Biased DNA Segregation

Abstract

Biased chromatid segregation refers to the nonrandom distribution of chromatids in mitotic cells so that specific daughters inherit specific chromosomes or deoxyribonucleic acid (DNA) strands. This unusual behaviour has been documented primarily in the context of differentiation, when one cell divides to produce two daughter cells with distinct fates. When cells divide asymmetrically to produce such daughters, it has been noted that the DNA in these different daughter cells is dissimilar. Two controversial hypotheses to account for such data have been envisioned thus far: one in which stem cells retain all chromosomes carrying ancestral DNA strands, and one in which precursors segregate one or more, epigenetically dissimilar, strands nonrandomly. Several cases of biased DNA segregation are presented, and the implications of this theory are discussed with a view to general biological issues, the proximate mechanisms underlying these phenomena and the ultimate reasons these might occur.

Key Concepts:

  • The biased segregation of DNA might function to specify the fate of cells.

  • It has been proposed that biased DNA segregation reduces DNA mutation load in the cell that retains ancestral, or original, DNA strands.

  • Stem cell self‐renewal and multipotency, which are accounted for by asymmetric cell division, are also proposed to be an outcome of biased DNA segregation.

Keywords: differentiation; asymmetric division; stem cells; epigenetics; mutation; cancer

Figure 1.

Two models of biased DNA segregation. (a) Depicts biased DNA segregation. A hypothetical precursor (which might be a stem cell or simply a precursor present during development) containing epigenetically distinct strands (shown in green and red). When segregated, these strands determine daughter cell fate as a consequence of the configuration of genes transcribed from those strands. Even though each daughter contains strands that are genetic copies, the epigenetic structure in the green versus red strands is different. These green and red strands are hypothesised to be nonrandomly segregated into specific cells in order to determine their fate. (b) Depicts ancestral strand retention as predicted by the immortal strand hypothesis. A stem cell contains ancestral strands (red) specified at some point during development to be retained in that cell if it divides asymmetrically. Following asymmetric division, these red strands are retained by the stem cell daughter, but not the nonstem cell daughter destined to differentiate. The retention of the red strands is hypothesised to minimise mutation load as the sequence in them is not recopied during the many S phases a stem cell undergoes throughout the lifetime of an organism. As above, it is also hypothesised that structural differences in the red strands could also play a role in differentiation.

close

References

Armakolas A and Klar AJ (2006) Cell type regulates selective segregation of mouse chromosome 7 DNA strands in mitosis. Science 311: 1146–1149.

Armakolas A and Klar AJ (2007) Left‐right dynein motor implicated in selective chromatid segregation in mouse cells. Science 315: 100–101.

Betschinger J and Knoblich JA (2004) Dare to be different: asymmetric cell division in Drosophila, C. elegans and vertebrates. Current Biology 14: R674–R685.

Betschinger J, Mechtler K and Knoblich JA (2006) Asymmetric segregation of the tumor suppressor brat regulates self‐renewal in Drosophila neural stem cells. Cell 124: 1241–1253.

Byrum CAW and Wikramanayake AH (2005) Autonomous cell specification: overview. In: Encyclopedia of Life Sciences. London, UK: Wiley.

Cairns J (1975) Mutation selection and the natural history of cancer. Nature 255: 197–200.

Cairns J (2002) Somatic stem cells and the kinetics of mutagenesis and carcinogenesis. Proceedings of the National Academy of Sciences of the USA 99: 10567–10570.

Cairns J (2006) Cancer and the immortal strand hypothesis. Genetics 174: 1069–1072.

Cavalli G and Paro R (1998) The Drosophila Fab‐7 chromosomal element conveys epigenetic inheritance during mitosis and meiosis. Cell 93: 505–518.

Chang JT, Palanivel VR, Kinjyo I et al. (2007) Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315: 1687–1691.

Conboy MJ, Karasov AO and Rando TA (2007) High incidence of non‐random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny. PLoS Biology 5: e102.

