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Cellular reproduction and Genetics Chapter.8 2 Basic terminology • All the DNA in a cell constitutes the cell s genome • A genome can consist of a single DNA molecule (common in prokaryotic cells) or a number of DNA molecules (common in eukaryotic cells) • DNA molecules in a cell are packaged into chromosomes • Eukaryotic chromosomes consist of chromatin, a complex of DNA and protein that condenses during cell division • Every eukaryotic species has a characteristic number of chromosomes in each cell nucleus • Somatic cells (non-reproductive cells) have two sets of chromosomes • Gametes (reproductive cells: sperm and eggs) have half as many chromosomes as somatic cells 3 DNA, Chromatin and Chromosome 4 Cells arise only from preexisting cells • Cell division perpetuates life – Cell division is the reproduction of cells – Virchow’s principle states “Every cell from a cell” • Roles of cell division – Reproduction of an entire single-celled organism – Growth of a multicellular organism – Growth from a fertilized egg into an adult – Repair and replacement of cells in an adult – Sexual reproduction • Sperm and egg production 100 µm (a) Reproduction 200 µm (b) Growth and development 20 µm (c) Tissue renewal 6 Cellular reproduction • Living organisms reproduce by two methods. • Asexual reproduction • produces offspring that are identical to the original cell or organism and • involves inheritance of all genes from one parent. • A clone is a group of genetically identical individuals from the same parent • Sexual reproduction • produces offspring that are similar to the parents, but show variations in traits and • involves inheritance of unique sets of genes from two parents. 7 Star Wars: Episode II- Attack of the Clones (2002) 8 Asexual reproduction 9 Prokaryotes reproduce by binary fission • Binary fission means “dividing in half” – Occurs in prokaryotic cells – Two identical cells arise from one cell – Steps in the process • A single circular chromosome duplicates, and the copies begin to separate from each other • The cell elongates, and the chromosomal copies separate further • The plasma membrane grows inward at the midpoint to divide the cells Copyright © 2009 Pearson Education, Inc. Plasma membrane Prokaryotic chromosome Cell wall 3 1 Duplication of chromosome and separation of copies 2 Continued elongation of the cell and movement of copies Division into two daughter cells Prokaryotic chromosomes THE EUKARYOTIC CELL CYCLE AND MITOSIS Distributing of chromosomes • In preparation for cell division, DNA is replicated and the chromosomes condense • Each duplicated chromosome has two sister chromatids (joined copies of the original chromosome), which separate during cell division • The centromere is the narrow waist of the duplicated chromosome, where the two chromatids are most closely attached 14 Chromosomes DNA molecules Sister chromatids Chromosome duplication Centromere Sister chromatids Chromosome distribution to the daughter cells 15 Chromosomes 1 Chromosomal DNA molecules Centromere Chromosome arm Chromosome duplication (including DNA replication) and condensation 2 Sister chromatids Separation of sister chromatids into two chromosomes 3 Cell cycle • Interphase vs mitosis – Visualized different stage under light microscope • Interphase : the period between mitotic cell divisions – Interphase (about 90% of the cell cycle) can be divided into subphases • G1 phase ( first gap ) • S phase ( synthesis ) • G2 phase ( second gap ) – The cell grows during all three phases, but chromosomes are duplicated only during the S phase Dynamic change in cell culture 19 INTERPHASE G1 S (DNA synthesis) G2 M (M) ITOTIC PHA SE The large, complex chromosomes of eukaryotes duplicate with each cell division • Eukaryotic chromosomes are composed of chromatin – Chromatin = DNA + proteins – To prepare for division, the chromatin becomes highly compact, and the chromosomes are visible with a microscope – Early in the division process, chromosomes duplicate • Each chromosome appears as two sister chromatids, containing identical DNA molecules • Sister chromatids are joined at the centromere, a narrow region Chromosome condensation Sister chromatids Chromosome duplication Centromere Sister chromatids Chromosome distribution to daughter cells Mitosis • Mitosis : eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets in two nuclei. • Sub-phases : The sequence of events is divided into stages corresponding to the completion of one set of activities and the start of the next. • interphase, prophase, prometaphase, metaphase, anaphase and telophase. Cell division is a continuum of dynamic changes • Mitosis progresses through a series of stages – – – – – Prophase Prometaphase Metaphase Anaphase Telophase • Cytokinesis often overlaps telophase • A mitotic spindle is required to divide the chromosomes – The mitotic spindle is composed of microtubules – It is produced by centrosomes, structures in the cytoplasm that – Organize microtubule arrangement – Contain a pair of centrioles in animal cells – The role of centrioles in cell division is unclear Multipolar spindle formation 26 Cell division • Interphase – In the cytoplasm • Cytoplasmic contents double • Two centrosomes form – In the nucleus • Chromosomes duplicate during the S phase • Nucleoli, sites of ribosome assembly, are visible • Prophase – In the cytoplasm – Microtubules begin to emerge from centrosomes, forming the spindle – In the nucleus – Chromosomes coil and become compact – Nucleoli disappear Cell division • Prometaphase – Spindle microtubules reach chromosomes, where they • Attach at kinetochores on the centromeres of sister chromatids • Move chromosomes to the center of the cell through associated protein “motors” – Other microtubules meet those from the opposite poles – The nuclear envelope disappears (NEBD: Nuclear envelope break down) • Metaphase – Spindle is fully formed – Chromosomes align at the cell equator • – Kinetochores of sister chromatids are facing the opposite poles of the spindle Anaphase – Sister chromatids separate at the centromeres – Daughter chromosomes are moved to opposite poles of the cell – Motor proteins move the chromosomes along the spindle microtubules – Kinetochore microtubules shorten • Cytokinesis – Cytoplasm is divided into separate cells INTERPHASE Chromatin Centrosomes (with centriole pairs) PROPHASE Early mitotic Centrosome spindle PROMETAPHASE Fragments of nuclear envelope Centromere Plasma Nuclear envelope membrane Chromosome, consisting of two sister chromatids Nucleolus Kinetochore Spindle microtubules METAPHASE ANAPHASE Metaphase plate Spindle Daughter chromosomes TELOPHASE AND CYTOKINESIS Cleavage furrow Nuclear envelope forming Nucleolus forming Aster Centrosome Sister chromatids Metaphase plate (imaginary) Microtubules Chromosomes Kinetochores Centrosome 1 µm Overlapping nonkinetochore microtubules Kinetochore microtubules 0.5 µm Spindle and kinetochore 32 Cytokinesis differs for plant and animal cells • Cleavage in animal cells – A cleavage furrow forms from a contracting ring of microfilaments, interacting with myosin – The cleavage furrow deepens to separate the contents into two cells • Cytokinesis in plant cells – A cell plate forms in the middle from vesicles containing cell wall material – The cell plate grows outward to reach the edges, dividing the contents into two cells – Each cell has a plasma membrane and cell wall (a) Cleavage of an animal cell (SEM) Cleavage furrow Contractile ring of microfilaments 100 µm (b) Cell plate formation in a plant cell (TEM) Vesicles forming cell plate Wall of parent cell Cell plate 1 µm New cell wall Daughter cells Daughter cells Factors affecting cell division • Factors that control cell division – Presence of essential nutrients – Growth factors, proteins that stimulate division – Presence of other cells causes density-dependent inhibition – Contact with a solid surface; most cells show anchorage dependence Scalpels 1 A sample of human connective tissue is cut up into small pieces. 2 Enzymes digest the extracellular matrix, resulting in a suspension of free fibroblasts. Petri dish 3 Cells are transferred to culture vessels. Without PDGF 4 PDGF is added to half the vessels. 10 µm With PDGF 36 Anchorage dependence Density-dependent inhibition Density-dependent inhibition 20 µm 20 µm (a) Normal mammalian cells (b) Cancer cells 37 Growth factors signal the cell cycle control system • Cell cycle control system – A set of molecules, including growth factors, that triggers and coordinates events of the cell cycle • Checkpoints – Control points where signals regulate the cell cycle • G1 checkpoint allows entry into the S phase or causes the cell to leave the cycle, entering a nondividing G0 phase • G2 checkpoint • M checkpoint Quiescence (cell cycle exit) G1 checkpoint (or Restriction point) G0 Control system G1 M M checkpoint G2 checkpoint G2 S Growth factors signal the cell cycle control system • Effects of a growth factor at the Restriction point – A growth factor binds to a receptor (Growth factor Receptor) in the plasma membrane – Within the cell, a signal transduction pathway propagates the signal through a series of relay molecules – The signal reaches the cell cycle control system to trigger entry into the S phase G0 G1 checkpoint G1 (a) Cell receives a go-ahead signal. G1 (b) Cell does not receive a go-ahead signal. 