chromosomal mutations

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chromosomal mutations

• Chromosomal mutations
• Changes in chromosome number
• Changes in chromosome structure
• Chromosome testing
• Karyotyping
• High resolution analysis
• Postnatal genetic testing

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I. Chromosomal Mutations

• possibly affecting more than one gene (multi-gene
  level)
• Changes in NUMBER
• Monoploid number (2n 1)
• Euploidy (multiples of n)
• Polyploid (3n, 4n, 5n)
• Triploid, tetraploid, pentaploid, hexaploid

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1. Polyploidy

• Usually lethal in mammals
• Does occur in some animals - Reproduction via
  parthenogenesis, Flatworms, leeches, brine
  shrimp, lizards, salamanders, salmonids

Polyploidy in plants much more common because
it can be tolerated by plants, can reproduce
asexually Important role in the evolution of
plants wheat 2n 14, 28, 42 chrysanthemum
2n 18, 36, 54, 72, 90
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sympatric speciation e.g. polyploidy in plants..

• Autopolyploidy due to meiosis error. Offspring
  can self fertilize.
• Allopolyploidy
• 2 different species mating, produce a hybrid that
  is polyploid
• The hybrid is fertile because the polyploid
  condition provides the homologous chromosomes
  for pairing during meiosis

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Endopolyploidy

• only certain cells in the organism are polyploid
• Liver cells, plant tissue (stem),
• larval gut tissue (mosquitos)

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2. Aneuploidy the total is not an exact
multiple of a set(2n /- x)

• Caused by Nondisjunction failure of normal
  chromatid division during meiosis, two
  chromosomes go to one pole, none in the other.
• Results in the wrong number of chromosomes.
• Results in a gene imbalance

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Fertilization of one of these affected gametes
produces a zygote w/ either 3 members (trisomy)
or only one member (monosomy) of the chromosome.
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gene imbalance - THE problem

• Aneuploids are more abnormal than polyploids,
  why? (polyploid plants are completely viable and
  usually bigger, whereas in Drosophila the only
  aneuploids that survive are trisomics and
  monosomics for chromosome 4, the smallest
  chromosome)
• Normal physiology of a cell depends on the proper
  ratio of gene products in the euploid cell.
• The amount of expression is correlated with the
  number of genes in a cell
• If 3 copies present 150 of the normal amount
  of protein will be made
• If 1 copy present 50 of the normal amount of
  protein will be made

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Nondisjunction responsible for Turners syndrome
and Kleinfelters syndrome Turners syndrome
produces sterile females with a normal of
autosomes and 1 X chromosome (XO). These are the
only human monosomics that survive Klienfelters
syndrome individuals are trisomic XXY, they are
sterile males that are typically tall, and thin
and some degree of mental retardation. XYY
trisomic males have mild mental retardation
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Aneuploid Conditions in Humans
Inherited disorders associated with aneuploidy.
Trisomies and variations in the sex chromosomes
result in mental retardation, organ defects,
sexual immaturity, etc.
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Trisomy 21, abnormal creases
Trisomy 18, diaphragmatic hernia
Turners syndrome, developmental abnormality
polydactyly
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Why is monosomy so bad?

• Monosomics for all human autosomes die in utero
• Any deleterious recessive alleles present on
  monosomic autosome will be automatically expressed

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B. Changes in chromosome structure

• A) Deletions
• B) Duplications
• C) Inversion
• D) Translocation

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Deletion loop
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1. Deletions

• Spontaneous breakage and rejoining
• Interstitial deletion
• Terminal deletion
• Crossing over between repetitive DNA

Region w/centromere usually maintained during
division, the other part will be lost
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Multigenic deletions

• If both homologs have the same deletion then it
  will be lethal
• If only on one homolog, the deletion can
  uncover lethal recessives in the heterozygous
  condition
• Psuedodominance when recessive alleles are
  expressed due to a deletion event

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partial monosomy
Caused by a heterozygous deletion of the tip of
the p arm of chromosome 5 phenotype
distinctive cat-like cry made by infants,
microencephaly moon-like face
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2. Duplications

