Chromosomal mutations

1. Chromosomal mutations • A mutation is a change in the DNA • Generally, mutations are considered at the gene level, but some types of mutations involve addition, loss, or change of DNA at the chromosomal level. • We basically consider two types of change: • Change in chromosome number • Change in chromosome structure

2. Changes in chromosome structure • Deletions • part is missing. • Duplications • extra piece • Inversions • section is flipped • Translocations • piece attached to another chromosome. www.slh.wisc.edu/.../Partials/ CoMApr98part.html ghr.nlm.nih.gov/ghr/info/ img,Duplication

3. Deletions are bad • Deletions mean that DNA is missing • whatever genes were in that region are gone • if two copies are needed, there’s trouble • If the remaining allele is lethal, there’s trouble • the bigger the deletion, the more likely it will be serious. • Deletions often accompany duplications • Duplications are caused by unequal crossing over • if some chromosome gets 2, another gets 0

4. Duplications Part of chromosome is doubled; visible in the banding pattern. Duplication can increase gene dosage; this is usually harmful. Duplications often caused by unequal crossing over: ghr.nlm.nih.gov/ghr/info/ img,Duplication

5. Red-green color blindness • X-linked trait: thus shows up much more often in males. • Genes for red and green vision are related to rhodopsin, are very similar to each other, and probably arose from a duplication event. • Because they are similar they sometimes line up with each during meiosis, causing unequal crossing over. Crossing over can also occur in the middle of a gene, causing partial color blindness.

6. Duplications can be bad • Bar eye in Drosophila • Flies heterozygous for a duplicated gene have a bar shaped eye instead of a normal one • Have 3 alleles total, the normal + the duplicate • Flies homozygous for this mutation (and thus have 2 extra copies of the gene) have a very small undeveloped eye. • Gene dosage issue. http://www.usask.ca/biology/genetics/Gene_Action/bar-eye.jpg

7. Inversions A portion of the chromosome is flipped relative to the rest. Most of the problems with inversion are due to complicated attempts by chromosomes to pair up properly during meiosis. See your text and next slide. http://www.dynagene.com/images/in10ideo.gif

8. Paracentric and pericentric inversions

9. Problems with inversions in meiosis Duplications, deletions, and dicentric and acentric chromosomes can result from funny pairing and subsequent crossing over. www.mun.ca/.../Drosophila_inversion_loop.htm

10. Translocations A piece of a chromosome winds up attached to another chromosome. Could be a swap (reciprocal) or not. Translocations occur between non-homologous chromosomes! Major problem is again pairing of chromosomes during meiosis, resulting in extra or missing pieces, leading to partial monosomies and trisomies. Semi-sterility: only some gametes good http://library.thinkquest.org/18258/media/translocation.gif

11. Non-reciprocal translocations Piece of one chromosome breaks off, attaches to another chromosome. Creates partial trisomies, monosomies, which are generally fatal.Robertsonian translocation: fusion of chromosomes near the centromere. One animation shows two centromeres, the other shows none. Definition describes fusion of centromeres. http://www.pdx.edu/~newmanl/Robertsonian.gif http://www.tokyo-med.ac.jp/genet/chm/rst.gif Cases of inherited Down syndrome involve translocation of part of Chromosome #21 to, typically, #14.

12. Rings, dicentrics, & acentrics • Chromosomes with damage can circularize • Ring chromosomes result from radiation damage • Dicentrics and acentrics • Radiation damage or crossing over between chromosomes that are inverted. www.lumc.nl/1050/research/Molecular_Cytogenet... http://www.uic.edu/classes/bms/bms655/gfx/figure10.gif

13. Mutations • Mutations are inheritable changes in the DNA • “Failure to faithfully store genetic information” • Changes can be to chromosomes or genes • Current focus: changes to DNA sequences. • This means an alteration in a basepair or • in the order of the basepairs.

14. Types of mutations-1 • Mutations can be classified in many, many ways • Some ways mutually exclusive, some not. • Spontaneous vs. Induced • Spontaneous happens naturally • Enzymatic errors, especially in copying • Various chemical reactions • Induced mutations: specifically caused, as by researcher • Treatment with various chemicals, radiation • Gametic (germ line) vs. somatic • Gametic mutations can be passed on to next generation • Somatic only affects individual (in metazoans)

15. Types of mutations-2How the mutations are observed • Morphological • Change in physical structure, readily observed • Nutritional/biochemical • Mutated enzyme results in phenotypic change • Bacterial auxotrophs; sickle cell anemia • Behavioral mutations • Regulatory mutations • Affect control of gene expression rather than protein

16. Types of mutations-3 • Lethal mutations: not easily studied unless: • Conditional mutations: expressed depending on environmental conditions, especially temperature. • a way to study lethal mutations: permissive and restrictive temperatures; esp. useful with bacteria • temp sensitive mutations occur naturally, continued in offspring: Siamese cats, Himalayan rabbits www.tcainc.org/photos/ farpoint/saavik1.jpg

17. Types of mutations-4 Classification of mutations by FUNCTION • Loss of function: knockout or null. • Hypomorphic: lowered expression, “leaky” • Hypermorphic: greater activity or more visible trait • typically regulatory mutation, results in increased expression • Gain of function: e.g. new enzymatic activity • a factor in evolution; • Dominant negative: bad apple spoils the bunch e.g. bad protein in multicomponent enzyme

18. Detection of mutations • Bacteria and fungi • Prototrophs and auxotrophs: microbe no longer able to synthesize or breakdown particular nutrient. • Change in behavior, e.g. motility • Various methods in plants and animals • Humans (“not suitable experimental organisms”) • Reliance on pedigrees • Possible to determine sex linkage, dominance

19. Mutations are rare (but not equally so) • Mutation rate depends on species and on gene • Generally, mutations are random • Hot spot: a location in DNA where mutations occur significantly more often than the usual 1/ 106. • Monotonous run of single nucleotide or tandem repeats: GGGGGGGGG or ATGGATGGATGG • Methylated cytosines • methylation is adding a CH3 group to something • Cytosines are methylated to help indicate which DNA strand is older (helps with DNA repair). • Problem occurs when a cytosine is chemically damaged by deamination. (more later)

20. Mutations • Our example: • information, 3 letters at a time, read consecutively • Point mutations: • Frameshift mutations: Insertion

21. more Mutations • Frameshift: deletion • Transposon mutagensis: transposons are segments of DNA that can jump into another spot in the DNA; they have information.

22. More types of mutations • Switch between A & G, or C & T: transition • Switch between purine and pyrimidine: transversion • Silent: 3rd position of codon usually means same amino acid, so change here has no effect. • Missense: typically a single nucleotide change, causes change in amino acid and noticeable effect. • Nonsense: change amino acid codon to STOP codon • Additions, deletions, and “stuttering” • Stuttering: repeated sequences sometimes copied incorrectly; enzyme gets confused?