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ScienceWeek
GENOME BIOLOGY: ON CROSSOVER INTERFERENCE
The following points are made by Kenneth J. Hillers (Current Biology 2004 14:R1036):
1) During prophase of meiosis in most eukaryotes, DNA recombination events between homologous chromosomes are induced to occur at high frequency, so there are usually multiple events per chromosome pair per meiosis. Whereas many of these recombination events are non-reciprocal, a subset results in reciprocal exchange of genetic material between chromosomes --"crossovers", which in the presence of appropriate markers can be detected as linkage alterations.
2) A genetic map is actually a map of the frequency and distribution of meiotic crossovers along a chromosome within a population. When researchers first began constructing genetic maps of Drosophila in the early part of the 20th century, they realized that the positions of multiple crossovers along a chromosome were not random with regard to each other. Hermann J. Muller (1890-1967) observed that the occurrence of one crossing-over interferes with the coincident occurrence of another crossing-over in the same pair of chromosomes, and I have accordingly termed this phenomenon 'interference' .
3) Interference has subsequently been shown to operate in most --but not all -- eukaryotes assayed. Interference results in widely spaced crossovers along chromosomes. Most eukaryotes average only a few crossovers per chromosome pair per meiosis. This means that interference can exert its effect across whole chromosomes (or chromosome arms). As chromosomes in many eukaryotes are large, interference must be able to act over megabase lengths of DNA. Indeed, in the nematode Caenorhabditis elegans, interference is capable of acting over a fusion chromosome of 50 Mb - nearly half the genome.
4) Interference, by definition, means that crossovers somehow discourage other crossovers from occurring nearby. One simple model for how interference works is that a crossover generates some crossover-discouraging signal or substance that then spreads for some variable distance along the chromosome on either side of the crossover. In this way, additional crossovers near the initial one would be infrequent, with the magnitude of the effect decreasing with increasing distance from the initial crossover. This model may indeed describe how interference works, but supporting evidence is scarce. Despite nearly a century of investigation we still do not know how interference is exerted.
5) Interference acts over widely varying DNA lengths in different eukaryotes: tens of kilobases in budding yeast, and tens of megabases in mice and humans. Chromosome fusion and bisection studies have shown that interference within a specific chromosome region can vary depending on the overall size and structure of the chromosome. This variability suggests that interference is not a property of DNA itself.
References (abridged):
1. Bishop, D.K. and Zickler, D. (2004). Early decision; meiotic crossover interference prior to stable strand exchange and synapsis. Cell 117, 9-15
2. Foss, E., Lande, R., Stahl, F.W. and Steinberg, C.M. (1993). Chiasma interference as a function of genetic distance. Genetics 134, 681-691
3. Kleckner, N., Zickler, D., Jones, G.H., Dekker, J., Padmore, R., Henle, J. and Hutchinson, J. (2004). A mechanical basis for chromosome function. Proc. Natl. Acad. Sci. USA 101, 12592-12597
4. Muller, H.J. (1916). The mechanism of crossing over. Am. Nat 50, 193-221
5. van Veen, J.E. and Hawley, R.S. (2003). Meiosis: when even two is a crowd. Curr. Biol. 13, R831-R833
Current Biology http://www.current-biology.com
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CELL BIOLOGY: ON MEIOSIS
The following points are made by E. Martinez-Perez and G. Moore (Science 2004 303:49):
1) Organisms exhibiting sexual reproduction carry two copies (homologs) of each chromosome. Meiosis is the specialized type of cell division that halves the number of chromosomes before sexual reproduction, thereby ensuring that chromosome number does not double with each generation. Before meiosis, each homolog is replicated, forming two sister "chromatids" that remain linked together. During meiosis, the homologs are correctly segregated so that each gamete (that is, sperm and egg) carries only a single copy of each chromosome. The chromosome complement is restored in the zygote (fertilized egg) after the fusion of the two gametes. A central question is how this complicated chromosome dance during meiosis is achieved.(1)
2) At the start of meiosis, each chromosome must recognize its homolog from among all the chromosomes present in the nucleus. The homologs must then become intimately aligned along their entire lengths and a proteinaceous structure known as the synaptonemal complex (SC) must be assembled between them, a process called synapsis. In this way, meiotic recombination (the exchange of DNA strands between the homologs) is completed, resulting in the formation of chiasmata, physical links that hold the homologs together after disassembly of the SC. After the resolution of these physical links, the homologs separate during the first meiotic division. The two sister chromatids forming each homolog are then separated during the second meiotic division.
3) Many components of the meiotic recombination machinery are known, especially in yeast, as well as some structural components of the SC. However, very little is understood about how homologs find each other in the first place and how this initial recognition is coordinated with synapsis and recombination. Pawlowski et al(1) have identified the phs1 (poor homologous synapsis 1) gene in maize that is necessary for the coordination of chromosome pairing, recombination, and synapsis.
