Mutation and its consequences. Notes at: tcd.ie/biology_teaching_centre/local/ junior-freshman/ by1101local

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1 Lecture 7 Mutation and its consequences CAMPBELL BIOLOGY Notes at: tcd.ie/biology_teaching_centre/local/ junior-freshman/ by1101local Natural variants and mutants 1. Genetic analysis would not be possible without the existence of natural variants: individuals that differ in the phenotypic expression of a given trait e.g. tall vs dwarf 2. Evolution would also not be possible without variants 3. Variants are sometimes referred to as mutants especially if they have been deliberately produced in the laboratory 4. How do variants or mutants arise? changes in the genetic information (DNA) that occur due to a process called mutation 1

2 Classification of Mutants Some Examples 1. Auxotrophs Nutritional Mutants (see lecture 6) e.g. auxotrophic mutants of Neurospora crassa. Wild-type can grow on minimal medium but mutants require nutritional supplements. 2. Homeotic Mutants These are mutants that show developmental defects i.e. They may for example have body parts in the wrong location e.g. the Drosophila antennapedia mutant has a pair of legs on its head where the antennae should be. Mutations in a group of genes central to development, the Hox genes, can cause in many cases lethal developmental defects. 3. Lethal Mutants The viability of the organism is affected. Typically such mutations are recessive and the organism can only survive if it is a heterozygote e.g. manx cat (tail-less). Hox Genes Mario Capecchi won the Nobel Prize in 2007 for his research on Hox genes & their role in defining the mammalian development plan. Individual Hox genes were mutated in mice and the effects of the mutations observed. 2

3 What causes mutations? 1. Internal Causes: errors in replicating genetic information a. Errors in chromosome construction or chromosome distribution e.g. into gametes b. Errors in DNA replication 2. External Causes: mutagenic agents that damage DNA a. Chemical mutagens b. Physical mutagens: radiation How frequently do mutations occur in nature? i.e. what is the natural or spontaneous mutation rate? Measure the frequency with which particular mutants are found in natural populations Humans: wild-type (normal) blood clotting h+ abnormal clotting (hemophilia) h- Frequency = 2 X 10-5 per gamete 3

4 MUTAGENS Mutagens are physical or chemical agents that cause mutations (Chernobyl example of induced mutations by mutagens) Mutagens act by increasing the spontaneous mutation rate. They can therefore be used to induce mutations 1. Physical mutagens include many types of radiation X-rays: in the 1920 s the geneticist H. Muller discovered that exposing the fruit fly Drosophila to X-rays greatly increased the frequency of mutants. (see lecture 6 - Beadle & Tatum used x-rays to mutate Neurospora crassa). The mutation rate is proportional to the radiation dose Ultra-violet (UV) light causes the production of thymidine dimers. Such mutations can lead to skin cancer. 2. Chemical Mutagens Chemicals that damage DNA often cause mutations or Chemicals that insert between the bases can also cause mutations Many chemical mutagens also cause cancers. Such chemicals are often called carcinogens Chemicals differ in how mutagenic they are e.g. Type of Mutagen Relative mutagenicity Epoxy butane 1 Methyl methane sulfonate 105 Naphthyl amine 1,400 Aflatoxin B (mouldy peanuts) 1,200,000 4

5 Mutation of DNA - Point Mutations These are mutations that change only one (or a few) base pairs in a DNA molecule Types of point mutation 1. Base-pair substitutions: a single base is altered g g g CCC a t a g g g CTC a t a 2. Insertions: an extra base is incorporated g g g CCC a t a g g g CCGC a t a 3. Deletions: a single base is deleted g g g CCC a t a g g g CC a t a Consequences of point mutations in DNA A point mutation in a gene may cause catastrophic changes in the properties of the protein product of that gene. Some point mutations are silent have no known effect. e.g. partial or total loss of function of the encoded protein (some recessive disorders) or may produce a protein which is toxic to the cell (some dominant disorders) If the protein functions in blood clotting e.g. Factor VIII Mutations in the Factor VIII gene can cause hemophilia resulting in uncontrolled bleeding If the protein functions to control cell division, then a mutation may result in uncontrolled cell divisions i.e. cancer 5

6 The sequence of bases in DNA determines the properties of the protein encoded by the gene Insertion or deletion of one base can shift the reading frame Wild-type Insertion of one base nonsense mutation Deletion of one base missense mutation 6

