OLM 11.02 Cell Division and Human Genetic Diversity.pptx

CELL DIVISION AND HUMAN GENETIC DIVERSITY Dr. David Rodda, PhD Learning Objectives 1. Contrast the segregation of chromosomes in Mitosis and Meiosis and the genetic make-up of the resulting cells. 2. Summarize how chromosome content (n) and DNA content (c) change through the cell cycle and meiosis...

CELL DIVISION AND HUMAN GENETIC DIVERSITY Dr. David Rodda, PhD Learning Objectives 1. Contrast the segregation of chromosomes in Mitosis and Meiosis and the genetic make-up of the resulting cells. 2. Summarize how chromosome content (n) and DNA content (c) change through the cell cycle and meiosis. 3. Contrast the major differences between spermatogenesis and oogenesis. 4. Describe the mechanisms that generate genetic diversity during sexual reproduction. 5. Explain how DNA sequence variants arise and describe them using standard genetic terminology. 6. Briefly compare the distribution of human genetic diversity in Africa and across the rest of the world. 7. Briefly describe the relationship between race and genetics. Behavior of Chromosomes During Cell Division Comparison of Spermatogenesis and Oogenesis Genetic Diversity in Humans Summary BEHAVIOR OF CHROMOSOMES DURING CELL DIVISION The Cell Cycle • A series of events which a cell undergoes as it grows and divides Phases 1. G1 (first ‘gap’).  Growth and metabolism 2. S (synthesis).  DNA and chromosomes replicate 3. G2 (second ‘gap’).  Growth, metabolism and preparation for cell division 4. M (mitosis and cytokinesis).  The cell divides and chromosomes segregate into daughter cells The Cell Cycle Functions Functions of the Cell Cycle & Cell Division 1. Reproduction (single-celled organisms) 2. Growth and development (multi-cellular organisms) 3. Renewal and repair DNA and Chromosome Content in the Cell Cycle n (ploidy number) • The number of complete sets of chromosomes in a cell   2n throughout the cell cycle Homologous Chromosomes • • Human chromosome counts and DNA content through the cell cycle Pairs of nearly identical chromosomes One maternal one paternal c (DNA content number) • The number of copies of DNA double helices of each chromosome in a cell • The c number doubles during S phase, and is halved during M phase   2c during G1 phase 4c during G2 phase Mitosis (M Phase) Entering Mitosis from G2 phase • n=2, c=4 • Each homologous chromosome pair:   1 maternal, 1 paternal Not identical • Each chromosome  2 identical sister chromatids During Mitosis • During mitosis, each homolog behaves independently • Sister chromatids are pulled apart • Each daughter cell receives one identical chromatid from every chromosome • The chromatid becomes the chromosome in the daughter cell • Daughter cells are genetically identical • n=2, c=2 Human Life from a Chromosomal Viewpoint 46,XX 46,XY Meiosis I Meiosis • 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   haploid daughter cells generated in 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 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 Contrasting Mitosis and Meiosis Summary: n and c numbers Stage n (ploidy) c (DNA Content) During G1 Phase 2 2 During G2 Phase 2 4 After Meiosis I 1 2 After Meiosis II (gametes) 1 1 Cell Cycle Meiosis Behavior of Chromosomes During Cell Division Comparison of Spermatogenesis and Oogenesis Genetic Diversity in Humans Summary COMPARISON OF SPERMATOGENESIS AND OOGENESIS Spermatogenesis vs. Oogenesis • Chromosomes behave identically in male and female meiosis, however there are important differences between spermatogenesis and oogenesis  Nb. Males produce far more spermatozoa than females produce ova • • • • Many more rounds of mitosis are required in males before meiosis begins to produce the larger number of gametes Each round of mitosis requires 1 round of DNA replication Each round of DNA replication potentially introduces mutations So, more mutations are inherited from fathers than from mothers Stages of Oogenesis and Spermatogenesis Behavior of Chromosomes During Cell Division Comparison of Spermatogenesis and Oogenesis Genetic Diversity in Humans Summary GENETIC DIVERSITY IN HUMANS Generation of Genetic Diversity In Sexual Reproduction • Genetic diversity in the offspring is produced in Meiosis I in 2 ways: 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. Which is passed is random and independent for each chromosome pair. 223 or 8.4 million possible combinations 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 Human Genetic Diversity • Human genomic sequences vary by ~0.1%  So, 3 million bp differ out of our 3 billion bp genomes • Sequence variants   Most arose long ago in our evolutionary history due to mutations Spread through the human population and became polymorphisms • Spread influenced by natural selection • Selection for variants that confer a survival advantage • Selection against variants that confer a survival disadvantage • Variants that confer nether and advantage or disadvantage spread more-or-less randomly Terminology Alleles • Different versions of a gene. • Alleles usually vary only by a small number of bases Wild-type Allele • The most common allele of a gene in the population Mutations • A DNA sequence variant arising due to DNA replication errors or other DNA damage • A mutation occurring in the germline may be passed to offspring and spread through the population Terminology Polymorphisms • A DNA sequence variant that is less common that the wild-type allele but found in ≥ 1% of the population • Polymorphisms that cause disease are often called mutations Variant • A general term referring to any alteration in DNA sequence from the wild-type Rare Variant • A variant found in less than 1% of the population 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 130,000-115,00 years ago i. • Died out but may have established in China 77,000-69,000 years ago ii. • A small group (<1000 people) crossed the Red Sea, migrated to India, then Southern Asia, Australia, and Europe Out of Africa Hypothesis Diversity in Human Populations Genetic Bottleneck Theory • As humans were migrating out of Africa their population was dramatically restricted. ie. a bottleneck  What caused the bottleneck? 