LECTURE 10: CHROMOSOMAL REARRANGEMENTS IReading for this and next lecture: Ch. 13, p. 441-460Problems for this and next lecture: Ch. 13, solved problems I, II; 13-2, 13-4 – 13-8, 13-11 –13-16So 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 ofchromosome structure that can affect expression of more than one gene and the pattern of genetransmission. 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 mutationrate is 2-12 x 10-6 mutations/gene/generation. The spontaneous mutation rate is affected by twomechanisms. First, mutations can arise by errors in DNA replication. It is important to note thatthe fidelity of DNA replication is amazing, and most errors are corrected by DNA repairsystems. Second, mutations can arise from environmental damage. Chemicals, transposableelements, and radiation can cause DNA damage, and in fact, geneticists use these to inducemutations. High energy radiation (ionizing radiation, e.g. X-rays) at low doses induces pointmutations, but at high doses, causes double stranded breaks in DNA. Sealing these breaks cancause a variety of mutations -- ionizing radiation is the leading cause of gross chromosomalmutations in humans. UV radiation can covalently link adjacent thymine bases, causing theformation of thymine dimers. Transposable elements, which you will discuss in a later lecture,also cause mutations.Types of mutationsMost mutations fall into 3 classes: (1) point mutations, (2) rearrangements, and (3) transposableelement-induced mutations. Point mutations change one base pair and usually alter the functionof one gene. Chromosomal rearrangements, the topic of the next two lectures, changechromosomal structure and can alter the function of one or more genes and can change thepattern of gene transmission. Transposable elements can insert into genes, altering their functionand can cause chromosomal rearrangements. Today and next time, we will talk about four typesof chromosomal rearrangements: deficiencies, duplications, inversions, and translocations. Eachtype of rearrangement has distinct cytological and genetic consequences.Deletion (Deficiency): A rearrangement that removes a segment of DNA. Df or Del is thesymbol used. Deletions can be located within a chromosome (interstitial) or can remove the endof 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 breakchromosomes), or from mistakes during recombination or replication.If the deleted region does not contain any genes essential for survival, an individual homozygousfor a deletion (Del/Del) will live. However, large deletions that span multiple genes usuallyresult in homozygous lethality because they remove essential genes. What about individualsheterozygous for a normal chromosome and a deficiency chromosome (Del/+)? In someinstances, heterozygotes are viable and fertile. There are at least two reasons why heterozygosityfor a deletion might be detrimental. (1) Gene dosage problems: a deletion heterozygote will haveonly half the normal dose of each gene that is missing in the deletion. In general, humans cannotsurvive (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 (oftencalled "pseudominance"). Individuals with retinoblastoma (malignant eye cancer) are oftenheterozygous for deletions on Chromosome 13; the disease results when a somatic mutation inthe remaining copy of the RB tumor suppressor gene occurs in retinal cells.ABCDEF - cen - G normal chromosomeABF - cen - G deficiency chromosome (lacks CDE)When homologous chromosomes pair during meiosis in a deletion heterozygote, one can observea deletion loop representing the unpaired region of the normal chromosome that corresponds tothe area deleted from the mutated homologous chromosome. You can see that recombinationcannot occur in this region, thus the genes within the deletion loop cannot be separated byrecombination and will always be inherited as a unit. This distorts map distances! The distancebetween 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 thedeletion chromosome as hemizygous for the genes in the deleted interval - we can use thedeletion chromosome in complementation tests, screens for new alleles, or to do fine scalemapping (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 tonormal), (4) reduced RF in heterozygotes (recombination frequency between genes flanking thedeficiency is lower than in control crosses), and (5) pseudodominance (sometimes a deficiencywill unmask recessive alleles on the non-deleted chromosome).Interestingly, deletions show different transmission in plants than in animals. A male animalheterozygous for a deletion produces equal numbers of sperm carrying one of the twochromosomes (the deleted vs. non-deleted chromosome). In contrast, the pollen produced by amale deletion heterozygote plant is either functional (carrying the non-deleted chromosome) ornonfunctional (aborted, carrying the deleted chromosome). Pollen, at least in non-polyploidplants, seems sensitive to changes in the amount of chromosomal material -- this might act toweed out deletions.Duplication: A rearrangement that results in an increase in copy number of a particularchromosomal region. Symbol used is Dp.In tandem duplications, the duplicated regions lie right next to one another, either in the sameorder or in reverse order. In non-tandem duplications, the repeated regions lie far apart on thesame chromosome or on different chromosomes. Duplications can occur due to unequalcrossing-over, chromosome breaks and faulty repair, or replication errors.The dominant Bar mutation (we talked about this mutation earlier) is a tandem duplication of the16A region of the Drosophila X chromosome.
View Full Document
Unlocking...