Chromosome segregation is the process ineukaryotes by which two sisterchromatids formed as a consequence ofDNA replication, or pairedhomologous chromosomes, separate from each other and migrate to opposite poles of thenucleus. This segregation process occurs during bothmitosis andmeiosis. Chromosome segregation also occurs inprokaryotes. However, in contrast to eukaryotic chromosome segregation, replication and segregation are not temporally separated. Instead segregation occurs progressively following replication.[1]
Duringmitosis chromosome segregation occurs routinely as a step in cell division (see mitosis diagram). As indicated in the mitosis diagram, mitosis is preceded by a round of DNA replication, so that each chromosome forms two copies calledchromatids. These chromatids separate to opposite poles, a process facilitated by a protein complex referred to ascohesin. Upon proper segregation, a complete set of chromatids ends up in each of two nuclei, and when cell division is completed, each DNA copy previously referred to as a chromatid is now called a chromosome.
Chromosome segregation occurs at two separate stages duringmeiosis calledanaphase I andanaphase II (see meiosis diagram). In a diploid cell there are two sets ofhomologous chromosomes of different parental origin (e.g. a paternal and a maternal set). During the phase of meiosis labeled “interphase s” in the meiosis diagram there is a round of DNA replication, so that each of the chromosomes initially present is now composed of two copies calledchromatids. These chromosomes (paired chromatids) then pair with the homologous chromosome (also paired chromatids) present in the same nucleus (see prophase I in the meiosis diagram). The process of alignment of paired homologous chromosomes is called synapsis (seeSynapsis). During synapsis, genetic recombination usually occurs. Some of the recombination events occur bycrossing over (involving physical exchange between two chromatids), but most recombination events involve information exchange but not physical exchange between two chromatids (seeSynthesis-dependent strand annealing (SDSA)). Following recombination, chromosome segregation occurs as indicated by the stages metaphase I and anaphase I in the meiosis diagram.
Different pairs of chromosomes segregate independently of each other, a process termed“independent assortment of non-homologous chromosomes”. This process results in each gamete usually containing a mixture of chromosomes from both original parents.
Improper chromosome segregation (seenon-disjunction,disomy) can result inaneuploid gametes having either too few or too many chromosomes.
The second stage at which segregation occurs during meiosis isprophase II (see meiosis diagram). During this stage, segregation occurs by a process similar to that during mitosis, except that in this case prophase II is not preceded by a round of DNA replication. Thus the two chromatids comprising each chromosome separate into differentnuclei, so that each nucleus gets a single set of chromatids (now called chromosomes) and each nucleus becomes included in a haploidgamete (see stages following prophase II in the meiosis diagram). This segregation process is also facilitated bycohesin. Failure of proper segregation during prophase II can also lead to aneuploid gametes. Aneuploid gametes can undergo fertilization to form aneuploid zygotes and hence to serious adverse consequences for progeny.
Meioticchromosomal crossover (CO) recombination facilitates the proper segregation ofhomologous chromosomes. This is because, at the end of meioticprophase I, CO recombination provides a physical link that holds homologous chromosome pairs together. These linkages are established bychiasmata, which are the cytological manifestations of CO recombination. Together withcohesion linkage between sisterchromatids, CO recombination may help ensure the orderly segregation of the paired homologous chromosomes to opposite poles. In support of this, a study of aneuploidy in single spermatozoa by whole genome sequencing found that, on average, human sperm cells with aneuploid autosomes exhibit significantly fewer crossovers than normal cells.[2] After the first chromosome segregation inmeiosis I is complete, there is further chromosome segregation during the second equational division ofmeiosis II. Both proper initial segregation of chromosomes in prophase I and the next chromosome segregation during equational division in meiosis II are required to generate gametes with the correct number of chromosomes.
CO recombinants are produced by a process involving the formation and resolution ofHolliday junction intermediates. As indicated in the figure titled "A current model of meiotic recombination", the formation of meiotic crossovers can be initiated by adouble-strand break (DSB). The introduction of DSBs in DNA often employs thetopoisomerase-like protein SPO11.[3] CO recombination may also be initiated by external sources of DNA damage such as X-irradiation,[4] or internal sources.[5][6]
There is evidence that CO recombination facilitates meiotic chromosome segregation.[2] Other studies, however, indicate thatchiasma, while supportive, are not essential to meiotic chromosome segregation. The budding yeastSaccharomyces cerevisiae is a model organism used for studying meiotic recombination. Mutants ofS. cerevisiae defective in CO recombination at the level ofHolliday junction resolution were found to efficiently undergo proper chromosome segregation. The pathway that produces the majority of COs inS. cerevisiae, and possibly in mammals, involves a complex of proteins including theMLH1-MLH3heterodimer (called MutL gamma).[7] MLH1-MLH3 binds preferentially to Holliday junctions.[8] It is anendonuclease that makes single-strand breaks insupercoiled double-stranded DNA,[8][9] and promotes the formation of CO recombinants.[10] Double mutants deleted for both MLH3 (major pathway) and MMS4 (which is necessary for a minor Holliday junction resolution pathway) showed dramatically reduced crossing over compared to wild-type (6- to 17-fold reduction); howeverspore viability was reasonably high (62%) and chromosomaldisjunction appeared mostly functional.[10]
TheMSH4 andMSH5 proteins form a hetero-oligomeric structure (heterodimer) inS. cerevisiae and humans.[11][12][13] InS. cerevisiae, MSH4 and MSH5 act specifically to facilitate crossovers betweenhomologous chromosomes during meiosis.[11] The MSH4/MSH5 complex binds and stabilizes doubleHolliday junctions and promotes their resolution into crossover products. An MSH4 hypomorphic (partially functional) mutant ofS. cerevisiae showed a 30% genome-wide reduction in crossover numbers, and a large number of meioses with non-exchange chromosomes.[14] Nevertheless, this mutant gave rise to spore viability patterns suggesting that segregation of non-exchange chromosomes occurred efficiently.[14] Thus it appears that CO recombination facilitates proper chromosome segregation during meiosis inS. cerevisiae, but it is not essential.
The fission yeastSchizosaccharomyces pombe has the ability to segregate homologous chromosomes in the absence of meiotic recombination (achiasmate segregation).[15] This ability depends on the microtubule motordynein that regulates the movement of chromosomes to the poles of themeiotic spindle.