Chapter 16 - Variations in Chromosome Structure and Function:

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• Chapter 16 - Variations in Chromosome Structure
  and Function
• Chromosome structure
• Deletion, duplication, inversion, translocation
• Focus of Cytogenetics
• Chromosome number
• Aneuploidy, monoploidy, and polyploidy.

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• Chromosomal mutations
• Arise spontaneously or can be induced by
  chemicals or radiation.
• Major contributors to human miscarriage,
  stillbirths, and genetic disorders.
• 1/2 of spontaneous abortions result from
  chromosomal mutations.
• Visible (microscope) mutations occur in 6/1,000
  live births.
• 11 of men with fertility problems and 6 of men
  with mental deficiencies possess chromosomal
  mutations.

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• Chromosomal structure mutations
• Deletion
• Duplication
• Inversion - changing orientation of a DNA segment
• Translocation - moving a DNA segment

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• Studying chromosomal structural mutations
• Polytene chromosomes
• Occur in insects, commonly in flies (e.g.,
  Drosophila).
• Chromatid bundles that result from repeated
  cycles of chromosome duplication without cell
  division.
• Duplicated homologous chromosomes are tightly
  paired and joined at the centromeres.
• Chromatids are easily visible under the
  microscope, and banding patterns corresponding to
  30 kb of DNA can be identified.

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• Chromosomal structural mutations - deletion
• Begins with a chromosome break.
• Ends at the break point are sticky, not
  protected by telomeres.
• Induced by heat, radiation, viruses, chemicals,
  transposable elements, and recombination errors.
• No reversion DNA is missing.
• Cytological effects of large deletions are
  visible in polytene chromosomes.

Fig. 16.2
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• Chromosomal structure mutations - effects of
  deletions
• Deletion of one allele of a homozygous wild type
  ? normal.
• Deletion of heterozygote ? normal or mutant
  (possibly lethal).
• Pseudodominance ? deletion of the dominant allele
  of a heterozygote results in phenotype of
  recessive allele.
• Deletion of centromere ? typically results in
  chromosome loss
• (usually lethal no known living human has a
  complete autosome deleted).
• Human diseases
• Cri-du-chat syndrome (OMIM-123450)
• Deletion of part of chromosome 5 1/50,000 births
• Crying babies sound like cats mental disability
• Prager-Willi syndrome (OMIM-176270)

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• Deletion mapping
• Used to map positions of genes on a chromosome
  e.g., detailed physical maps of Drosophila
  polytene chromosomes.

• Fig. 16.3, Deletion mapping used to determine
  physical locations of Drosophila genes by Demerec
  Hoover (1936).

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• Chromosomal structure mutations - duplication
• Duplication doubling of chromosome segments.
• Tandem, reverse tandem, and tandem terminal
  duplications are three types of chromosome
  duplications.
• Duplications result in un-paired loops visible
  cytologically.

Fig. 16.5
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Fig. 16.6, Drosophila Bar and double-Bar results
from duplications caused by unequal crossing-over
(Bridges Müller 1930s).
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Unequal crossing-over produces Bar mutants in
Drosophila.
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• Multi-gene families - result from duplications
• Hemoglobins (Hb)
• Genes for the ?-chain are clustered on one
  chromosome, and genes for the ?-chain occur on
  another chromosome.
• Each Hb gene contains multiple ORFs adults and
  embyros also use different hemoglobins genes.
• Adult and embryonic hemoglobins on same
  chromosomes share similar sequences that arose by
  duplication, further maintained by gene
  conversion.
• ? and ? hemoglobins also are similar gene
  duplication followed by sequence divergence.
• Different Hb genes contribute to different
  isoforms with different biochemical properties
  (e.g., fetal vs. adult hemoglobin).

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• Linkage map of human hemoglobins
• In humans, 8 genes total on 2 different linkage
  groups
• ?-chain ?, ?1, ?2
• ?-chain ?, ?G, ?A, ?, ?
• In birds, 7 genes total on 2 different linkage
  groups
• ?-chain ?, D, A
• ?-chain ?, ?, H, A
• The ?-chain genes are ordered in the sequence
  they are expressed.

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Vijay G. Sankaran and Stuart H. Orkin Cold
Spring Harb Perspect Med 2013 doi
10.1101/cshperspect.a011643
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• Chromosomal structural mutations - inversion
• Chromosome segment excises and reintegrates in
  opposite orientation.
• Two types of inversions
• Pericentric include the centromere
• Paracentric do not include the centromere
• Generally do not result in lost DNA.

Fig. 16.7
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• Chromosomal structure mutations - inversion
• Linked genes often are inverted together, so gene
  order typically remains the same.
• Homozygous ADCBEFGH ? no developmental problems
• ADCBEFGH
• Heterozygote ABCDEFGH ? unequal-crossing
• ADCBEFGH
• Gamete formation differs, depending on whether it
  is a paracentric inversion or a pericentric
  inversion.

