Genetic Mutations Good, bad or neutral?

Mutations Inheritable errors made in DNA during replication 3 broad groups: Beneficial Deleterious Neutral Most mutations are neutral, either because they occur in introns, or because of the redundancy inherent in our genome

Mutations Mistakes in the DNA sequence can alter the function of proteins produced Diploid organisms have two copies of each gene so error may be masked in the phenotype

Causes of Mutations 1) Spontaneous mutations (copying errors) 2) Induced mutations (exposure to mutagens)

Spontaneous Mutations Occur under normal conditions. Caused by errors during DNA replication that are go uncorrected May involve mispairing during replication Can also be caused by errors made during crossover in meiosis

Induced Mutations: 2 kinds of mutagens: Physical mutagens physically damage DNA strands (X-rays, UV light) Chemical mutagens alter the molecular structure of DNA without damaging it physically (carbon monoxide, ethidium bromide) Note: mutagens that also cause cancer are called carcinogens

Environmental Causes of Mutation

Physical Mutagens For example, radiation

Causes of Genetic Mutations Cancer is a genetic disease because it is always a result of a mutation in the genetic sequence. Mutations result in oncogenes - genes that control cell growth and division. Cancer

Categories of Mutations 1. Point mutations Mutations at a specific base pair on the genome 2. Chromosomal mutations One DNA fragment is moved from one site on the genome to another

Types of DNA Replication Errors: Small scale, point mutations effect only a small group of base pairs: Substitution Insertion or deletion Inversion http://www.youtube.com/watch?v=kp0esidDr-c

Analogy: Split this sentence into codons! Thesunwashotbuttheoldmandidnotgethishat. It should look like this... The sun was hot but the old man did not get his hat. What if we substituted one of the letters?

Substitution Analogy: The sun was hot but the old man did not get his hat. The son was hot but the old man did not get his hat. The bun was hot but the old man did not get his hat.

Mutations: Substitutions Substitution: TAG CAT GAG Becomes TCG CAT GAG = Similar protein with one different A.A

Mutations: Substitutions Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons Pro-Glu-Glu-Cys-Gly Amino acids Substitution mutation GGTCACCTCACGCCA ↓ CCAGUGGAGUGCGGU Pro-Arg-Glu-Cys-Gly Substitutions will only affect a single codon Their effects may not be serious unless they affect an amino acid that is essential for the structure and function of the finished protein molecule (e.g. sickle cell anaemia)

The genetic code is degenerate A mutation to have no effect on the phenotype Changes in the third base of a codon often have no effect. (The wobble hypothesis) © 2010 Paul Billiet ODWS

No change Normal gene Substitution mutation GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons Pro-Glu-Glu-Cys-Gly Amino acids Substitution mutation GGTCTTCTCACGCCA ↓ CCAGAAGAGUGCGGU Pro-Glu-Glu-Cys-Gly © 2010 Paul Billiet ODWS

Disaster Normal gene Substitution mutation GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons Pro-Glu-Glu-Cys-Gly Amino acids Substitution mutation GGTCTCCTCACTCCA ↓ CCAGAAGAGUGAGGU Pro-Glu-Glu-STOP © 2010 Paul Billiet ODWS

Mutations: Insertions Addition: TAG CAT GAG becomes TTA GCA TGA G

Analogy: Split this into codons! Thesunwashotbuttheoldmandidnotgethishat. It should look like this... The sun was hot but the old man did not get his hat. What if we added an extra letter?

Analogy: Insertion Split this sentence into codons: Thesunwashotbuttheoldmandidnotgethishatt. Does this sentence still make sense? The sun was hot but the old man did not get his hat t.

Analogy: Insertion Split this sentence into codons: Theesunwashotbuttheoldmandidnotgethishat. Does this sentence still make sense? The esu nwa sho tbu tth eol dma ndi dno tge thi sha t.

Mutations: Additions A frame shift mutation Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons Pro-Glu-Glu-Cys-Gly Amino acids Addition mutation GGTGCTCCTCACGCCA ↓ CCACGAGGAGUGCGGU Pro-Arg-Gly-Val-Arg © 2010 Paul Billiet ODWS

Mutations: Deletions Deletion: TAG CAT GAG Becomes TGC ATG AG A

Analogy: Split this into codons! Thesunwashotbuttheoldmandidnotgethishat. It should look like this... The sun was hot but the old man did not get his hat. What if we removed a random letter?

Analogy: Insertion Split this sentence into codons: Thesunwashotbuttheoldmandidnotgethisht. Does this sentence still make sense? The sun was hot but the old man did not get his ht.

Analogy: Insertion Split this sentence into codons: Heesunwashotbuttheoldmandidnotgethishat. Does this sentence still make sense? Hes unw ash otb utt heo ldm and idn otg eth ish at.

Mutations: Deletions A frame shift mutation Normal gene GGTCTCCTCACGCCA ↓ CCAGAGGAGUGCGGU Codons Pro-Glu-Glu-Cys-Gly Amino acids Deletion mutation GGTC/CCTCACGCCA ↓ CCAGGGAGUGCGGU Pro-Gly-Ser-Ala-Val © 2010 Paul Billiet ODWS

Inversion: AUG UUU UUG CCU UCC UUG UUU GUA Two adjoining base pairs or entire chromosomal segment reverses its orientation. Gene control is affected.

Inversion The reversal of a segment of DNA within a chromosome. No gain or loss of genetic information. A gene may be disrupted.

Translocation Characterized by relocation of groups of base pairs from one place in the genome to another. “Jumping genes” are called Transposable elements.

Translocation The transfer of a fragment of DNA from one site in the genome to another location. Usually occurs between two nonhomologous chromosomes. Result is a fusion protein with an altered function

Transposable Elements Also known as “jumping genes”. Certain fragments of DNA consistently move from one location to another. If they are added to a coding region of a gene, it will leave it inactive.

Effects of DNA Mutations Single point mutations in the population cause genetic variations in individuals called SNPs (single nucleotide polymorphisms) They are very common and variable in non-coding portions of the genome Why?

Effects of DNA Mutations As you can see, the type of error can have very different effects on protein production. Mutations can be categorized into 4 groups: Silent mutations Missense mutations Nonsense mutations Frame shift mutations

Examples: Regular DNA Strand Genetic code as inherited from parents:

1) Silent Mutations Due to the wobble effect, this base pair change has no effect on the amino acid produced

Silent Mutation Does not result in a phenotypic change. Primarily occurs in the introns. Could be due to redundancy of genetic code e.g. phenylalanine coded for by UUU and UUC…a change in the 3rd base does not change the amino acid.

2) Missense Mutations Point mutation produces a different amino acid in the polypeptide chain Can be neutral, harmful or beneficial

Substitutions: Missense Mutation A single substitution of one base in a codon, resulting in a different amino acid. E.g., Sickle cell anemia.

Sickle Cell Anaemia Sickle cell anemia Blood smear (normal) Image Credit: http://explore.ecb.org/ Blood smear (normal) Image Credit: http://lifesci.rutgers.edu/~babiarz/

3) Nonsense Mutations Point mutation produces a premature STOP codon rather an amino acid Protein produced is usually non-functional

4) Frameshift Mutations Insertion or deletion shifts the entire reading frame of the codons, usually resulting in different amino acids being incorporated from that point onwards. Eg. Tay sachs

Frameshift Mutation Causes changes in the reading frame. Caused by an insertion: Addition of one or more base pairs in a DNA sequence. Caused by a deletion: Removal of one or more base pairs in a DNA sequence.

Question: Why would the deletion of 3 nucleotides be better then 2?

Review of Mutation Effects: