LECTURE 10 CHROMOSOMAL REARRANGEMENTS I Reading for this and next lecture Ch 13 p 441 460 Problems for this and next lecture Ch 13 solved problems I II 13 2 13 4 13 8 13 11 13 16 So far we ve concentrated mainly on phenotypic changes caused by mutations in single genes Today and next time we ll talk about chromosomal rearrangements reorganizations of chromosome structure that can affect expression of more than one gene and the pattern of gene transmission Your book describes four types of rearrangements Deletions Duplications Inversions and Translocations How do mutations arise Mutations can arise spontaneously at a very low frequency The average spontaneous mutation rate is 2 12 x 10 6 mutations gene generation The spontaneous mutation rate is affected by two mechanisms First mutations can arise by errors in DNA replication It is important to note that the fidelity of DNA replication is amazing and most errors are corrected by DNA repair systems Second mutations can arise from environmental damage Chemicals transposable elements and radiation can cause DNA damage and in fact geneticists use these to induce mutations High energy radiation ionizing radiation e g X rays at low doses induces point mutations but at high doses causes double stranded breaks in DNA Sealing these breaks can cause a variety of mutations ionizing radiation is the leading cause of gross chromosomal mutations in humans UV radiation can covalently link adjacent thymine bases causing the formation of thymine dimers Transposable elements which you will discuss in a later lecture also cause mutations Types of mutations Most mutations fall into 3 classes 1 point mutations 2 rearrangements and 3 transposable element induced mutations Point mutations change one base pair and usually alter the function of one gene Chromosomal rearrangements the topic of the next two lectures change chromosomal structure and can alter the function of one or more genes and can change the pattern of gene transmission Transposable elements can insert into genes altering their function and can cause chromosomal rearrangements Today and next time we will talk about four types of chromosomal rearrangements deficiencies duplications inversions and translocations Each type of rearrangement has distinct cytological and genetic consequences Deletion Deficiency A rearrangement that removes a segment of DNA Df or Del is the symbol used Deletions can be located within a chromosome interstitial or can remove the end of a chromosome terminal Deletions can be small intragenic affecting only one gene or can span multiple genes multigenic Deletions can arise from DNA damage X rays or chemical agents that break chromosomes or from mistakes during recombination or replication If the deleted region does not contain any genes essential for survival an individual homozygous for a deletion Del Del will live However large deletions that span multiple genes usually result in homozygous lethality because they remove essential genes What about individuals heterozygous for a normal chromosome and a deficiency chromosome Del In some instances heterozygotes are viable and fertile There are at least two reasons why heterozygosity for a deletion might be detrimental 1 Gene dosage problems a deletion heterozygote will have only half the normal dose of each gene that is missing in the deletion In general humans cannot survive even as heterozygotes with deletions that remove more than 3 of the genome 2 Somatic mutation of the remaining normal copy of an essential gene may lead to defects often called pseudominance Individuals with retinoblastoma malignant eye cancer are often heterozygous for deletions on Chromosome 13 the disease results when a somatic mutation in the remaining copy of the RB tumor suppressor gene occurs in retinal cells ABCDEF cen G normal chromosome ABF cen G deficiency chromosome lacks CDE When homologous chromosomes pair during meiosis in a deletion heterozygote one can observe a deletion loop representing the unpaired region of the normal chromosome that corresponds to the area deleted from the mutated homologous chromosome You can see that recombination cannot occur in this region thus the genes within the deletion loop cannot be separated by recombination and will always be inherited as a unit This distorts map distances The distance between C D and E will be zero and the distance between B and F will be shorter than expected fewer crossovers occur in the now shorter region Deletion heterozygotes can uncover mutations in the non deleted chromosome Think of the deletion chromosome as hemizygous for the genes in the deleted interval we can use the deletion chromosome in complementation tests screens for new alleles or to do fine scale mapping see Fig 13 6 Thus the cytological and genetic consequences of deletions are 1 formation of deletion loops 2 recessive lethality often 3 lack of reversion deletion chromosomes never revert to normal 4 reduced RF in heterozygotes recombination frequency between genes flanking the deficiency is lower than in control crosses and 5 pseudodominance sometimes a deficiency will unmask recessive alleles on the non deleted chromosome Interestingly deletions show different transmission in plants than in animals A male animal heterozygous for a deletion produces equal numbers of sperm carrying one of the two chromosomes the deleted vs non deleted chromosome In contrast the pollen produced by a male deletion heterozygote plant is either functional carrying the non deleted chromosome or nonfunctional aborted carrying the deleted chromosome Pollen at least in non polyploid plants seems sensitive to changes in the amount of chromosomal material this might act to weed out deletions Duplication A rearrangement that results in an increase in copy number of a particular chromosomal region Symbol used is Dp In tandem duplications the duplicated regions lie right next to one another either in the same order or in reverse order In non tandem duplications the repeated regions lie far apart on the same chromosome or on different chromosomes Duplications can occur due to unequal crossing over chromosome breaks and faulty repair or replication errors The dominant Bar mutation we talked about this mutation earlier is a tandem duplication of the 16A region of the Drosophila X chromosome One model for how tandem duplications like Bar arise is by an unequal crossing over during meiosis that lead to a chromosome with the Bar tandem
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