another recently discovered example of inequality in gene dosage in mammals'''

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another recently discovered example of inequality
in gene dosage in mammals...

• Genomic Imprinting

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Genomic Imprinting

• In mammals, a small number of genes (40 so far)
  are passed on to the zygote in an inactive form
  embryos therefore inherit only one active gene
• some of these genes are inactivated in the egg
  some in the sperm
• if one parent passes an imprinted gene and the
  other passes a mutation, offspring will show
  mutant phenotype ( e.g. Prader-Willi Syndrome
  maternal imprinting)

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Prader-Willi Syndrome The result of inheriting
deletion on chromosome 15 when the deletion
chromosome is contributed by the male...

• mental retardation
• large appetite/ obesity
• lack of muscle tone (hypotonia)
• short stature small hands and feet
• hypogonadism and infertility

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DISORDER IS USUALLY THE RESULT OF DELETION OF
GENE ON NON IMPRINTED LOCUS

• How is inactivation effected?
• Mechanism is still unclear
• seems to be associated with methylation of DNA
  of the imprinted site this chemical tag may be
  a signal for deactivation/activation
• mechanism of inactivation may share similarities
  to X chromosomal activation...

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Micro-RNAs mediate RNA interference (pp. 665-68
670-72)

• Early 1990s- originally characterized in
  nematodes and associated with control of
  particular genes
• Nobel Prize awarded two years ago to Andrew Fire
  and Craig Mello for their discovery of a process
  through which microRNAs effect control of gene
  expression- RNA interference
• 2000-2005 micro-RNAs identified and
  characterized in numerous organisms
• RNA interference trans-acting single stranded
  micro-RNAs that regulate eukaryotic gene
  expression
• May be derived from introns of protein coding
  transcripts
• May be derived from primary transcripts devoid of
  ORFs
• Number of miRNAs may exceed the number of
  protein coding genes

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Micro-RNAs mediate RNA interference.

• miRNAs distinguished by 60-120 ribonucleotide-long
  segments of reverse sequence complimentarity
  will snap back spontaneously into hairpin
  stem-loop structures.
• Involved in posttranscriptional regulation and
  trans acting transcription factors
• Provides a method for development of powerful new
  RNA-based therapies for treatment of diseases.

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Examples of Primary Transcripts containing micro
RNAs
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Micro-RNA processing and modes of action

• Immediately after transcription, pri-miRNAs are
  recognized by enzyme which crops
• out pre-miRNA stem loops from larger RNA.
• Pre-miRNAs undergo active transport from nucleus
  to cytoplasm where they are recognized by
  enzyme Dicer
• Dicer reduces the pre-miRNA into a short-lived
  miRNAmiRNA duplex which is released and picked
  up by RISC.

Fig. 18.18a
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Two modes of RNAi translational interference

• If miRNA and its target mRNA contain perfectly
  complementary sequences, miRISC cleaves the mRNA.
  RNase rapidly degrades cleavage product.
• If miRNA and its target mRNA have only partial
  complementarity, cleavage does not occur. miRISC
  remains bound to its target and represses its
  movement across ribosomes.

There are probably other potential modes of RNAi
translational repression
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RNA silencing can also occur at the level of
Transcription
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Aberrations due to Variations in Chromosome
Number (ch. 13)
Sources of Chromosomal Aneuploidy nondisjunction
(e.g during meiosis)
n 1
n - 1
Aneuploidy Additions or losses of parts of the
genome
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Abnormalities in mitotic segregation can also
occur during embryogenesis...
e.g. Chromosomal Loss
2n
2n-1
Abnormal segregation could lead to an embryo
mosaic for chromosomal aneuploidies
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• Turner Syndrome 45X
• frequency about 1/5,000 live female births, but
  the most frequent abnormality seen in abortuses
• short stature
• webbed neck arms held at a characteristic angle
• prepubescent secondary sexual characteristics,
  sterile
• usually normal intelligence, but may show some
  space/form blindness

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Why does 45, X lead to abnormal development?

• X inactivation
• there must be a counting and inactivation
  mechanism (Xce and XIST in XIC Xq13)
• X inactivation center (XIC) Xce which X is
  active?
• XIST gene in XIC involved in inactivation (RNA)
• transcription from inactive XRNA binds to
  chromosome
• methylation of DNA associated with inactivation
  (c.f. genomic imprinting)
• not all of X is inactivated
• region of Xp expressed from both X chromosomes
  (pseudoautosomal region also RPS4, near XIST)

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• Klinefelter Syndrome 47 XXY
• frequency about 1/1,000 male births
• taller than normal
• gynecomastia (enlarged breasts in 20 of cases)
• usually sterile
• often show mildly depressed intelligence

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Double Y Syndrome

• Karyotype 47, XYY frequency about 1/1000 male
  births
• tend to be tall, but are otherwise
  phenotypically normal normally fertile with
  offspring of normal karyotype
• an elevated incidence of this syndrome among
  incarcerated prisoners raised the speculation
  that this syndrome was associated with violent
  behavior
• further studies suggest that those imprisoned
  with the syndrome were not charged with violent
  crimes
• slightly depressed intelligence or social
  factors may lead to greater likelihood for
  incarceration?

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Autosomal Aneuploidies 47, 21 Down Syndrome

• The most common of the autosomal aneuplodies
  frequency of approximately 1/800 births
• hypotonia lax musculature
• epicanthic eyefolds slanting eyes
• large tongue, small arched palate
• unusual dematoglyphics (ridges, palm creases)
• congenital heart defects
• mental retardation

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• Trisomy 13 Patau Syndrome
• Frequency much rarer than Down Syndrome
  2/10,000 births
• cleft lip and palette
• cardiac abnormalities
• polydactyly (additional digits)
• severe mental retardation
• death usually by 3 months

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• Trisomy 18 Edwards Syndrome
• Frequency much rarer than Down Syndrome
  2-3/10,000 births
• about 80 are female
• multiple congenital problems, often cardiac
  problems
• low-set, malformed ears
• severe mental retardation
• death occurs usually within the first 6 months

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Structural Chromosomal Polymorphisms
Population polymorphisms that do not lead to
clinical problems are often associated with
constitutive heterochromatin
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• Clastogen substance that can introduce
  chromosome breakage
• chemicals
• ionizing radiation
• some viruses

Abnormal ends tend to undergo fusion or
repair...
Breakage-fusion-bridge cycle...
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Reciprocal Translocations suppose breaks and
fusions occur in nonhomologous chromosomes...
Balanced translocations
Acentric and dicentric chromosomes
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Translocation heterozygote
Alternate segregation will produce balanced
gametes...
Adjacent segregation causes duplications and
difficiencies in gametes...
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Breaks occur to either side of centromere in
centromeric heterochromatin...
Long arms of two acrocentrics joined together
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Ideogram of human and chimpanzee genomes
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Translocation heterozygote
Normal gamete translocation gamete
Missing 21 (aborted) duplication for 21
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Translocation Down Syndrome
Carrier is normal in phenotype
Progeny has heritable form of Down Syndrome