1. 2. The relatively small group of people who migrated out of Africa in the second wave A mass extinction due to an eruption of the Toba supervolcano about 75,000 years ago. • Greatly reduced genetic diversity • Small, scattered human settlements developed • Geographic barriers limited interbreeding. Mutations arose and became established in these geographic regions as polymorphisms • Most genetic diversity in humans arose only over the last ~70,000 years. • There is remarkably little genetic diversity between ethnic groups, at least outside of Africa Admixture with Neanderthals in most areas of the world, outside of Africa, likely also increased human genetic diversity Race and Genetics • Historically, the 5 races of humans (African, European, Asian, Oceanic and Native American) were described based largely on appearance https://sitn.hms.harvard.edu/flash/ 2017/science-genetics-reshapingrace-debate-21st-century/ • It was assumed there was an underlying genetic and biological basis for race • We now know this is false Race and Genetics https://sitn.hms.harvard.edu/flash/ 2017/science-genetics-reshapingrace-debate-21st-century/ • Most human genetic variation occurs within racial groups, relatively little occurs across races • The vast majority of alleles are found in multiple races • Alleles found in every member of a race are extremely rare and also occur in other races • It is impossible to define a race genetically • Race is a social construct, it is not biological • Specific alleles do corelate with the geographic ancestry of individuals, but not the racial ancestry Then why are there different health outcomes among the races? Socially defined racial groups do differ in health outcomes  Due to systematic differences in lived experience, including institutional racism What about genetic diseases that occur at high frequencies in specific races?  There are many examples. Here are a few: • • •  Sickle Cell is most common among Blacks Cystic Fibrosis is most common among Whites Tay Sachs is most common among Ashkenazi Jews These higher disease frequencies have to do with the geographic ancestry of the affected individuals. They are NOT inherent to the race. We will discuss this in depth in Population Genetics. • Eg. Sickle Cell is most common among people whose ancestors lived in regions where Malaria is common. It is not a trait inherent to Blacks. Behavior of Chromosomes During Cell Division Comparison of Spermatogenesis and Oogenesis Genetic Diversity in Humans Summary SUMMARY Summary 1 Behavior of Chromosomes During Cell Division 1. During standard cell division, mitosis, sister chromatids from each chromosome segregate into the two daughter cells. 2. After mitosis the resulting daughter cells are genetically identical. 3. During meiosis, homologues segregate into daughter cells in the first cell division, and sister chromatids segregate in the second cell division. 4. Due to segregation of homologs and crossing-over, gametes produced during meiosis have considerable genetic variation. 5. In G1 phase n=2, c=2. During S phase DNA replicates and in G2 phase n=2, c=4. After segregation of chromatids in mitosis the cell begins the next cycle in G1 n=2, c=2. 6. During meiosis, primary oocytes/spermatocytes enter meiosis 1 after DNA replication, n=2, c=4. Summary 2 7. During meiosis 1 homologous chromosomes segregate into daughter cells, n=1, c=2. 8. During meiosis 2 sister chromatids segregate into the gamates, n=1, c=1. Comparison of Spermatogenesis and Oogenesis 9. Spermatogenesis begins at puberty and continues through the life of a male. It lasts about 2 months. Each round of meiosis produces 4 spermatids. In order to produce the hundreds of millions of spermatozoa in each ejaculate, 100s of rounds of mitosis are needed before meiosis begins. 10.Oogenesis begins during embryogenesis but arrests at Prophase 1 until menstruation begins, so last from 10 to 50 years. Each round of meiosis produces 1 ovum and 3 nonfunctional polar bodies. 1 ovum is released during each menstrual cycle. Only 20-30 rounds of mitosis occur before meiosis begins to produce the required number of primary oocytes. Summary 3 Genetic Diversity In Humans 1. In sexual reproduction, the combined effect of independent assortment of chromosomes and crossingover in Meiosis 1 create a tremendous amount of genetic diversity among the offspring. 2. DNA sequence variants arise due to mutations which pass through the germline and spread through the population. 3. Polymorphisms are DNA sequence variants found in >1% of the population, rare variants are found at <1%. 4. Alleles are variations of genes found in the population. Individuals have 2 alleles of most genes (except males who have 1 allele of genes found on the X and Y chromosomes). 5. The wild-type allele is the most common allele in the population. Summary 4 Genetic Diversity In Humans (continued) 6. Human evolution began in Africa where most genetic diversity arose. During human migration, a genetic bottleneck resulted in dramatically less genetic diversity across the rest of the world. 7. Most genetic variants are distributed across multiple racial groups. There are no genetic variants that define the races. Individuals within racial groups have relatively large genetic diversity. 8. Therefore, race is a social construct with no biological basis.