BIOL 23373 - General Genetics Lecture 13 - Mutation & Repair I (FALL 2024) PDF

BIOL 23373 – General Genetics Fall 2024 Lecture 13 Mutation & Repair I Announcements Bonus Quiz 4 (available after today’s class) is due before class on Monday, Sept. 23. Exam 1 (Friday, Sept. 13). You should be able to view your submission and the a...

BIOL 23373 – General Genetics Fall 2024 Lecture 13 Mutation & Repair I Announcements Bonus Quiz 4 (available after today’s class) is due before class on Monday, Sept. 23. Exam 1 (Friday, Sept. 13). You should be able to view your submission and the answers. Don’t forget that you get to drop your lowest exam score among the four hour exams and the final exam. If you want to meet (in person or via Zoom), email me 3 or 4 meeting day/time options. Tutoring Tutoring @ the CORD offers 1-on-1 and small group assistance in over 100 U of A courses. Students can meet with tutors in person or online by scheduling an appointment or accessing drop-in services. Learn more about Tutoring services and book an appointment at: https://success.uark.edu/academic-initia tives/tutoring.php Corresponding Readings Chapter sections: 15.1-15.7 Mutations Generate Variation Mutations are heritable changes in the DNA sequence of the genome Parent cell to daughter cell during cell division Parent to offspring during reproduction Mutation generates alleles (new variants of genes) Mutations provide variation on which natural selection can act Spatiotemporal Effects of Mutation The timing and location of a mutation determines its severity and the heritability Germ-line cells: can be passed on to offspring via gametes Somatic cells: patches of cells with mutation (mosaicism) Mutations Are Random Mutations occur randomly (time & place) Every organism carries mutant alleles whether they manifest in distinct phenotypes or not What effect a mutation has depends largely on when and where the mutation occurs Most mutations are silent or neutral and have no effect on fitness, but some may have a slightly deleterious (negative) effect and a few may be lethal 7 Mutations are Rare Mutations occur in every generation Average human rate is 0.000000021 mutations per site per generation (very small) Humans acquire ~70 new mutations each generation 2.1 x 10-8 per site per generation * 3.2 x 109 sites in genome = 67.2 mutations per genome per generation Most come from the father (~75%) and it increases with age. Mutation Frequency In bacteria and other haploid organisms, mutation frequency is measured as the number of times mutation alters a particular gene Mutation frequency is defined and studied differently in sexually reproducing diploids (e.g., many eukaryotes) Defined as the number of mutational events in a given gene over a defined period of time (most often per DNA replication cycle or per generation) 9 Study of Mutation Frequency Dominant mutations are easier to detect than recessive mutations and are thus easier to study Mutation frequencies differ considerably among organisms, but are low in all genomes Mutation frequencies vary among genes within a single species 10 Variation in Mutation Frequency Each species has an average mutation frequency Rates are low, but highly variable among species On average, species with larger genomes have higher mutation frequencies Within species, genomic regions vary in mutation rate Regions with elevated mutation frequencies are called mutation hotspots Mutation hotspots are often associated with large gene sizes 11 Gene Mutations Modify DNA Sequence Gene mutations substitute, add, or delete one or more DNA base pairs Localized mutations, or point mutations, occur at a specific, identifiable position in a gene Such mutations have varying consequences depending on the type of sequence change and the location of the affected part of the gene e.g., coding, non-coding, regulatory, etc. 12 Base-Pair Substitution Mutations Base-pair substitution mutation: replacement of one nucleotide base pair by another Two categories: Transition mutations: one purine replaces another purine, or one pyrimidine replaces another pyrimidine A-G or G-A; C-T or T-C Transversion mutations: a pyrimidine is replaced by a purine or vice versa A-C, A-T, G-C, G-T, C-A, T-A, C-G, T-G Transitions are more common than transversions 13 Consequences of Base-Pair Substitution Mutations in Coding Sequence Silent mutation: a base-pair change that does not alter the resulting amino acid sequence due to the redundancy of the genetic code (synonymous substitution) No change to protein 14 Consequences of Base-Pair Substitution Mutations in Coding Sequence Missense mutation: a base-pair change that results in an amino acid change in the protein (nonsynonymous substitution) Likely to change protein; severity depends on amino acid chemistry and location within protein 15 Consequences of Base-Pair Substitution Mutations in Coding Sequence Nonsense mutation: a base-pair change that creates a stop codon in place of a codon specifying an amino acid Produces a truncated polypeptide; probably not functional 16 Frameshift Mutations in Coding Sequence Insertion or deletion (indel) of one or more base pairs leads to addition or deletion of mRNA nucleotides, altering the reading frame These are called frameshift mutations The wrong amino acid sequence and premature stop codons are produced downstream of the indel site Results in wrong protein with uncertain effect (usually bad) 17 Regulatory Mutations Some point mutations alter the amount (but not the amino acid sequence) of protein product produced by a gene via altering gene expression These regulatory mutations affect regions such as promoters, introns, 5-UTRs, and 3-UTRs 18 Promoter Mutations Mutations that alter consensus sequence nucleotides of promoters are called promoter mutations These mutations interfere with initiation of transcription and may cause mild to moderate reductions in transcription levels or even prevent it 19 Splicing Mutations Efficient splicing of introns from mRNA requires specific sequences at 5’ and 3’ ends of the intron Mutations that alter these nucleotides are called splicing mutations These can result in splicing errors and the production of mutant proteins due to the retention of intron sequence in the mRNA 20 21 Cryptic Splice Sites Some base-pair substitution mutations produce new splice sites that replace or compete with authentic splice sites during mRNA processing These are called cryptic splice sites 22 Mutations can be Classified by their Effect Mutations can be: beneficial (good), neutral, or deleterious (bad) in terms of survival and reproductive success (natural selection) Loss-of-function mutation: function of gene product is reduced or lost Complete loss of function = null mutation Effect could be neutral if other allele is functional and makes enough product (haplosufficient) Effect could be negative if not enough product is made by the other allele (haploinsufficient) Gain-of-function mutation: gene product with enhanced or new function Effect could be positive if new function is beneficial, but could be negative if too much gene product is made 23 Forward Mutation and Reversion Forward mutation: converts a wild-type allele to a mutant allele Reverse mutations or reversions or suppressor mutations: convert mutant alleles to wild-type or near wild-type Multiple types of reversions 24 Types of Reversion True reversion: wild-type DNA sequence is restored by a second mutation within the same codon 25 Types of Reversion Intragenic reversion: occurs through mutation elsewhere in the same gene 26 Types of Reversion Second-site reversion: occurs by mutation in a different gene and together the two mutations restore the organism to wild-type 27 X