Crittenden SL, Leonhard KA, Byrd DT and Kimble J (2006) Cellular analyses of the mitotic region in the Caenorhabditis elegans adult germ line. Molecular Biology of the Cell 17: 3051–3061.

Dalgaard JZ and Klar AJ (2001) Does S. pombe exploit the intrinsic asymmetry of DNA synthesis to imprint daughter cells for mating‐type switching? Trends in Genetics 17: 153–157.

Deng W and Lin H (1997) Spectrosomes and fusomes anchor mitotic spindles during asymmetric germ cell divisions and facilitate the formation of a polarized microtubule array for oocyte specification in Drosophila. Developmental Biology 189: 79–94.

Falconer E, Chavez EA, Henderson A et al. (2010) Identification of sister chromatids by DNA template strand sequences. Nature 463: 93–97.

Fei JF and Huttner WB (2009) Nonselective sister chromatid segregation in mouse embryonic neocortical precursor cells. Cerebral Cortex 19(suppl. 1): i49–i54.

Freeman MR and Doe CQ (2001) Asymmetric prospero localization is required to generate mixed neuronal/glial lineages in the Drosophila CNS. Development 128: 4103–4112.

Gilbert SF (2000) Developmental Biology, 6th edn. Sunderland: Sinauer Associates, Inc.

Green RA and Kaplan KB (2003) Chromosome instability in colorectal tumor cells is associated with defects in microtubule plus‐end attachments caused by a dominant mutation in APC. Journal of Cell Biology 163: 949–961.

Griffiths A, Miller JH, Suzuki D, Lewontin RC and Gelbart WM (1996) An Introduction to Genetic Analysis, 6th edn. New York: W.H. Freeman and Company.

Gruss C and Sogo JM (1992) Chromatin replication. BioEssays 14: 1–8.

Gruss C, Wu J, Koller T and Sogo JM (1993) Disruption of the nucleosomes at the replication fork. EMBO Journal 12: 4533–4545.

Gundersen GG and Bretscher A (2003) Cell biology. Microtubule asymmetry. Science 300: 2040–2041.

Helleday T (2003) Pathways for mitotic homologous recombination in mammalian cells. Mutation Research 532: 103–115.

Hu Y, Lu X, Barnes E et al. (2005) Recql5 and Blm RecQ DNA helicases have nonredundant roles in suppressing crossovers. Molecular and Cellular Biology 25: 3431–3442.

Ito K and McGhee JD (1987) Parental DNA strands segregate randomly during embryonic development of Caenorhabditis elegans. Cell 49: 329–336.

Ito K, McGhee JD and Schultz GA (1988) Paternal DNA strands segregate to both trophectoderm and inner cell mass of the developing mouse embryo. Genes & Development 2: 929–936.

Jablonka P and Jablonka E (1982a) Non‐random sister chromatid segregation by cell type. Journal of Theoretical Biology 99: 427–436.

Jablonka P and Jablonka E (1982b) On the control of hnRNA production. Journal of Theoretical Biology 99: 407–425.

Jackson V (1988) Deposition of newly synthesized histones: hybrid nucleosomes are not tandemly arranged on daughter DNA strands. Biochemistry 27: 2109–2120.

Karpowicz P, Morshead C, Kam A et al. (2005) Support for the immortal strand hypothesis: neural stem cells partition DNA asymmetrically in vitro. Journal of Cell Biology 170: 721–732.

Karpowicz P, Pellikka M, Chea E et al. (2009) The germline stem cells of Drosophila melanogaster partition DNA non‐randomly. European Journal of Cell Biology 88: 397–408.

Kiel MJ, Radice GL and Morrison SJ (2007) Lack of evidence that hematopoietic stem cells depend on N‐cadherin‐mediated adhesion to osteoblasts for their maintenance. Cell Stem Cell 1: 204–217.

Klar AJ (1999) Genetic models for handedness, brain lateralization, schizophrenia, and manic‐depression. Schizophrenia Research 39: 207–218.

Kuroki T and Murakami Y (1989) Random segregation of DNA strands in epidermal basal cells. Japanese Journal of Cancer Research 80: 637–642.

