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Chapter 12: Genomes, mutation and cancer Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-1 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-2 Table 12.1: Genome sizes Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-3 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.) Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-4 Fig. 12.4: Some types of sequences found in a human chromosome Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-5 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-6 Fig. 12.5: Sequences in genomic DNA Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-7 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-8 Fig. 12.6: Relative amounts of DNA sequences in the human genome Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-9 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-10 Fig. 12.7: The cluster of β-globin genes found on human chromosome 11 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-11 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-12 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-13 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) Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-14 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.) Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-15 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-16 Fig. 12.9a: Substitution Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-17 Fig. 12.9b: Insertion Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-18 Fig. 12.9c: Deletion Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-19 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-20 Fig. 12.10a: DNA repair mechanisms Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-21 Fig. 12.10b: DNA repair mechanisms Copyright © The Bergman Collection Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-22 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.) Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-23 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-24 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-25 Fig. 12.11a: Mutations in dominant oncogenes stimulate proliferation Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-26 Fig. 12.11b: Mutations in dominant oncogenes stimulate proliferation Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-27 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-28 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-29 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-30 Fig. 12.12a: Normal, healthy individual Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-31 Fig. 12.12b: Hereditary retinoblastoma Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-32 Fig. 12.12c: Non-hereditary retinoblastoma Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-33 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 Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-34 Table 12.2: DNA repair defects cause some human diseases Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-35 Fig. 12.13a: Response of a normal cell to DNA damage Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-36 Fig. 12.13b: Cell lacking p53 gene Copyright 2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 12-37