Molecular Biology II Molecular Medicine 1 - Genome RearrangementsLecture 28[Page 1]Chromosomal Abnormalities:Traditionally, only large gains/ losses could be detected (>4Mbp)Now smaller changes can be detected ² molecular cytogenetics and FISH detectionMost abnormalities are due to:
Broken chromosomes
Improper recombination
Mal-segregation during mitosis / meiosis
Fertilisation & early development errorse.g. polyploidy
p
Multiplex FISH (Fluorescent In Situ Hybridisation):Used to visualise chromosomesChromosome Painting:3 fluorochromes are used in different combinations to give many coloursChromosome specific probes are used
each with a different colour If 2 colours are seen on one chromosome
then chromosome translocation has taken place
Molecular Biology II Molecular Medicine 1 - Genome RearrangementsLecture 28[Page 2]Chromosomal Abnormalities:
Constitutive abnormality ² all cells, occurs early in development e.g. fertilisation
Somatic abnormality ² mosaic
Numerical - Triploidy (~2% conceptions)- Tetraploidy (four sets of chromosomes, lethal ² unless on X chromosome)- Trisomy (one extra chromosome, survival rates depend on chromosome)
o
D
own syndrome (trisomy 21) ² can survive longer -
Nullisomy (missing chromosome, embryonic lethal)
D
eletions, inversions, duplications, insertions
Unequal parental contribution (rare)
o
¶
male-driven· evolution
p
driven by abnormalities in sperm
o
More divisions in sperm formation,
o
mutations in sperm
Many diseases and syndromes are involved with chromosomal abnormalitiesSmall-scale Mutations:
Nucleotide substitution (synonymous / silent), deletions, insertions
Protein polymorphisms
E
xpression polymorphisms
Single nucleotide polymorphisms (SNPs)
Restriction site polymorphisms1.5% human genome is coding, 3-4% is regulatory
E
rror rate in
D
NA replication is ~10
-10
before correctionA coding gene is ~1.65kb on average
@
1.65 x 10
-7
mutations / gene / division10
16
mitotic cycles in a human lifetime, 10
9
mutations will occur within coding genes in a lifetimeMost will only affect one cell, so inconsequential for the organism (apart from cancer)Larger-scale Mutations:
V
ariable Number Tandem Repeats (
V
NTR) polymorphisms
o
Simple - Rarely in genes or regulatory sequences but can affect expression- Microsatellites (1-9nt long, overall length ~100)- Minisatellites (9-10nt long, overall length ~100s)
o
Large scale - -satellite repeats, rRNA
Transposition repeat polymorphisms
o
LINE,
Alu
,
LTR-based
Oft
e
n involv
ed
in
DNA
e
xch
a
ng
es
a
n
d
in
s
t
ab
ility
Molecular Biology II Molecular Medicine 1 - Genome RearrangementsLecture 28[Page 3]Repeated
D
NA leads to pathogenesis:
Tandem Repeat Mutation
E
xample
V
ery short repeats in genes
D
eletion / frameshift Slipped strand miss-pairing (SSM)Moderate sized intergenic repeats Intra-genic deletion Unequal cross-over Partial / total gene deletion Unequal cross-over Large tandem repeats of whole genes Altered gene sequence / gene conversion Allele conversionInterspersed Repeats Mutation
E
xampleShort direct repeats
D
eletion SSM / recombinationInterspersed repeats (e.g. Alu)
D
eletion / duplication U
E
C / U
E
SC
E
Inverted repeats Inversion Intrachromosomal exchangeActive (retro-) transposons Intragenic insertion
Genetic Mechanisms for Sequence
E
xchange:Replication slippage / slipped strand miss-pairing
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