1. 12-1 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Chapter 12: Genomes, mutation and cancer

2. 12-2 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

3. 12-3 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Table 12.1: Genome sizes

4. 12-4 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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.)

5. 12-5 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.4: Some types of sequences found in a human chromosome

6. 12-6 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

7. 12-7 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.5: Sequences in genomic DNA

8. 12-8 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

9. 12-9 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.6: Relative amounts of DNA sequences in the human genome

10. 12-10 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

11. 12-11 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.7: The cluster of β-globin genes found on human chromosome 11

12. 12-12 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

13. 12-13 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

14. 12-14 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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)

15. 12-15 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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.)

16. 12-16 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

17. 12-17 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.9a: Substitution

18. 12-18 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.9b: Insertion

19. 12-19 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.9c: Deletion

20. 12-20 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

21. 12-21 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.10a: DNA repair mechanisms

22. 12-22 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.10b: DNA repair mechanisms Copyright © The Bergman Collection

23. 12-23 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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.)

24. 12-24 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

25. 12-25 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

26. 12-26 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.11a: Mutations in dominant oncogenes stimulate proliferation

27. 12-27 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.11b: Mutations in dominant oncogenes stimulate proliferation

28. 12-28 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

29. 12-29 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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

30. 12-30 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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 G 1 into S phase of the cell cycle

31. 12-31 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.12a: Normal, healthy individual

32. 12-32 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.12b: Hereditary retinoblastoma

33. 12-33 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.12c: Non-hereditary retinoblastoma

34. 12-34 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint 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 cell-cycle is arrested until the damage is repaired Mutations in these genes lead to tumours following DNA damage

35. 12-35 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Table 12.2: DNA repair defects cause some human diseases

36. 12-36 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.13a: Response of a normal cell to DNA damage

37. 12-37 Copyright  2005 McGraw-Hill Australia Pty Ltd PPTs t/a Biology: An Australian focus 3e by Knox, Ladiges, Evans and Saint Fig. 12.13b: Cell lacking p53 gene