41 Growth factor Plasma membrane Receptor protein Signal transduction pathway Relay proteins Restriction point Control system G1 M G2 S Cyclins and Cyclin-Dependent Kinases • Two types of regulatory proteins are involved in cell cycle control: cyclins and cyclin-dependent kinases (Cdks) • Cdks activity fluctuates during the cell cycle because it is controled by cyclins, so named because their concentrations vary with the cell cycle • MPF (maturation-promoting factor) is a cyclin-Cdk complex that triggers a cell s passage past the G2 checkpoint into the M phase 43 M G1 S G2 M G1 S G2 M G1 MPF activity Cyclin concentration Time (a) Fluctuation of MPF activity and cyclin concentration during the cell cycle Cdk Degraded cyclin Cyclin is degraded G2 Cdk checkpoint MPF Cyclin (b) Molecular mechanisms that help regulate the cell cycle 44 Growing out of control and cancer cells • Cancer cells escape controls on the cell cycle – Cancer cells divide rapidly, often in the absence of growth factors – They spread to other tissues through the circulatory system – Growth is not inhibited by other cells, and tumors form • Benign tumors remain at the original site • Malignant tumors spread to other locations by metastasis • Cancer treatments – Localized tumors can be treated with surgery or radiation – Chemotherapy is used for metastatic tumors Cancer • Classification of cancer by origin – Carcinomas arise in external or internal body coverings – Sarcomas arise in supportive and connective tissue – Leukemias and lymphomas arise from blood-forming tissues • Cancer stage (ex in lung cancer) – – – – Stage I : Cancer in nodule Stage II : Cancer in lung Stage III : Cancer in Chest Stage IV : Cancer in Body Lymph vessels Tumor Blood vessel Glandular tissue A tumor grows from a single cancer cell. Cancer cells invade neighboring tissue. Cancer cells spread through lymph and blood vessels to other parts of the body. Loss of cell cycle controls in cancer cells • Cancer cells do not respond normally to the body s control mechanisms • Cancer cells may not need growth factors to grow and divide – They may make their own growth factor – They may convey a growth factor s signal without the presence of the growth factor – They may have an abnormal cell cycle control system • A normal cell is converted to a cancerous cell by a process called transformation • Cancer cells that are not eliminated by the immune system, form tumors, masses of abnormal cells within otherwise normal tissue • If abnormal cells remain at the original site, the lump is called a benign tumor • Malignant tumors invade surrounding tissues and can metastasize, exporting cancer cells to other parts of the body, where they may form additional tumors • Recent advances in understanding the cell cycle and cell cycle signaling have led to advances in cancer treatment 48 49 50 MEIOSIS AND CROSSING OVER Chromosomes are matched in homologous pairs • Somatic cells have pairs of homologous chromosomes, receiving one member of each pair from each parent • Homologous chromosomes are matched in – Length – Centromere position – Gene locations • A locus (plural, loci) is the position of a gene – Each gene has a specific location called a locus on a certain chromosome • Different versions of a gene may be found at the same locus on maternal and paternal chromosomes • The human sex chromosomes X and Y differ in size and genetic composition (XY for male, XX for female) • The remaining 22 pairs of chromosomes are called autosomes Karyotyping 53 Human chromosomes • A diploid cell (2n) has two sets of chromosomes • For humans, the diploid number is 46 (2n = 46) • A gamete (sperm or egg) contains a single set of chromosomes, and is haploid (n) • For humans, the haploid number is 23 (n = 23) • Each set of 23 consists of 22 autosomes and a single sex chromosome • In an unfertilized egg (ovum), the sex chromosome is X • In a sperm cell, the sex chromosome may be either X or Y 54 Homologous pair of chromosomes Centromere Sister chromatids One duplicated chromosome Key 2n = 6 Maternal set of chromosomes (n = 3) Paternal set of chromosomes (n = 3) Sister chromatids of one duplicated chromosome Two nonsister chromatids in a homologous pair Centromere Pair of homologous chromosomes (one from each set) 56 Gametes have a single set of chromosome • Meiosis is a process that converts diploid nuclei to haploid nuclei – Diploid cells have two homologous sets of chromosomes – Haploid cells have one set of chromosomes – Meiosis occurs in the sex organs, producing gametes—sperm and eggs – Each gametes : a single set of chromosomes • N=22+X (Y) • Fertilization is the union of sperm and egg – The zygote (fertilized egg) has a diploid chromosome number, one set from each parent – The zygote produces somatic cells by mitosis and develops into an adult Haploid gametes (n = 23) n Egg cell n Sperm cell Meiosis Fertilization Diploid zygote (2n = 46) Multicellular diploid adults (2n = 46) Mitosis and development 2n Meiosis • Meiosis : cell division to produce haploid gametes in diploid organisms • Like mitosis, meiosis is preceded by interphase – Chromosomes duplicate during the S phase • Unlike mitosis, meiosis has two divisions – During meiosis I, homologous chromosomes separate • The chromosome number is reduced by half – During meiosis II, sister chromatids separate • The chromosome number remains the same • Meiosis results in four daughter cells • Each daughter cell has only half as many chromosomes as the parent cell Interphase Pair of homologous chromosomes in diploid parent cell Duplicated pair of homologous chromosomes Sister chromatids Chromosomes duplicate Diploid cell with duplicated chromosomes Meiosis I 1 Homologous chromosomes separate Haploid cells with duplicated chromosomes Meiosis II 2 Sister chromatids separate Haploid cells with unduplicated chromosomes 60 Meiosis • Events in the nucleus during meiosis I – Prophase I • Chromosomes coil and become compact • Homologous chromosomes come together as pairs by synapsis • Each pair, with four chromatids, is called a tetrad • Nonsister chromatids exchange genetic material by crossing over – Important step for genetic variability Meiosis • Events in the nucleus during meiosis I – Metaphase I • Tetrads align at the cell equator – Anaphase I • Homologous pairs separate and move toward • Events in the nucleus during meiosis I – Telophase I – Duplicated chromosomes have reached the poles – A nuclear envelope forms around chromosomes in some species – Each nucleus has the haploid number of chromosomes Copyright © 2009 Pearson Education, Inc. MEIOSIS I: Homologous chromosomes separate INTERPHASE Centrosomes (with centriole pairs) Nuclear envelope PROPHASE I Sites of crossing over Spindle Sister Chromatin chromatids Tetrad METAPHASE I ANAPHASE I Microtubules Metaphase Sister chromatids attached to remain attached plate kinetochore Centromere (with kinetochore) Homologous chromosomes separate Meiosis • Meiosis II follows meiosis I without chromosome duplication • Each of the two haploid products enters meiosis II • Events in the nucleus during meiosis II – Prophase II • Chromosomes coil and become compact • Events in the nucleus during meiosis II – Metaphase II – Duplicated chromosomes align at the cell equator – Anaphase II – Sister chromatids separate and chromosomes move – Events in the nucleus during meiosis II – Telophase II – Chromosomes have reached the poles of the cell – A nuclear envelope forms around each set of chromosomes – With cytokinesis, four haploid cells are produced MEIOSIS II: Sister chromatids separate TELOPHASE II AND CYTOKINESIS PROPHASE I METAPHASE II ANAPHASE II TELOPHASE II AND CYTOKINESIS Cleavage furrow Sister chromatids separate Haploid daughter cells forming Mitosis and meiosis • Which characteristics are similar for mitosis and meiosis? – One duplication of chromosomes • Which characteristics are unique to meiosis? – Two divisions of chromosomes – Pairing of homologous chromosomes – Exchange of genetic material by crossing over • What is the outcome of each process? – Mitosis: two genetically identical cells, with the same chromosome number as the original cell – Meiosis: four genetically different cells, with half the chromosome number of the original cell 67 MITOSIS MEIOSIS Parent cell (before chromosome duplication) Site of crossing over MEIOSIS I Prophase I Prophase Duplicated chromosome (two sister chromatids) Tetrad formed by synapsis of homologous chromosomes Chromosome duplication Chromosome duplication 2n = 4 Chromosomes align at the metaphase plate Metaphase Anaphase Telophase Sister chromatids separate during anaphase 2n 2n Daughter cells of mitosis Tetrads align at the metaphase plate Homologous chromosomes separate (anaphase I); sister chromatids remain together No further chromosomal duplication; sister chromatids separate (anaphase II) Metaphase I Anaphase I Telophase I Haploid n=2 Daughter cells of meiosis I MEIOSIS II n n n n Daughter cells of meiosis II SUMMARY Property Mitosis Meiosis DNA replication Occurs during interphase before mitosis begins Occurs during interphase before meiosis I begins Number of divisions One, including prophase, metaphase, anaphase, and telophase Two, each including prophase, metaphase, anaphase, and telophase Synapsis of homologous chromosomes Does not occur Occurs during prophase I along with crossing over between nonsister chromatids; resulting chiasmata hold pairs together due to sister chromatid cohesion Number of daughter cells and genetic composition Two, each diploid (2n) and genetically identical to the parent cell Four, each haploid (n), containing half as many chromosomes as the parent cell; genetically different from the parent cell and from each other Role in the animal body Enables multicellular adult to arise from zygote; produces cells for growth, repair, and, in some species, asexual reproduction Produces gametes; reduces number of chromosomes by half and introduces genetic variability among the gametes 69 70 Independent orientation of chromosomes in meiosis • Reshuffling of the gene during sexual reproduction ! genetic variation • Independent orientation at metaphase I – Each pair of chromosomes independently aligns at the cell equator – There is an equal probability of the maternal or paternal chromosome facing a given pole – The number of combinations for chromosomes packaged into gametes is 2n where n = haploid number of chromosomes • For humans (n = 23), there are more than 8 million (223) possible combinations of chromosomes • Random fertilization – The combination of each unique sperm with each unique egg increases genetic variability Possibility 1 Possibility 2 Two equally probable arrangements of chromosomes at metaphase I Metaphase II Gametes Combination 1 Combination 2 Combination 3 Combination 4 Homologous chromosomes • Separation of homologous chromosomes during meiosis can lead to genetic differences between gametes – Homologous chromosomes may have different versions of a gene at the same locus – One version was inherited from the maternal parent, and the other came from the paternal parent – Since homologues move to opposite poles during anaphase I, gametes will receive either the maternal or paternal version of the gene – Total number of possible combination of chromosomes = 2^23 = 8.4 million – Random fusion of a sperm with a oocyte = 8.4 million X 8.4 million = 70 trillion Brown coat (C); black eyes (E) White coat (c); pink eyes (e) Coat-color genes Eye-color genes Brown Black C E C E C E c e c e c White e Pink Tetrad in parent cell (homologous pair of duplicated chromosomes) Meiosis Chromosomes of the four gametes Crossing over • Genetic recombination is the production of new combinations of genes due to crossing over • Crossing over involves exchange of genetic material between homologous chromosomes – Nonsister chromatids join at a chiasma (plural, chiasmata), the site of attachment and crossing over – Corresponding amounts of genetic material are exchanged between maternal and paternal (nonsister) chromatids Tetrad Chiasma Centromere Coat-color genes C Eye-color genes E c e 1 Breakage of homologous chromatids C E c e 2 C Tetrad (homologous pair of chromosomes in synapsis) Joining of homologous chromatids E Chiasma c e C E Chiasma e c 3 Separation of homologous chromosomes at anaphase I C E C e c E c 4 C e Separation of chromatids at anaphase II and completion of meiosis E Parental type of chromosome C e c E c e Recombinant chromosome Recombinant chromosome Parental type of chromosome Gametes of four genetic types ALTERATIONS OF CHROMOSOME NUMBER AND STRUCTURE Karyotype • A karyotype shows stained and magnified versions of chromosomes – Karyotypes are produced from dividing white blood cells, stopped at metaphase by colchicine – Colchicine : mitotic arrest (due to spindle damage) – Karyotypes allow observation of – Homologous chromosome pairs – Chromosome number – Chromosome structure Hypotonic solution Packed red and white blood cells Fixative Stain Centrifuge Blood culture 2 White blood cells 3 1 Fluid 4 Centromere Sister chromatids Pair of homologous chromosomes 5 Classic karyotype: a dye specific for phosphate group of DNA - Each chromosome has a characteristic binding patterns Spectral karyotype (SKY technique) : Fluorescently labeled probes for each chromosome Example of karyotype in biological research Nat.Biotech. 2007 Lee JS. Stem Cells 2009 85 An extra copy of chromosome 21 in Down syndrome • Trisomy 21 : three copies of chromosome 21 – Trisomy 21 is the most common human chromosome abnormality – An imbalance in chromosome number causes Down syndrome, which is characterized by – Characteristic facial features, Susceptibility to disease, Shortened life span, Mental retardation, Variation in characteristics – The incidence increases with the age of the mother Copyright © 2009 Pearson Education, Inc. Infants with Down syndrome (per 1,000 births) 90 80 70 60 50 40 30 20 10 0 20 25 40 30 35 Age of mother 45 50 Accidents during meiosis • Nondisjunction is the failure of chromosomes or chromatids to separate during meiosis – During Meiosis I – Both members of a homologous pair go to one pole – During Meiosis II – Both sister chromatids go to one pole • Fertilization after nondisjunction yields zygotes with altered numbers of chromosomes Copyright © 2009 Pearson Education, Inc. Nondisjunction in meiosis I Normal meiosis II Gametes n+1 n+1 n–1 n–1 Number of chromosomes Normal meiosis I Nondisjunction in meiosis II Gametes n+1 n–1 n n Number of chromosomes 92 94 Abnormal numbers of sex chromosomes • Sex chromosome abnormalities tend to be less severe as a result of – Small size of the Y chromosome – X-chromosome inactivation – In each cell of a human female, one of the two X chromosomes becomes tightly coiled and inactive – This is a random process that inactivates either the maternal or paternal chromosome – Inactivation promotes a balance between the number of X chromosomes and autosomes Calico Cat “Tortoiseshell”, exclusively found in female cats 96 New species can arise from errors in cell division • Polyploid species have more than two chromosome sets – Observed in many plant species – Seen less frequently in animals • Example – Diploid gametes are produced by failures in meiosis – Diploid gamete + Diploid gamete → Tetraploid offspring – The tetraploid offspring have four chromosome sets Copyright © 2009 Pearson Education, Inc. Polyploid: multiple sets of chromosome • Polyploidy is pervasive in plants and some estimates suggest that 30–80% of living plant species are polyploid, • Polyploid plants can arise spontaneously in nature by several mechanisms, including meiotic or mitotic failures, and fusion of unreduced (2n) gametes. • Polyploid plants tend to be larger and better at flourishing in early succession habitats such as farm fields • In the breeding of crops, the tallest and best thriving plants are selected for. Thus, many crops (and agricultural weeds) may have unintentionally been bred to a higher level of ploidy. • In some situations polyploid crops are preferred because they are sterile. For example many seedless fruit varieties are seedless as a result of polyploidy. 98 Alterations of chromosome for birth defects and cancer • Structure changes result from breakage and rejoining of chromosome segments – – – – Deletion is the loss of a chromosome segment Duplication is the repeat of a chromosome segment Inversion is the reversal of a chromosome segment Translocation is the attachment of a segment to a nonhomologous chromosome; can be reciprocal • Altered chromosomes carried by gametes cause birth defects • Chromosomal alterations in somatic cells can cause cancer Copyright © 2009 Pearson Education, Inc. Deletion Duplication Homologous chromosomes Inversion Reciprocal translocation Nonhomologous chromosomes Chromosome 9 Chromosome 22 Reciprocal translocation “Philadelphia chromosome” Activated cancer-causing gene The result of the translocation is the oncogenic BCR-ABL gene fusion, located on the shorter derivative 22 chromosome. This gene encodes the Bcr-abl fusion protein. - Cause of 90% of CML Imatinib (Glivec) 103