chromosomes

• Chromosome


  A structure in the nucleus of a cell that contains the genetic material (DNA) and associated proteins
• Portrait of a Chromosome

  • Range of mutations: single base changes to entire set of chromosomes (chromosomal aberration)
  • In general, excess genetic material has milder effects on health than a deficit
  • Most large-scale chromosomal abnormalities disrupt or halt prenatal development
  • Around only 0.65% of all newborns have chromosomal abnormalities that produce symptoms
• Cytogenetics


  A branch of genetics that is concerned with the study of the structure and function of the cell, especially the chromosomes
• Chromosome duplication and transmission

  Chromosome is duplicated and transmitted to the next generation via mitosis and meiosis
• Chromosome structure

  • Distinguishable, using stain: heterochromatin (darker part), euchromatin (lighter part)
  • Heterochromatin: mostly of highly repetitive DNA sequences
  • Euchromatin: Has more protein-encoding sequences
• Telomeres


  Chromosome tips. In human, each telomere is many repeats of TTAGGG sequence
• Centromere


  Largest constriction part of chromosome<|>Where spindle fibers attach<|>Certain centromere-associated proteins form kinetochore, a structure that contacts the spindle fibers, enabling the cell to divide
• Cell cycle

  1. Interphase (G1, S, G2)

  2. Mitosis (Prophase, Metaphase, Anaphase, Telophase, Cytokinesis)

  3. G0 (when a cell decides which course of action to follow)
• Centromere duplication

  1. Centromeres are replicated toward the end of S phase

  2. Duplication of centromeres is controlled by centromere protein A (CENP-A)

  3. CENP-A stays with centromeres during chromosomes duplication

  4. When the replicated (sister) chromatids separate at anaphase, each member of the pair retains some CENP-A
• Subtelomere


  Includes some protein-encoding genes. It is like a bridge between the gene-rich regions and the telomere repeats
• Karyotype


  A chart that displays chromosome pairs in size order (largest to smallest), then X and Y chromosomes
• Karyotype

  • Dyes/stains are used to make it easier to distinguish chromosomes as they form patterns of bands
  • Centromere position distinguishes chromosomes
• In terms of karyotype, human closest relative is pygmy chimpanzee (bonobo) / Pan paniscus
• DNA replication

  1. Helicase unwinds a segment of DNA by breaking the hydrogen bonds between two complimentary DNA strands

  2. DNA polymerase adds new nucleotides to synthesis leading strand DNA continuously in 5' to 3'

  3. Replication of the lagging strand is more complex. Lagging strand is synthesized in short, separated segments
• Homologous chromosome


  A set of one maternal chromosome and one paternal chromosome that pair up with each other inside a cell during meiosis. These copies have the same genes in the same locations, or loci, as one another
• Sister chromatids


  Generated when a single chromosome is replicated into two copies of itself
• Visualizing chromosomes

  1. Any cell other than a mature erythrocyte can be used

  2. Easiest way: Buccal cells from the inside of the cheek

  3. Common ways for prenatal testing: amniocentesis, chorionic villus sampling (CVS), chromosome microarray analysis
• Amniocentesis


  1. 14-16th weeks of pregnancy

  2. A needle passed through the woman's abdominal wall for sample collection from amniotic fluid

  3. Ultrasound is used to follow the needle movement

  4. Cells are cultured (7-10 days), then karyotyped

  5. The most common chromosomal abnormality detected is trisomy (one extra chromosome)

  6. The sampled amniotic fluid may also indicate an inborn error of metabolism
• Chorionic villus sampling (CVS)

  1. 10-12th weeks of gestation

  2. Cells are collected from the chorionic villi (finger-like structures that develop into the placenta)

  3. Normally karyotype is prepared directly from the collected cells

  4. Chromosomes obtained from CV cells should be identical to chromosomes obtained from fetus, as CV cells descend from the fertilized ovum

  5. Occasionally, a chromosomal aberration occurs only in a cell of the embryo, or only in CV cells → chromosomal mosaicism

  6. CVS does not sample amniotic fluid, so tests for inborn errors of metabolism are not possible

  7. The advantage of CVS is earlier results
• Chromosomal Microarray Analysis (CMA)

  1. Using a high technology technique: microarray

  2. This technique identifies chromosomal abnormalities, including extremely small sections of missing or extra DNA

  3. CMA displays specific sequences, detecting many disorders that other technique miss
• Fluorescence in situ hybridization (FISH)


  A DNA probe is tagged with a fluorescent dye/marker<|>The probe and target DNA are denatured, and the probe is allowed to hybridize with the target<|>The fluorescent tag is then detected with a fluorescent microscope
• A human karyotype is abnormal if the number of chromosomes in a somatic cell is not 46
• Polyploidy

  A cell with extra set of chromosome. Examples: Triploid (3N), tetraploid (4N). Usually caused by fertilization of an oocyte by two sperms, or formation of diploid gamete (meiotic error). Very rarely, an infant survives as long as a few days, with defects in nearly all organs. However, certain human cells may be polyploid. As example, some hepatocytes have 4N, even 8N cells
• Aneuploidy


  Cells missing a single chromosome, or having an extra one. Rarely, aneuploids can have more than one missing or extra chromosome. Defective meiosis in parent. Most aneuploids are spontaneously aborted. Mental retardation is common in aneuploidy. Meiotic error → nondisjunction
• Nondisjunction

  1. At meiosis I

  2. At meiosis II
• Autosomal aneuploids


  Most autosomal aneuploids cease developing long before birth. The most frequently seen extra autosomes in newborns are chromosomes 21, 18, and 13. These chromosomes carry far fewer protein-encoding genes than the other autosomes
• Trisomy 21 (Down syndrome)

  An autosomal aneuploidy where there are three copies of chromosome 21
• Genes associated with Trisomy 21 Down syndrome
• Sex chromosome aneuploids

  People with sex chromosome aneuploidy have extra or missing sex chromosomes
• Klinefelter syndrome

  A sex chromosome aneuploidy with 47, XXY chromosomes
• Polyploid


  Cells with more than the normal number of chromosomes
• Hepatocytes


  • Some have 4N, even 8N cells
• Aneuploidy


  Cells missing a single chromosome, or having an extra one
• Rarely, aneuploids can have more than one missing or extra chromosome
• Most aneuploids are spontaneously aborted
• Mental retardation is common in aneuploidy
• Nondisjunction at meiosis I


  Nondisjunction at meiosis II
• Most autosomal aneuploids cease developing long before birth
• The most frequently seen extra autosomes in newborns are chromosomes 21, 18, and 13
• These chromosomes carry far fewer protein-encoding genes than the other autosomes