Slide 1Chromosomes as organelles in cell division and gametogenesis
MD Pertile VCGS Pathology, Royal Children’s Hospital, Parkville, VIC 3052
Chromosomal basis of hereditary
Genetics: A conceptual approach 2002 B A Pearce
DNA and chromosomes Chromosome = “colored body” Gk, chroma + soma [Heinrich Wilhelm Waldeyer 1888]
Each chromosome consists of a single molecule of DNA + histone and non-histone proteins (= chromatin)
Nucleosome is an octomer of histones 2 x [H2A, H2B, H3 and H4]
146-bp DNA + 55-bp DNA assoc. with linker [H1]
DNA and chromosomes
Chromosomes highly condensed during mitosis (10,000-fold compaction)
Chromosomes only visible cytologically during cell division
Chromosome number
• Common aim is faithful passage of DNA into
daughter cells
Mouse karyotype
X & Y sex chromosomes
Centromere Cytologically visible as primary constriction
Typically associated with large arrays of AT-rich repetitive DNA (0.5 - 4.0 Mb in humans)
No DNA sequence conservation b/w species (centromeric chromatin is epigenetically determined)
Site of kinetochore assembly and spindle attachment
Dawe & Henikoff 2006 Trends Biochem Sci 31(12), 662-669
C-banding
Adapted from Santaguida and Musacchio (2009). EMBO J 28: 2511-2531.
Centromeric chromatin
CENPA replaces Histone H3 within the centromere associated nucleosomes
Kinetochore assembles just before and during the early stages of mitosis
Assembles on poleward (CENPA) face and recruits centromere and spindle binding proteins
Mammalian mitotic cell cycle
Cell grows, duplicates DNA and divides into identical daughter cells
Mammalian cell cycle ~20-24 hrs (G1 12 hr, S 7 hr, G2 4 hr, M 1 hr)
Checkpoints ensure fidelity of DNA replication and cell division
cyclin-dependent kinases (CDKs) regulate cell cycle
CDK inhibitors (CKIs) cause cell cycle to halt
Checkpoints demand successful completion of prior phase before next phase proceeds
2n, 2c
2c → 4c
2n, 4c
2n, 2c
2n, 2c
Mitosis Spindle checkpoint proteins avert aneuploidy by delaying anaphase onset until c’somes align
2 identical daughter cells produced from mitotic division
H3-GFP fusion gene in mouse embryonic fibroblast cells
Courtesy Dr. Damien Hudson Chromosome & Chromatin Research Lab, MCRI
Meiosis Specialised cell division that occurs in gonads
C’some replication in S phase is followed by two consecutive cell divisions
Homologous chromosomes pair and recombine during first meiotic division (reduction division 2n→n)
Second meiotic division is similar to mitosis (without S phase)
Produces haploid gametes (4 x n in males and 1 x n in females)
Biology 6th Edition 2001 Raven / Johnson
Reduction division
Recombination during Prophase of Meiosis I Prophase of Meiosis I
Biology 6th Edition 2001 Raven / Johnson
Crossing over visualised as chiasmata (visible in diplotene) Occurs during fetal life in females (14-15 wks pc) At least one ‘obligatory’ chiasma per arm for each pair of homologues
Meiosis I
Meiosis II
Normal meiosis
Maternal MI errors predominate amongst trisomies
In females, first division is initiated prenatally and suspended in dictyotene until ovulation 12-50 yrs later
Second division completed after fertilization
Achiasmate bivalents never engage in genetic recombination and drift independently across metaphase plate [40-50% of all DS conceptions from MI non-disjunction result from achiasmate bivalents; freq similar in younger and older mothers]
Origin of human trisomies
Altered genetic recombination and aneuploidy Significant reductions in recombination found in all MI-derived trisomies studied (T15, 16, 18, 21, XXX & XXY of mat origin & T21 and XXY of pat origin)
Telomeric exchanges contribute to trisomy amongst younger women but less important in older women (bivalents more susceptible to non- disjoin)
Post zygotic errors of chromosome division
Post zygotic non-disjunction or anaphase lag leads to chromosomal mosaicism [normal + aneuploid cells]
Very common in early human conceptions (perhaps 50- 60% of preimplantation embryos)
5% of early miscarriages
May manifest as confined placental mosaicism (CPM), generalised mosaicism, tissue limited mosaicism (e.g. Pallister-Killian syndrome)
Chromosomes as organelles in cell division and gametogenesis
Chromosomal basis of hereditary
Mouse karyotype
Normal meiosis
Post zygotic errors of chromosome division
Slide Number 23