair of double strand breaks per se.

    Note that in mammalian cells (but not in avian cells), the "recombination" of the immunoglobulin genes is a breakage and ligation process that has no requirement for sequence homology that is the hallmark of true recombinagenic processes.

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  2. Professor Moran, can you explain to me how mitotic recombination does not cause mutations or new genes every time? (excluding accidents during recombination).

    If two different alleles of a gene gets crossed, shouldn't it generate a brand new allele, most of the times ?

    My understanding is that because crossovers are only allowed to happen where there is a long identical sequence on both strands (within a gene or outside of it in junk DNA), this minimizes true mutations.

    Can you expand on the subject or point me to an article ?

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  3. _Atrhur asks,

    ... can you explain to me how mitotic recombination does not cause mutations or new genes every time? (excluding accidents during recombination).

    We're talking about homologous recombination. It's the same kind of recombination that takes place during meiosis.

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  4. Where you get into genomic trouble with crossover recombination is when the recombining molecules are not aligned sister chromatids (usual mitotic case) or parental homologs (classic meiotic case) but rather very highly self-similar low copy repetitive genomic sequences. These account for over 5% of the human genome ( http://projects.tcag.ca/humandup/ ) and are found within and between all human chromosomes. So-called "non-allelic homologous recombination (NAHR)" between these loci in meiosis causes a number of genomic disorders including Smith-Magenis syndrome, DiGeorge syndrome, and half of the most severe form of hemophilia (http://genome.cshlp.org/content/10/5/597 -- dated, but a good introduction to the topic). The role of mitotic NAHR in cancer is an active area of current study.

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  5. Yes, I consider the NAHR (non-allelic homologous recombination ) to be true (accidental) mutations.

    My point is, does a crossover between heterozygous (different) alleles generates new alleles variants?

    In is my understanding that it does not, in the vast majority of cases, but I don't understand how the mechanism of Recombination prevents it.

    If crossovers could happen in any random spot in a gene, suppose we have allele A and allele B,
    after a crossover, we would end up with alleles
    Ab and aB, I mean, the "head" of one allele with the "tail" of the other, potentially giving rise to an infinity of alleles, if the crossover "spot" is random.

    I know this his not what actually happens in biology.
    Please explain how the mechanism of recombination prevents it.

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  6. Your sentence :
    the frequency of recombination during meiosis can be 10,000 times greater that the frequency of crossing over in somatic cells

    Shouldn't it be "... greater than" instead of ".... greater that"? I've seen similar sentences often and have always wonder why it is different from what I have been taught in school. Can you explain. Thanks.

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  7. anonymous asks,

    Shouldn't it be "... greater than" instead of ".... greater that"?

    Yes. I fixed it.

    Thanks.

    ReplyDelete
  8. Thanks Professor Morgan:) i just check my text book but only there r meiosis...i want to know abt mitosis...ur posting is so useful~~~thanks a lot:)

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