Nuclear Structure and Function Research Group

Objectives
The material covered in this lecture, coupled with the recommended reading, should enable you to:
• understand the concept of a cell cycle
• describe the processes of mitosis and meiosis, and the essential differences between them
• understand that recombination allows genes to be shuffled, so new combinations can be tested by evolution

Mitotic cycle
During interphase chromatin forms dense mass, but during cell division (mitosis) it condenses into discrete chromosomes (Fig). Mitosis divides parental cell equally between 2 daughters; mitochondria and vesicles derived from endoplasmic reticulum segregate randomly, chromosomes precisely.
Cell cycle (Fig): G1, S (Fig), G2, M (Fig). G0 (non-dividing, differentiated, cells); programmed cell death, apoptosis; S originally recognized using [³H]thymidine.
M visible in LM (nuclear membrane breaks down, chromatin condenses into chromosomes, attach to spindle containing tubulin (Fig), segregated accurately by spindle, contractile ring containing actin pinches cell into two; Fig). Spindle inhibitors (Fig). M divided into pro-, meta-, ana- (A and B), telo-phase (Fig).
Metaphase chromosome: 2 chromatids connected at centromere (spindle attachment and correct segregation); telomere (cap, prevents joining; Fig).
Classify: metacentric (centromere in middle), acrocentric (towards one end), telocentric (at end). Alternatively: sex + autosomes (44 autosomes + 2 X in female, or 1 X + 1 Y in male). Karyotype characteristic of species (eg 46 in human, 40 in house mouse; Fig).
Centrosome - densely-staining pair of centrioles surrounded by amorphous matrix (Fig); radiating microtubules (microtubule organizing center, aster). Split and moves during cycle (Fig). Some tubules catch centromeres, then spindle pulls apart the 2 chromosome sets.

Meiotic cycle (Fig)
Somatic cell - diploid (2n) amount of DNA in G1, tetraploid (4n) in G2. Sexual reproduction involves production of haploid (1n) gametes during meiosis, fusion of 2 gametes to give (2n) zygote. DNA of 2n cell duplicated, then 2 successive nuclear divisions generate 4 haploid gametes. Fertilization restores diploidy. So alternation of haploid + diploid generations. In most higher organisms, haploid phase brief.
Two features meiosis ensure that the haploid generation receives a mixed set of genes, and so increased genetic variation: (i) segments of homologous chromosomes are exchanged (recombined) at random, (ii) maternal and paternal homologs are assorted (segregated) semi-randomly at the first division (Fig). The new gene combinations can be tested by evolution - fit survive and reproduce successfully, less fit culled.
Meiosis can be considered a 3-stage process: DNA of 2n cell replicated to generate chromosomes with attached chromatids in 4n cell, chromosomes divided among 4 haploid cells by consecutive divisions (meiosis I and II). During I (reductional division), homologous chromosomes pair, segregate (pairing required for proper segregation). During II (equational division), sister chromatids segregated.
Almost invariably, each of resulting 4 haploid cells differs genetically from other 3. Variability arises because (i) new variants generated by recombination, (ii) chromosomal set split semi-randomly among haploid cells, and (iii) additional variation introduced during fertilization when different male and female gametes fuse; therefore, each diploid egg carries unique set of genes. First source of variation arises from high levels of homologous recombination that occur during meiosis I. Bivalent, join (chiasma or chiasmata; Fig). Second source discovered by Mendel - semi-random segregation of chromosomes that occurs during meiosis I (segregation not random in that each haploid cell eventually receives only 1 copy of each homolog, but completely random in that different homologs segregate independently; Fig).
Stages of meiosis I. Prophase (can occupy 90% of meiosis) when duplicated chromosomes partially condense to become visible as chromosomes, dance and apparently 'feel' among crowd for their partners. Once correct partners identified (during stage called leptotene), homologs pair off or synapse (zygotene), tightly align (role of synaptonemal complex during pachytene; Fig), unpair (desynapse during diplotene) and move apart (diakinesis; Fig). When meiosis I has ended, cells in many organisms pass quickly through meiosis II. No DNA made during this interval, and meiosis II is similar to a normal mitosis, except that only 1 (duplicated) copy of each chromosome present.

Recombination
Plays important roles in most cells (eg in bacteria, main role enables replicating complex to bypass lesion in parental strand by exchanging daughter templates), but central role in meiosis (rate >1000x that in mitotic cycle).
During meiotic recombination, DNA sequences exchanged between homologous chromosomes - allows different versions of genes (ie alleles) to be shuffled, so new combinations can be tested by evolution. Although different organisms use different pathways, they share same principles (Fig):
(i) 2 homologous DNA duplexes cross-over (double helices broken, broken ends joined). (ii) Initiation depends on a homology search (DNA-DNA pairing). (iii) Gives staggered heteroduplex joint (strand from one duplex paired with complementary strand from other) - role of key X-shaped Holliday junction (Fig), branch migration (Fig). (iv) Cleavage and rejoining generally precise, so sequence at point of exchange remains unchanged (reciprocal v non-reciprocal recombination). (iv) Overall effect is to move genes between homologs, without normally changing relative positions on chromosome.

References
Sections in Chapter 17, 18, 20 in Alberts, B. et al. (2002). 'Molecular Biology of the Cell'. 4th Edition. Garland Publishing, NY and London.
Chapters 7, 8 in Cook, P.R. (2001). 'Principles of Nuclear Structure and Function'. J. Wiley and Sons, New York. [Web link]
Hochwagen, A. (2008). Meiosis. Curr. Biol. 18, R641-645. [PubMed]

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