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Fig. 16.8, Unequal crossing-over w/paracentric
inversion (inversion does not include the
centromere)
Results 1 normal chromosome 2 deletion
chromosomes (inviable) 1 inversion
chromosome (all genes present viable)
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Fig. 16.9, Unequal crossing-over w/pericentric
inversion (inversion includes the centromere)
Results 1 normal chromosome 2
deletion/duplication chromosomes (inviable) 1
inversion chromosome (all genes present viable)
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• Chromosomal structural mutations - translocation
• Change in location of chromosome segment no DNA
  is lost or gained. May change expression
  position effect.
• Intrachomosomal
• Interchromosomal
• Reciprocal - segments are exchanged.
• Non-reciprocal - no two-way exchange.
• Several human tumors are associated with
  chromosome translocations myelogenous leukemia
  (OMIM-151410) and Burkitt lymphoma (OMIM-113970).
  

Fig. 16.10
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• How translocation affects the products of meiotic
  segregation
• Gamete formation differs for homozygotes and
  heterozygotes
• Homozygotes translocations lead to altered gene
  linkage.
• If duplications/deletions are unbalanced,
  offspring may be inviable.
• Homozygous reciprocal translocations ? normal
  gametes.
• Heterozygotes must pair normal chromosomes (N)
  with translocated chromosomes (T) heterozygotes
  are semi-sterile.
• Segregation occurs in three different ways (if
  the effects of crossing-over are ignored)
• Alternate segregation, 50 4 complete
  chromosomes, each cell possesses each chromosome
  with all the genes (viable).
• Adjacent 1 segregation, 50 each cell
  possesses one chromosome with a duplication and
  deletion (usually inviable).
• Adjacent 2 segregation, rare each cell
  possesses one chromosome with a duplication and
  deletion (usually inviable).

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Fig. 16.11, Meiosis in translocation
heterozygotes with no cross-over.
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Variation in chromosome number Organism with
one complete set of chromosomes is said to be
euploid (applies to haploid and diploid
organisms). Aneuploidy variation in the number
of individual chromosomes (but not the total
number of sets of chromosomes). Nondisjunction
during meiosis I or II (Chapter 12) ?
aneuploidy.
Fig. 12.18
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• Variation in chromosome number
• Aneuploidy not generally well-tolerated in
  animals primarily detected after spontaneous
  abortion.
• Four main types of aneuploidy
• Nullisomy loss of one homologous chromosome
  pair.
• Monosomy loss of a single chromosome.
• Trisomy one extra chromosome.
• Tetrasomy one extra chromosome pair.
• Sex chromosome aneuploidy occurs more often than
  autosome aneuploidy (inactivation of X
  compensates).
• e.g., autosomal trisomy accounts for 1/2 of
  fetal deaths.

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Fig. 16.11, Examples of aneuploidy.
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• Variation in chromosome number
• Down Syndrome (trisomy-21, OMIM-190685)
• Occurs in 1/286 conceptions and 1/699 live
  births.
• Probability of non-disjunction trisomy-21
  occurring varies with age of ovaries and testes.
• Trisomy-21 also occurs by Robertsonian
  translocation ? joins long arm of chromosome 21
  with long arm of chromosome 14 or 15.
• Familial down syndrome arises when carrier
  parents (heterozygotes) mate with normal parents.
• 1/2 gametes are inviable.
• 1/3 of live offspring are trisomy-21 1/3 are
  carrier heterozygotes, and 1/3 are normal.

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Fig. 16.18
14
14
21
21
Trisomy Inviable Inviable Inviable Carri
er Normal
Fig. 16.19, Segregation patterns for familial
trisomy-21
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Relationship between age of mother and risk of
trisomy-21
Age Risk of trisomy-21
16-26 7.7/10,000
27-34 4/10,000
35-39 3/1000
40-44 1/100
45-47 3/100
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Trisomy-13 - Patau Syndrome 2/10,000 live
births Trisomy-18 - Edwards
Syndrome 2.5/10,000 live births
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• Variation in chromosome number
• Changes in complete sets of chromosomes
• Monoploidy one of each chromosome (no
  homologous pair)
• Polyploidy more than one pair of each
  chromosome.

Fig. 16.22
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• Variation in chromosome number
• Monoploidy and polyploidy
• Result from either (1) meiotic division without
  cell division or (2) non-disjunction for all
  chromosomes.
• Lethal in most animals.
• Monoploidy is rare in adult diploid species
  because recessive lethal mutations are expressed.
• Polyploidy tolerated in plants because of
  self-fertilization plays an important role in
  plant speciation and diversification.
• Two lineages of plants become reproductively
  isolated following genome duplication, can lead
  to instantaneous speciation.
• Odd- and even-numbered polyploids
• Even-numbered polyploids are more likely to be
  fertile because of potential for equal
  segregation during meiosis.
• Odd-numbered polyploids have unpaired
  chromosomes and usually are sterile. Most
  seedless fruits are triploid.

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