• Extra copy of some particular region Rare, and
  difficult to detect
• Usually due to unequal crossing over during
  meiosis, or through replication error prior to
  meiosis
• Not as problematic as deletions, but some
  problems are associated
• Bar eye in Drosophila (gene imbalance)

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3. Inversions

• Region breaks, rotates 180 degrees and rejoins
• Generally viable, and show no abnormalities at
  the phenotypic level

Paired homologs form an During synapsis, one
chromosome must twist into a loop to pair up
w/the genes on the other
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Types of inversions
1) Paracentric centromere outside of the
inversion Cross over products dicentric and
acentric chromosome 2) Paricentric inversion
spans centromere Cross over products
duplication, and deletion
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During meiosis, homologs still pair up, even
w/inversions -Inversion loop makes this possible
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Crossing over produces affected
chromatids Duplication Deletion events
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4. Translocation-movement of chromosomal
fragments to a new location.

• Semisterility an organism that is heterozygous
  for a reciprocal translocation usually produces
  about half as many offspring as normal
• due to difficulty in chromosome segregation in
  meiosis.
• Translocation cross because of the
  translocations, the pairing of homologous regions
  leads to the unusual structure that contains four
  pairs of sister chromatids.

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• Nonreciprocal translocation (unbalanced)
• Centromeric regions of two nonhomologous
  acrocentric chromosomes become fused to form
  single centromere.

-Down Syndrome chromosome 21 14 rearrangement
leads to familial Down Syndrome. The
heterozygote is normal, the 3 chromosomes must
separate during meiosis (only 2/6 are normal, the
rest either monosomic or trisomic)
-Cancer (CML) type of leukemia, translocation
between chromosome 9 22, leads to the movement
of a gene where it will be overexpressed
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Fragile sites susceptible to breakage

• Fragile X syndrome
• Most common form of inherited mental retardation
  (1/4000 males, 1/8000 females)
• FMR1 gene, has several trinucleotide repeats CGG
  in the 5UTR region
• Normal individuals 6 to 54 repeats
• Affected individuals gt230 repeats, region
  becomes modified (bases are highly methylated
  gene NOT expressed)
• Link between fragile sites cancer
• Chromosome 3 FRA3B region, FHIT gene often
  altered or missing in tumor cells taken from
  individuals w/ cancer

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II. Chromosome Testing

• Chromosomes
• Karyotyping
• High resolution chromosome analysis

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A. karyotyping

• adding a dye to metaphasic chromosomes different
  dyes that affect different areas of the
  chromosomes are used for a range of
  identification purposes.
• Giemsa dye is effective because it markedly
  stains the bands on a chromosome Each chromosome
  can then be identified by its banding pattern
• Amniocentesis
• Chorionic Villi Biopsy

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Prenatal genetic testing cont.

• Maternal Serum Amniotic fluid
• Alpha-fetoprotein (AFP)
• Unconjugated estriol (uE3)
• Dimeric inhibin A (DIA)
• Fetal cell sorting

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B. High resolution chromosome analysis

• SKY uses probes. Each of the individual probes
  complementary to a unique region of one
  chromosome - together, all of the probes make up
  a collection of DNA that is complementary to all
  of the chromosomes within the human genome.
• Each probe is labeled with a fluorescent color
  that is designated for a specific chromosome..
• the probes hybridize, the fluorescent probes
  essentially paint the full set of chromosomes,
  can be analyzed to determine whether any of them
  exhibits translocations or other structural
  abnormalities.

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2) In situ hybridization used to map specific
deletions insertions
No binding, 13.1-13.3 deleted
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(FISH) analysis of a normal individual (D) and
patient with a chromosome 22 deletion using a
probe for the UFD1 gene. The patient has only one
copy of UFD1 seen in blue (white arrows).
Chromosome 22 was labeled with a red fluorescent
marker (yellow arrows).
http//www.ggc.org/clinical.htm