Transcript Chapter 12

Chapter 12: Genomes, mutation
and cancer
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PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint
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Genomes
•
The genome is the sum of all genetic information
encoded in the DNA
– includes nuclear and organelle (mitochondria and
chloroplast) genomes
•
•
•
Genomes vary enormously in size and in the total
number of genes
There is no strict relationship between organism
complexity and gene number
Genomes of related organisms share gene and
organisational structures
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Table 12.1: Genome sizes
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Types of DNA sequences
•
•
•
Coding sequences are found in genes—ultimately
translated into a peptide
A small minority of the genome is coding sequence
—about 2 per cent in mammals
Eukaryotic genes are frequently interrupted by
non-coding introns, which may be much larger
than the protein-coding regions
(cont.)
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Fig. 12.4: Some types of sequences found in a
human chromosome
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Types of DNA sequences (cont.)
•
Non-coding regions include the following
–
–
–
–
–
•
•
5’ and 3’ untranslated regions of genes
enhancer and silencer elements
origins and termini of DNA replication
centromeres and telomeres
ribosomal DNA
Even these sequences account for only a small
proportion of the non-coding DNA
Much DNA is repetitive sequence DNA with no
known function
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Fig. 12.5: Sequences in genomic DNA
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Repetitive DNA sequences
•
•
Microsatellite sequences of single bases, or
dinucleotide or trinucleotide repeats
Intermediate repeated DNA—highly repeated
sequences interspersed throughout genome
– LINEs (long interspersed nuclear elements), e.g. L1 and
THE-1 (transposable human element family)
– SINEs (short interspersed nuclear elements), e.g. Alu
family
•
A number of these repeat-sequence elements are
transposable—their structure allows them to move
within and between genomes
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Fig. 12.6: Relative amounts of DNA sequences in
the human genome
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Gene families
•
Functionally similar genes
• Share sequence homology
• May have arisen by duplication of ancestral gene
• Often clustered (see Fig. 12.7)
• May be on different chromosomes
• Duplication and specialisation of gene family
members is an important part of the evolution of
complexity
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Fig. 12.7: The cluster of β-globin genes
found on human chromosome 11
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Genome maps
•
May be either genetic or physical
• Genetic maps
– based on recombination frequencies between genetic
markers at meiosis
– differences in recombination frequency between markers
can be used to order the markers
•
Physical maps
– use specific sequence sites such as genes to measure
real physical nucleotide distances
– sequence information must be available to provide sites
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Genes and genetic programs
•
Coordinated groups of genes respond to changes
in circumstance
• Genes may be highly conserved across evolution,
with similar genes regulating related processes in
quite different organisms
• Essential and non-essential genes
– genes may not be strictly required for viability under
controlled conditions
– those genes may enhance survival under variable
conditions or be responsible for higher activities such as
behaviour
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Fig. 12.8: (a) Conservation of the sequence of the patched gene in
the vinegar fly, Drosophila melanogaster. (b) The epidermal
structures found in a wild-type (+) Drosophila embryo. (c) Mutation
of the patched gene disrupts formation of the epidermis in the
Drosophila embryo. (d–e) Mutation of the patched gene in humans
also results in developmental defects in the epidermis.
(a)
(b)
(c)
(d)
(e)
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Genetic variation
•
Alterations to DNA sequence are called mutations
• Mutations are the source of genetic variation
• No two genomes are identical (except for identical
twins)
• Although mutations may be harmful, they are also
essential for evolution
• Natural selection acts on phenotypic differences
produced by mutation
(cont.)
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Genetic variation (cont.)
•
Point mutations involve small changes in
sequence
– base substitution
– deletions
– insertions
•
Mutations arise
– during DNA synthesis
– due to environmental mutagens such as radiation or
chemical attack
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Fig. 12.9a: Substitution
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Fig. 12.9b: Insertion
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Fig. 12.9c: Deletion
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Mutagens
•
Electromagnetic radiation may induce breaks in
DNA
– X-rays
– gamma rays
– ultraviolet light
•
Chemicals
– mustard gas cause breaks or misincorporation of bases
– base analogues mimic the normal DNA bases, e.g. AZT
used as an antiviral agent
– DNA-binding compounds interfere with DNA replication,
e.g. ethidium bromide
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Fig. 12.10a: DNA repair mechanisms
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Fig. 12.10b: DNA repair mechanisms
Copyright © The Bergman Collection
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Genomes, mutation and cancer
•
Cancers arise when cells survive, proliferate and
become invasive
• Cancer formation is a sequential process
• A series of mutations causes progressive loss of
cellular controls on growth and death
• Cancer is a genetic disease
– inherited mutations may predispose to cancer formation
– acquired DNA damage leads to mutations in particular
cells
(cont.)
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Genomes, mutation and cancer
(cont.)
•
Two major classes of genes are mutated in cancer
cells
– dominant oncogenes
– tumour suppressor genes
•
•
Oncogenes are mutated normal cellular
proto-oncogenes
The mutation may cause
– over-expression of the gene product
– aberrant activity
– imitation of normal growth and death signals
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Dominant oncogenes
•
Perpetual growth
– the ras oncogene encodes a signal transduction protein
involved in cellular responses to growth factors
– the signals stimulate mitosis and thus increase the
proliferation of cells
– some dominant mutations of Ras cause it to be
constitutively active
– proliferation continues even in the absence of the growth
factor signal
•
Mutations in any of the components in the pathway
will have this effect
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Fig. 12.11a: Mutations in dominant
oncogenes stimulate proliferation
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Fig. 12.11b: Mutations in dominant
oncogenes stimulate proliferation
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Blocking cell death
•
•
•
•
Programmed cell death or apoptosis is an
important component of cell differentiation
Selective death is used to sculpt body tissues and
remove unwanted cells
Oncogenes such as Bcl2 are responsible for
blocking apoptosis
Mutations in Bcl2 keep alive cells that would
normally die
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Tumour suppressor genes
•
Normal genes whose function is lost in tumour
cells
• Inferred by the behaviour of fused cells, where the
normal cell imposes growth regulation on the fused
tumour cell
• Tumour susceptibility is dominant, but both alleles
must be inactivated for tumours to form
• Familial cancers may be due to the inheritance of
one non-functional tumour suppressor allele
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Retinoblastoma
•
Inherited as a dominant familial trait
• Very few cells develop into tumours
• Knudsen proposed the two-hit hypothesis
– susceptibility caused by inheritance of one inactive Rb
allele
– during the person’s life, tumours result when a mutation
inactivated the second Rb allele
– sporadic tumours arise from spontaneous mutation of
both Rb alleles
•
The normal Rb gene is known to repress progress
from G1 into S phase of the cell cycle
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Fig. 12.12a: Normal, healthy individual
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Fig. 12.12b: Hereditary retinoblastoma
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Fig. 12.12c: Non-hereditary retinoblastoma
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Integrity of the genome
•
Many cancers exhibit chromosomal abnormalities
– aneuploidy
– rearrangements
– deletions
•
Some tumour suppressor genes are involved in
– DNA repair (see Table 12.2)
– cell-cycle checkpoint control—if DNA is damaged the cellcycle is arrested until the damage is repaired
•
Mutations in these genes lead to tumours following
DNA damage
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Table 12.2: DNA repair defects cause some
human diseases
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Fig. 12.13a: Response of a normal cell to
DNA damage
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Fig. 12.13b: Cell lacking p53 gene
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