What makes a mutant?

Mutation is a change in the normal National Cancer Institute Understanding Cancer and Related Topics Understanding Cancer Genomics Mutations Mutation is a change in the normal base pair sequence All mutations are changes in the normal base sequence of DNA. These changes may occur in either coding or noncoding regions. Mutations may be silent and have no effect on the resulting protein. This is especially true if they occur in noncoding regions of the DNA. But even base pair changes in the coding region may be silent because of the redundancy of the code. For example, a mutation within a codon may occur, yet still call for the same amino acid as was called for earlier. Mutations may involve a single base change--called a point mutation--or may involve larger sections of DNA through deletions, insertions, or translocations. Commonly used to define DNA sequence changes that alter protein function NCI Web site: http://cancer.gov/cancertopics/understandingcancer

Learning Outcomes Explain the outcomes of mutations What happens when mutations occur in regulatory regions How can we use stem cells DNA structure!

Mutations: Somatic and Germline National Cancer Institute Understanding Cancer and Related Topics Understanding Cancer Genomics Somatic mutations Germline mutations Occur in non-germline tissues Present in egg or sperm Are heritable Are non-heritable Cause cancer family syndrome Most cancers arise from several genetic mutations that accumulate in cells of the body over a person’s lifespan. These are called somatic mutations, and the genes involved are usually located on autosomes (non-sex chromosomes). Cancer may also have a germline mutation component, meaning that they occur in germ cells, better known as the ovum or sperm. Germline mutations may occur de novo (for the first time) or be inherited from parents’ germ cells. An example of germline mutations linked to cancer are the ones that occur in cancer susceptibility genes, increasing a person’s risk for the disease. Non- heritable Mutation in egg or sperm All cells affected in offspring Somatic mutation (e.g., breast) NCI Web site: http://cancer.gov/cancertopics/understandingcancer

Mutations National Cancer Institute Understanding Cancer and Related Topics Understanding Cancer Genomics Definition – random event that causes changes to the genetic organism Think what could happen to DNA …. Point mutations, single base changes in DNA sequences, are the most common type of alteration in DNA. They can have varying effects on the resulting protein. A missense point mutation substitutes one nucleotide for a different one, but leaves the rest of the code intact. The impact of these point mutations depends on the specific amino acid that is changed and the protein sequence that results. If the change is critical to the protein’s catalytic site or to its folding, damage may be severe. Nonsense mutations are point mutations that change an amino acid codon to one of the three stop codons, which results in premature termination of the protein. Nonsense mutations may be caused by single base pair substitutions or by frameshift mutations. NCI Web site: http://cancer.gov/cancertopics/understandingcancer

Gene (point) Mutations National Cancer Institute Understanding Cancer and Related Topics Understanding Cancer Genomics Normal Inversion Insertion Point mutations, single base changes in DNA sequences, are the most common type of alteration in DNA. They can have varying effects on the resulting protein. A missense point mutation substitutes one nucleotide for a different one, but leaves the rest of the code intact. The impact of these point mutations depends on the specific amino acid that is changed and the protein sequence that results. If the change is critical to the protein’s catalytic site or to its folding, damage may be severe. Nonsense mutations are point mutations that change an amino acid codon to one of the three stop codons, which results in premature termination of the protein. Nonsense mutations may be caused by single base pair substitutions or by frameshift mutations. Deletion Substitution NCI Web site: http://cancer.gov/cancertopics/understandingcancer

Abnormal Cell Growth: Oncogenes National Cancer Institute Understanding Cancer and Related Topics Understanding Cancer Genomics Abnormal Cell Growth: Oncogenes Normal genes (regulate cell growth) 1st mutation (leads to accelerated cell division) Most cancers have mutations in proto-oncogenes, the normal genes involved in the regulation of controlled cell growth. These genes encode proteins that function as growth factors, growth factor receptors, signal-relaying molecules, and nuclear transcription factors (proteins that bind to genes to start transcription). When the proto-oncogene is mutated or overregulated, it is called an oncogene and results in unregulated cell growth and transformation. At the cellular level, only one mutation in a single allele is enough to trigger an oncogenic role in cancer development. The chance that such a mutation will occur increases as a person ages. Proto-oncogene to oncogene NCI Web site: http://cancer.gov/cancertopics/understandingcancer

Tumor Suppressor Genes National Cancer Institute Understanding Cancer and Related Topics Understanding Cancer Genomics Tumor Suppressor Genes Tumor suppressor genes Normal genes (regulate cell growth) Tumor suppressor genes 1st mutation (leads to accelerated cell division) Most cancer susceptibility genes are tumor suppressor genes. Tumor suppressor genes are just one type of the many genes malfunctioning in cancer. These genes, under normal circumstances, suppress cell growth. Some do so by encoding transcription factors for other genes needed to slow growth. For example, the protein product of the suppressor gene TP53 is called p53 protein. It binds directly to DNA and leads to the expression of genes that inhibit cell growth or trigger cell death. Other tumor suppressor genes code for proteins that help control the cell cycle. Active oncogene NCI Web site: http://cancer.gov/cancertopics/understandingcancer

Mutations in Tumor Suppressor Genes National Cancer Institute Understanding Cancer and Related Topics Understanding Cancer Genomics Mutations in Tumor Suppressor Genes Tumor suppressor genes Normal genes (regulate cell growth) Tumor suppressor genes Active oncogene 1st mutation (susceptible carrier) No brakes! 2nd mutation or loss (leads to cancer) Both copies of a tumor suppressor gene must be lost or mutated for cancer to occur. A person who carries a germline mutation in a tumor suppressor gene has only one functional copy of the gene in all cells. For this person, loss or mutation of the second copy of the gene in any of these cells can lead to cancer. No brakes! Active oncogene NCI Web site: http://cancer.gov/cancertopics/understandingcancer

Model Organisms Scientists want to study cancers. Which model would you choose? Why?

Model Organisms Biological characteristics are similar to those of related organisms Scientists want to study cancers, to prevent/ or try to understand how they grow for drugs to suppress. Use stem cells instead

Use of stem cells Leukaemia and lymphoma treated by bone marrow cells called haemopoetic stem cells. Skin graft , from getting skin stem cells close to site and then regenerated – spray on cells Cornea repairs, stem cells from edge of cornea are scaffold to frame and then can be implanted without risk of rejection

Ethical Concerns Ethics refers to the moral value and rules that ought to govern human conduct. Removing cells from embryo (no more than 14days) results in the destruction of the embryo. Is an embryo of less than 2 weeks a human?

Regulation Keeps quality and safety uses of embryos

Review - What is the difference between haploid and diploid? What is a germline cell? Briefly describe how a diploid germline cell produces haploid gametes Which type of cell (somatic or germline) is a mutation not passed on to the members of the next generation?