BMS 532 Cytogenetics Intro and Meiosis PDF

Block 2: Principles of Heredity and Cytogenetics THIS BLOCK FOCUSES ON CHROMOSOMES AND PATTERNS OF INHERITANCE Human Cytogenetics: A VERY Brief History Lesson CY T O G E N E T I C S = T H E S T U DY O F I N H E R I TA N C E A S R E L AT E D T O CHROMOSOME STRUCTURE AND FUNCTION CHROMOSOMES CAN BE T...

Block 2: Principles of Heredity and Cytogenetics THIS BLOCK FOCUSES ON CHROMOSOMES AND PATTERNS OF INHERITANCE Human Cytogenetics: A VERY Brief History Lesson CY T O G E N E T I C S = T H E S T U DY O F I N H E R I TA N C E A S R E L AT E D T O CHROMOSOME STRUCTURE AND FUNCTION CHROMOSOMES CAN BE THOUGHT OF AS FUNCTIONAL UNITS OF HEREDITY T H I S I S V E RY M U C H BO T H A N O L D A N D A YO U N G F I E L D I F YO U C O N S I D E R M O D E R N A N A LY S E S A S B E I N G B A S E D I N CY T O G E N E T I C S  An important history: Thomas Hunt Morgan Experimentally demonstrated Chromosome Theory of Inheritance using Drosophila 1st solid link between a specific gene on a specific chromosome causing a trait Also determined the role of biological sex in the inheritance of a trait (sex-linked inheritance) Why MORE Science is Beneficial… For more than 30 years it was scientific consensus that humans have 48 chromosomes due to the first report on human chromosomes citing 48 Tijo and Levan using a modified technique that produced more clear chromosome spreads concluded 46 was the absolute number; This was confirmed by Ford and Hamerton In science, relying on one finding can lead down false paths Once a finding is confirmed and reproducible by others it can be elevated to fact This is particularly important in clinical analysis as sample sizes tend to be very small and can sometimes be misleading Meiosis: A Chromosome Perspective BMS 532 BLOCK 2 LECTURE 1  Objectives 1. Explain the following terms and their relationship to both genotype and phenotype: chromosome, homologous chromosome, sister chromatid, autosome, bivalent, independent assortment, alignment, segregation, linkage, cis vs trans, and recombination 2. Describe the process of chromosome separation during meiosis by stage and explain how crossing-over contributes to chromosome behavior and repulsion during prophase I ◦ Summarize the steps of meiosis with emphasis on chromosome behavior and content ◦ List the sequential sub-phases of prophase I of meiosis and describe the major events of each sub-phase 3. Explain the concept of regions of homology and how they contribute to chromosome behavior during alignment, homologous recombination, and separation ◦ Define regions of homology and describe how they are generated ◦ Link regions of homology to the processes that enable two or more nonhomologous chromosomes to align 4. Evaluate the processes involved in generating genetic variation in offspring and explain how changes in the steps and stages associated with meiosis affect outcomes ◦ Describe the two factors associated with increasing variation of offspring: 1) Crossing-over or Recombination vs. 2) alignment and segregation ◦ Explain the process of recombination and the corresponding consequences of different forms of crossing over ◦ Explain how alignment and segregation relate to independent assortment ◦ List the potential consequences of alignment and segregation for multiple chromosomes 5. Assess the consequences for genotype and phenotype with parental and recombinant chromosomes with consideration of cis and trans arrangements 6 LO1, LO2 Meiosis 7  Chromosomes Quick LO1 Introduction Chromosomes consist of linear sequences of genes ◦genetic information which specifies the physical expression of a phenotypic trait  Genetic Linkage Introduction Homologous pairs of chromosomes contain genes whose information is often non-identical = alleles Different alleles of the same gene segregate at Meiosis I Alleles of different genes assort independently in gametes Genes on the same chromosome exhibit linkage ◦ Inherited together ◦ Violates Mendel’s assortment law LO1  Homologs vs. Sister Chromatids Humans diploid cells contain 46 total chromosomes, 44 autosomes and 2 sex chromosomes. Chromosomes are inherited in haploid sets with one set from maternal lineage and one from paternal lineage The chromosomes of each set have a companion chromosome in the other set = Homologous Chromosomes or Homologs Homologous chromosomes contain the same sequence of genes which may vary in expression = alleles ◦ NOTE: Sequence of genes does NOT equal sequence of bases! Sister chromatids = duplicated versions of the LO1chromosomes connected at a constriction point 10  MITOSIS LO1, LO2  MEIOSIS I LO1, LO2  MEIOSIS II LO1, LO2  Meiosis: Prophase I Multiple Distinct Stages for Chromosome Condensation Leptoten e Zygotene Pachyten e Diplotene Diakinesi s LO1, LO2  Leptotene to Zygotene Leptotene = First phase of