Cell Division & Human Genetic Diversity Lecture Notes PDF

Cell division & the human genetic diversity Zsolt Fábián M.D., Ph.D., Dr. Habil.  Cell division & the human genetic diversity Lesson 1 - Cell division Zsolt Fábián M.D., Ph.D., Dr. Habil.  The cell cycle Life stages of the cell...

Cell division & the human genetic diversity Zsolt Fábián M.D., Ph.D., Dr. Habil.  Cell division & the human genetic diversity Lesson 1 - Cell division Zsolt Fábián M.D., Ph.D., Dr. Habil.  The cell cycle Life stages of the cell t  The cell cycle Life stages of the cell S - DNA and chromosomes replicate G2 - Growth, metabolism, G1 - Growth and preparation for M metabolism M - The cell divides and chromosomes segregate into daughter cells al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Life stages of the cell 1. Reproduction (single-cell organisms) 2. Growth and development (multi-cellular organisms) 3. Renewal and repair al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle DNA content during the cell cycle DNA content number (c) M G2 2 The number of copies S of DNA double DNA content helices of each G1 G1 1 chromosome in a cell The c number  2c during G1 phase  doubles during S t phase  4c during G2 phase  halved during M phase  The cell cycle DNA content during the cell cycle Ploidy number (n) The number of complete sets of chromosomes in a cell 2n throughout the cell cycle Homologous Chromosomes Pairs of nearly identical chromosomes One maternal one paternal The cell cycle Mitosis Entering mitosis from G2 phase n=2, c=4 each homologous chromosome pair: – 1 maternal, 1 paternal – NOT necessarily identical each chromosome – 2 identical sister chromatids During Mitosis each homolog behaves independently sister chromatids are pulled apart each daughter cell receives one identical chromatid from every chromosome Chromatid becomes the chromosome in the daughter cell Daughter cells are genetically identical n=2, c=2  The cell cycle Mitosis - prophase al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Mitosis - prometaphase al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Mitosis - prometaphase al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Mitosis - prometaphase al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Mitosis - metaphase al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Mitosis - metaphase al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Mitosis - anaphase al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Mitosis – Spindle checkpoint al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Mitosis - anaphase al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Mitosis - telophase edit: Michael Abbey (Science photo library)  The cell cycle Cytokinesis al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Cell cycle checkpoints al., Molecular Biology - Principles of Genome Function, 2e, Oxford University Press, (2014)  The cell cycle Tissue homeostasis - atrophy ssac et al., J. Clin. Invest. 2018;128(7):2702–2712.  The cell cycle Tissue homeostasis – hypertrophy, hyperplasia, dysplasia ssac et al., J. Clin. Invest. 2018;128(7):2702–2712.  The cell cycle Anticancer drugs & the cell cycle z et al., Molecular and Clinical Oncology, (2015) 3:37-43  The cell cycle Key points Cell cycle is an ordered series of events of living eukaryotic cells Cell cycle consists of 2 major stages: interphase and cell division Intephase consists of the G1, S and G2 phases These phases have distinct functional characteritics Cell division consists of Mitosis and Cytokinesis Mitosis has substages with dedicated functions in the distribution of genetic material and the generation of daughter cells Cytokinesis is the finishing step in the formation of new cells Precisely controlled cell cycle is a key feature of tissue homeostasis  Cell division & the human genetic diversity Lesson 2 – Meiosis, Spermato- & Oogenesis Zsolt Fábián M.D., Ph.D., Dr. Habil.  The cell cycle Preserving the DNA content across generations 46,XX 46,XY  The cell cycle Meiosis I Generates haploid gametes Occurs only in the germline Entering Meiosis I from G2 n=2, c=4 During Meiosis I Homologous chromosomes associate forming bivalents – 2 joined chromosomes with 4 DNA double helices In Prophase I – Crossing-Over or Homologous Recombination between homologues – In females, meiosis arrests for 10-50 years Homologs are pulled into daughter cells Resulting cells are haploid n=1, c=2 The cell cycle Meiosis II entering Meiosis II  n=1, c=2 during Meiosis II  sister chromatids are pulled apart into daughter cells resulting cells are gametes  n=1, c=1 gametes are not genetically identical paternal or maternal homologues crossing-over/recombination  The cell cycle Meiosis versus Mitosis  The cell cycle Summary of the n & c numbers Stage n (ploidy) c (DNA Content) Cell Cycle During G1 Phase 2 2 During G2 Phase 2 4 Meiosis After Meiosis I 1 2 After Meiosis II (gametes) 1 1  The cell cycle Spermatogenesis versus Oogenesis  The cell cycle Spermatogenesis versus Oogenesis Stage Females Males Begins Early embryonic Puberty life Duration 10-50 years 60 days Number of mitoses before 20-30 30-500 meiosis Gametes produced/meiosis 1 ovum+3 polar 4 spermatozoa bodies Gametes produced 1 ovum / period 100-200 million/ejaculation  Cell division & the human genetic diversity Lesson 3 - Human genetic diversity Zsolt Fábián M.D., Ph.D., Dr. Habil.  Lesson 3 - Human genetic diversity Generation of Genetic Diversity In Sexual Reproduction 1. Independent Assortment of Chromosomes – Individuals have 23 pairs of maternal and paternal chromosomes – For each pair, they pass only one, either their maternal or paternal, onto their offspring. – Selection is random and independent for each chromosome pair.  Lesson 3 - Human genetic diversity Generation of Genetic Diversity In Sexual Reproduction 2. Crossing-Over / Homologous Recombination – Occurs at least once in every bivalent during Prophase I An average of 2 times in humans – Resulting chromatids have a combination of maternally and paternally inherited DNA – The number of possible combinations effectively becomes infinite  Lesson 3 - Human genetic diversity Human genetic variation Human genomic sequences average ~0.1% variation – ~3 million base-pairs differ out of 3 billion base-pairs – Individuals carry ~10 unique ‘sequence variants’ – variations in sequence arise by mutation & then spread throughout population during evolution causing genetic “polymorphism” – Alleles are different versions of an identified gene normally differ by only a small number of nucleotides – “Wild-type allele” = the most common allele for a gene within a population – “a polymorphism” = an allele that is less common than the wild-type allele, but occurs more than 1% of the time – “Variant” – generally just refers to a change in DNA  Lesson 3 - Human genetic diversity Diversity in Human Populations Out of Africa Hypothesis Anatomically modern humans first appeared ~250,000 years ago in Africa – Most human genetic diversity arose during human evolution in Africa – Today there is more genetic diversity in Africa than anywhere else 2 waves of migration i. 130,000-115,00 years ago Died out but may have established in China ii. 77,000-69,000 years ago A small group (1% of the population, rare variants are found at