4) After SC disassembly in wild-type maize, the 10 pairs of homologs are present as 10 bivalents (each bivalent consists of a pair of homologs held together by chiasmata). However, maize plants carrying a mutation in the phs1 gene have 20 unpaired chromosomes instead of 10 bivalents, suggesting that chiasma formation has failed. This could be due to a direct consequence of problems in the late events leading to chiasma formation (2), defects in SC formation (3), or problems in initial homolog pairing (4). By following a single site on each homolog in phs1 mutants, Pawlowski et al(1) found that the homologs were paired in only 5% of the cells at a time, whereas wild-type cells showed 100% pairing. Surprisingly, SC formation appears normal in phs1 mutants, resulting in the indiscriminate association of nonhomologous chromosomes in these plants.(5)
References (abridged):
1. W. P. Pawlowski et al., Science 303, 89 (2004)
2. S. M. Lipkin et al., Nature Genet. 31, 385 (2002)
3. S. J. Armstrong, A. P. Caryl, G. H. Jones, F. Christopher, H. Franklin, J. Cell Sci. 115, 3645 (2002)
4. A. J. MacQueen, A. M. Villeneuve, Genes Dev. 15, 1674 (2001)
5. J.-Y. Leu, P. R. Chua, G. S. Roeder, Cell 94, 375 (1998)
Science http://www.sciencemag.org
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CELL BIOLOGY: ON MEIOTIC RECOMBINATION
Notes by ScienceWeek:
In this context, the term "diploid" refers in general to a chromosome state in which each type of chromosome is represented twice. In contrast, the term "haploid" refers to a chromosome state in which each chromosome is represented singly. In humans, somatic cells are diploid and gametes are haploid.
In this context, the term "meiosis" (reduction division) refers to the process whereby a nucleus divides by two divisions (meiosis I and meiosis II) into four nuclei, each containing half the original number of chromosomes, in most cases forming a genetically nonuniform haploid. This is a necessary aspect of eukaryotic sexual reproduction, for without it fertilization would usually double the chromosome number every generation.
The following points are made by E.J. Louis and R.H. Borts (Current Biology 2003 13:R953):
1) Meiotic cell division is specialized to separate homologous chromosomes into the haploid germ cells. The accurate segregation of chromosomes in meiosis, and consequent reduction of ploidy from 2N to 1N, depends on their being sufficient, properly distributed crossovers, or recombination sites. This process involves an intricate set of chromosomal and DNA interactions (1,2).
2) At a gross chromosomal level, the homologous chromosomes exhibit transient interactions that progress to pairing along their lengths. This culminates in the construction of a highly ordered proteinaceous structure called the "synaptonemal complex", and concomitantly physical connections called "chiasmata" are formed. These provide the tension necessary for proper alignment of the homologues on the meiosis I metaphase spindle, and are revealed only after the synaptonemal complex has broken down and the chromosomes are pulled to opposite poles.
3) Chiasmata are sites of DNA exchange -- crossovers -- between the homologues. They are non-randomly distributed as a result of a mysterious process termed "interference", such that all chromosomes obtain at least one crossover necessary for proper disjunction of the homologues. In most organisms studied, too few crossovers or crossovers in the wrong places can lead to aneuploidy as a result of missegregation (3).
4) A "Holliday junction" (Holliday structure) is one of the junctions between four strands of DNA that are important intermediates in genetic recombination. At the DNA level, meiotic recombination initiates as double-strand breaks which are processed through several steps. These include strand resection, one-ended single-strand invasion of homologous sequences, priming of DNA synthesis from the invasion, second-end capture, and the formation of double "Holliday junctions", followed by resolution as a crossover (4,5). More double-strand breaks are made than result in crossovers, though non-crossover interactions still result in recombination -- these can be detected genetically by non-Mendelian segregation patterns such as gene conversions. At some stage, therefore, many events are processed into non-crossovers without maturing into fully ligated double Holliday junctions. The big questions that remain to be answered are when, and how, the decision to be, or not to be, a crossover is made.
5) A number of genes have been identified in which mutations cause a reduction in crossovers and/or a loss of interference, resulting in the production of aneuploid gametes (1-3,5). But until very recently, we knew of no genes where loss of function led to an increase in meiotic crossing over. This has changed with the recent evidence of Rockmill et al (2003), who have shown that the budding yeast RecQ helicase SGS1 has a meiosis-specific role in limiting the number of crossovers.
References (abridged):
1 Roeder, G.S. (1997). Meiotic chromosomes: it takes two to tango. Genes Dev. 11, 2600-2621
2 Zickler, D. and Kleckner, N. (1999). Meiotic chromosomes: integrating structure and function. Annu. Rev. Genet. 33, 603-754
3 Hassold, T., Sherman, S., and Hunt, P. (2000). Counting cross-overs: characterizing meiotic recombination in mammals. Hum. Mol. Genet. 9, 2409-2419
4 Hunter, N. and Kleckner, N. (2001). The single-end invasion: an asymmetric intermediate at the double-strand break to double-holliday junction transition of meiotic recombination. Cell 106, 59-70
5 Allers, T. and Lichten, M. (2001). Differential timing and control of noncrossover and crossover recombination during meiosis. Cell 106, 47-57
Current Biology http://www.current-biology.com
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