Lambert JD and Nagy LM (2002) Asymmetric inheritance of centrosomally localized mRNAs during embryonic cleavages. Nature 420: 682–686.

Lark KG (1967) Nonrandom segregation of sister chromatids in Vicia faba and Triticum boeoticum. Proceedings of the National Academy of Sciences of the USA 58: 352–359.

Lark KG, Consigli RA and Minocha HC (1966) Segregation of sister chromatids in mammalian cells. Science 154: 1202–1205.

Leffak IM (1984) Conservative segregation of nucleosome core histones. Nature 307: 82–85.

Leffak IM, Grainger R and Weintraub H (1977) Conservative assembly and segregation of nucleosomal histones. Cell 12: 837–845.

Leffak M (1988) Nonrandom assembly of chromatin during hydroxyurea inhibition of DNA synthesis. Biochemistry 27: 686–691.

Lew DJ, Burke DJ and Dutta A (2008) The immortal strand hypothesis: how could it work? Cell 133: 21–23.

Li M, McGrail M, Serr M and Hays TS (1994) Drosophila cytoplasmic dynein, a microtubule motor that is asymmetrically localized in the oocyte. Journal of Cell Biology 126: 1475–1494.

Lin H and Spradling AC (1993) Germline stem cell division and egg chamber development in transplanted Drosophila germaria. Developmental Biology 159: 140–152.

Luger K (2001) Nucleosomes: structure and function. In: Encyclopedia of Life Sciences. London, UK: Wiley.

McGrail M and Hays TS (1997) The microtubule motor cytoplasmic dynein is required for spindle orientation during germline cell divisions and oocyte differentiation in Drosophila. Development 124: 2409–2419.

Merok JR, Lansita JA, Tunstead JR and Sherley JL (2002) Cosegregation of chromosomes containing immortal DNA strands in cells that cycle with asymmetric stem cell kinetics. Cancer Research 62: 6791–6795.

Mochizuki K and Gorovsky MA (2004) Small RNAs in genome rearrangement in Tetrahymena. Current Opinion in Genetics & Development 14: 181–187.

Molofsky AV, Pardal R, Iwashita T et al. (2003) Bmi‐1 dependence distinguishes neural stem cell self‐renewal from progenitor proliferation. Nature 425: 962–967.

Nedelec F, Surrey T and Karsenti E (2003) Self‐organisation and forces in the microtubule cytoskeleton. Current Opinion in Cell Biology 15: 118–124.

Neff MW and Burke DJ (1991) Random segregation of chromatids at mitosis in Saccharomyces cerevisiae. Genetics 127: 463–473.

Neumuller RA and Knoblich JA (2009) Dividing cellular asymmetry: asymmetric cell division and its implications for stem cells and cancer. Genes & Development 23: 2675–2699.

Patterton D and Wolffe AP (1996) Developmental roles for chromatin and chromosomal structure. Developmental Biology 173: 2–13.

Picco V, Hudson C and Yasuo H (2007) Ephrin‐Eph signalling drives the asymmetric division of notochord/neural precursors in Ciona embryos. Development 134: 1491–1497.

Potten CS (1977) Extreme sensitivity of some intestinal crypt cells to X and gamma irradiation. Nature 269: 518–521.

Potten CS, Hume WJ, Reid P and Cairns J (1978) The segregation of DNA in epithelial stem cells. Cell 15: 899–906.

Potten CS, Owen G and Booth D (2002) Intestinal stem cells protect their genome by selective segregation of template DNA strands. Journal of Cell Science 99: 10567–10570.

Quyn AJ, Appleton PL, Carey FA et al. (2010) Spindle orientation bias in gut epithelial stem cell compartments is lost in precancerous tissue. Cell Stem Cell 6: 175–181.

Randall SK and Kelly TJ (1992) The fate of parental nucleosomes during SV40 DNA replication. Journal of Biological Chemistry 267: 14259–14265.

Rando TA (2007) The immortal strand hypothesis: segregation and reconstruction. Cell 129: 1239–1243.