prophase I when the chromosome become visible under the light microscope. Nucleus remains intact and process appears similar to prophase of mitosis. Condensation of the chromosomes continues LO1, LO2 15  Zygotene to Pachytene Zygotene = Second phase of prophase I Continued chromosome condensation and homolog pairing The homologs will synapse initiating crossing over (crossing-over begins during zygotene) Synapse represents a very tight association between the sister chromatids of each homolog. The two homologs when synapsed form what is called a bivalent Different numbers of chromosomes involved in synapse are given different names Solo chromosome = univalent 3 chromosomes = trivalent Pachytene = continued chromosome condensation and Chiasmata present but difficult to visualize LO1, LO2 16  Pachytene to Diplotene Diplotene begins homolog “repulsion” Forces to drive exchange and separation begin Chiasmata are more clear as chromosomes have condensed further Each chiasma is formed by a breakage and rejoining event between nonsister chromatids (HOMOLOGOUS RECOMBINATION) Synaptonemal complex breaks down and the arms of the bivalent separate. LO1, LO2 17  A Bivalent of a Pair of Homologous Chromosomes LO1, LO2  Diplotene to Diakinesis Chromosome condensation continues. Diakinesis = maximum forces to drive chromosomes apart (maximum contraction) Concludes with breakdown of nuclear membrane and weaker association between homologs LO1, LO2 19  Meiosis: Metaphase I Metaphase I – the bivalents positioned with the centromeres of the two homologs on opposite sides of the metaphase plate As each bivalent moves onto the metaphase plate, its centromeres are oriented randomly with respect to the poles of the spindle Genes on different chromosomes undergo independent assortment because nonhomologous chromosomes align at random in metaphase I LO1, LO2  Meiosis Summary LO1, LO2  Meiosis and Genetic Variation There are two mechanisms that generate genetic variation during meiosis. Random separation of homologs (alignment and segregation) Crossing over during prophase I LO1, LO3, LO4 22  Alignment and Segregation Each homologous pair is independent. Random segregation can produce >8.3 million unique combinations of human chromosomes. Premature separation of chromosomes is a major mechanism of aneuploidy Multiply this by the amount of variation that comes from recombination (unknown large LO1, LO3, LO4 number). 2 LO1, LO3, LO4  Crossing Over During Prophase I Crossing over creates novel combinations of alleles on the chromosomes. While it is highly probable that every pair will undergo at least one recombination event, many will actually undergo multiple events dramatically increasing genetic variation in the daughter cells 25 LO1, LO3, LO4, LO5 Recombination Recombination between linked genes located on the same chromosome involves homologous crossing-over ◦ allelic exchange between them Recombination changes the allelic arrangement on homologous chromosomes = recombinant  Recombination Recombination between linked genes occurs at the same frequency whether alleles are in cis or trans configuration Recombination frequency is specific for a particular pair of genes Recombination frequency increases with increasing distances between genes No matter how far apart two genes may be, the maximum frequency of recombination between any two genes is 50 percent. LO1, LO3, LO4, LO5  Cis, Trans, Parental, and Recombinants In double heterozyote: Cis configuration = mutant alleles of both genes are on the same chromosome = ab/AB Trans configuration = mutant alleles are on different homologues of the same chromosome = Ab/aB LO1, LO3, LO4, LO5 LO1, LO3, LO4, LO5 LO1, LO3, Making Connections to Past and LO4, LO5 Future Homologous recombination repair utilizes many of the mechanisms we associate with traditional homologous recombination ◦ Regions of homology enabling strand crossover and exchange is very similar to homology search and strand invasion Recombination when done correctly as intended should not produce error Inappropriate alignment can result in duplications and deletions similar to our strand slippage during replication ◦ Repetitive regions do not always align perfectly ◦ If crossing over occurs after inappropriate alignment, one copy will have too much info (duplications) and one will have too little (deletion) ◦ Chromosome deletions are among the most common genetic abnormality observed clinically Questions At which point would you expect to be able to observe chiasmata and bivalent chromosomes clearly? (LO2) What does it mean for two genes to be linked and arranged in cis? In trans? (LO1) What do you expect for chromosome content for two genes that are unlinked if the original parent is a heterozygote? (LO4) What factors ensure that two chromosomes will line up and exchange information? (LO3)