7 Point Mutations: Base-pair Substitutions No effect on protein missence mutation nonsense mutation Recessive Epidermolysis Bullosa (EB) skin blistering disorder fqbsu4yqofw/s1600/mutagen.jpeg Point mutations can lead to many inherited genetic disorders 7

8 Rhodopsin protein structure. Mutations in Rhodopsin can cause an inherited eye disorder termed Retinitis Pigmentosa (RP) Mutations in the gene encoding rhodopsin can result in an encoded protein with a changed structure & this mutant protein can eventually cause photoreceptor cells to die and lead to blindness. 8

9 Mutations due to Chromosome Abnormalities 1. Abnormal numbers of chromosomes Aneuploidy = Loss or gain of individual chromosomes e.g. extra chromosome 21 causes Down s syndrome Caused by nondisjunction = failure of chromosomes to separate properly during meiosis Some gametes carry an extra copy of one chromosome ( n + 1) Some gametes lack a chromosome (n-1) 1. Abnormal chromosome structures (a) deletions - a segment of a chromosome is deleted (b) duplications - a segment of a chromosome is duplicated (c) translocations - a piece of one chromosome becomes attached to a different chromosome Babies born with trisomy 13 frequently have some combination of the following findings: Central nervous system defects Severe mental retardation (IQ 20-35) Posterior scalp lesions Oral-facial clefts Small, abnormally shaped eyes (microphthalmia) Heart defect An extra pinky finger (polydactyly) Additional organ anomalies 90% of babies born with trisomy 13 do not survive past 1 year 9

10 Next Generation Sequencing (NGS) technology. 1,000 Genomes Project involves sequencing the genomes of at least 1,000 people to ascertain information on biomedically relevant DNA variation between humans - announced in Jan Sequence of 1,000 human genomes available end Oct Project now expanded to include more genomes. Funded by Groups / Institutes in many countries 10

11 Companies such as decode & 23andMe provide services to genotype people for certain disease mutations amongst other traits. Issues of privacy, conselling etc must be considered fully 11

12 23andMe (adop-on, deep ancestry, ethnicity, genealogy, health) African Ancestry (deep ancestry) AfricanDNA (FTDNA affiliate) (deep ancestry, ethnicity, genealogy) Ancestry By DNA (deep ancestry, ethnicity) AncestryDNA, a subsidiary of Ancestry.com (ethnicity, genealogy) Britains DNA (formerly Ethnoancestry) (deep ancestry, ethnicity) Cambridge DNA Services (deep ancestry, ethnicity) decode gene-cs (genealogy, health) DNA Ancestry and Family Origin (FTDNA affiliate in the Middle East) (adop-on, deep ancestry, full mtdna sequencing, genealogy) DNA Canada (genealogy, paternity, rela-onship) DNA Diagnos-cs Center (adop-on, DNA storage, genealogy, iden-ty, immigra-on, paternity, rela-onship) DNA Consultants DNA Lab Center (DNA storage, genealogy, iden-ty, immigra-on, infidelity, paternity, rela-onship) DNA Solu-ons (deep ancestry, paternity, rela-onship) DNA Tribes (ethnicity) DNA Worldwide (FTDNA affiliate) (deep ancestry, ethnicity, genealogy, paternity, rela-onship) easydna (deep ancestry, ethnicity, paternity, rela-onship) Ethnoancestry - see Britains DNA Family Tree DNA (adop-on, deep ancestry, full mtdna sequencing, genealogy, iden-ty, rela-onship) FamilyBuilder (deep ancestry, genealogy) Geneplanet (deep ancestry, genealogy, health) Genebase (deep ancestry, genealogy) Genelex (deep ancestry, genealogy, health, immigra-on, paternity, rela-onship) Genographic Project (deep ancestry, genealogy) igenea (FTDNA affiliate) (deep ancestry, genealogy) Lumigenix (deep ancestry, health) Oxford Ancestors (deep ancestry, genealogy) Knome (health) Navigenics (health) Pathway Genomics (deep ancestry and health) Scotlands DNA - See Britains DNA (formerly Ethnoancestry) Sorenson Molecular Genealogy Founda-on (genealogy) Roots for Real (deep ancestry, ethnicity, genealogy) Warrior Roots (Y- DNA, sports) Lots of companies provide information re: genealogy / ancestry genetic roots! They use information from the nuclear genome (23 pairs chromosomes) & the mitochondrial genome (mtdna) 12