Rehen SK, McConnell MJ, Kaushal D et al. (2001) Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proceedings of the National Academy of Sciences of the USA 98: 13361–13366.

Rivolta MN and Holley MC (2002) Asymmetric segregation of mitochondria and mortalin correlates with the multi‐lineage potential of inner ear sensory cell progenitors in vitro. Brain Research. Developmental Brain Research 133: 49–56.

Robinson JT, Wojcik EJ, Sanders MA, McGrail M and Hays TS (1999) Cytoplasmic dynein is required for the nuclear attachment and migration of centrosomes during mitosis in Drosophila. Journal of Cell Biology 146: 597–608.

Rose LS and Basham SE (2006) Caenorhabditis elegans embryo: establishment of asymmetry. In: Encyclopedia of Life Sciences. London, UK: Wiley.

Rosenberger RF and Kessel M (1968) Nonrandom sister chromatid segregation and nuclear migration in hyphae of Aspergillus nidulans. Journal of Bacteriology 96: 1208–1213.

Shinin V, Gayraud‐Morel B, Gomes D and Tajbakhsh S (2006) Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nature Cell Biology 8: 677–682.

Smith CM, Haimberger ZW, Johnson CO et al. (2002) Heritable chromatin structure: mapping “memory” in histones H3 and H4. Proceedings of the National Academy of Sciences of the USA 99(suppl. 4): 16454–16461.

Smith GH (2005) Label‐retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands. Development 132: 681–687.

Song X, Zhu CH, Doan C and Xie T (2002) Germline stem cells anchored by adherens junctions in the Drosophila ovary niches. Science 296: 1855–1857.

Sotiropoulou PA, Candi A and Blanpain C (2008) The majority of multipotent epidermal stem cells do not protect their genome by asymmetrical chromosome segregation. Stem Cells 26: 2964–2973.

Staiber W (2006) Chromosome elimination in germ line‐soma differentiation of Acricotopus lucidus (Diptera, Chironomidae). Genome 49: 269–274.

Staiber W (2007) Asymmetric distribution of mitochondria and of spindle microtubules in opposite directions in differential mitosis of germ line cells in Acricotopus. Cell and Tissue Research 329: 197–203.

Sun Y, Goderie SK and Temple S (2005) Asymmetric distribution of EGFR receptor during mitosis generates diverse CNS progenitor cells. Neuron 45: 873–886.

Tannenbaum E, Sherley JL and Shakhnovich EI (2005) Evolutionary dynamics of adult stem cells: comparison of random and immortal‐strand segregation mechanisms. Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics 71: 041914.

Tannenbaum E, Sherley JL and Shakhnovich EI (2006) Semiconservative quasispecies equations for polysomic genomes: the haploid case. Journal of Theoretical Biology 241: 791–805.

Tomasovic SP and Mix MC (1974) Cell renewal in the gill of the freshwater mussel, Margaritifera margaritifera: an autoradiographic study using high specific activity tritiated thymidine. Journal of Cell Science 14: 561–569.

White MA, Eykelenboom JK, Lopez‐Vernaza MA, Wilson E and Leach DR (2008) Non‐random segregation of sister chromosomes in Escherichia coli. Nature 455: 1248–1250.

Wilson A and Trumpp A (2006) Bone‐marrow haematopoietic‐stem‐cell niches. Nature Reviews. Immunology 6: 93–106.

Wu L and Hickson ID (2003) The bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426: 870–874.

Yamashita YM, Jones DL and Fuller MT (2003) Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 301: 1547–1550.

Yamashita YM, Mahowald AP, Perlin JR and Fuller MT (2007) Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 315: 518–521.

Yang AH, Kaushal D, Rehen SK et al. (2003) Chromosome segregation defects contribute to aneuploidy in normal neural progenitor cells. Journal of Neuroscience 23: 10454–10462.

Further Reading

Tajbakhsh S and Gonzalez C (2009) Biased segregation of DNA and centrosomes: moving together or drifting apart? Nature Reviews. Molecular Cell Biology 10: 804–810.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Karpowicz, Phillip(Sep 2010) Biased DNA Segregation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022543]