chromosomal rearrangements Genetic variation AlterationsAlterations inin ChromosomeChromosome StructureStructure ! There are two primary ways in which the structure of chromosomes can be altered – 1. The total amount of genetic information in the chromosome can change " Decrease: Deficiencies/Deletions " Increase: Duplications & Insertions – 2. The genetic material may remain the same, but is rearranged " Inversions " Translocations PeCtoerp Jy.r Riguhsts e©llT, ihGee nMetciGcsr: aCwop-Hyriilgl hCt o©m Ppeaanriseosn, IEndcu.c Pateiromn,i sInsico.,n p ruebqliusihriendg faosr B reenpjarmodinu cCtuiomnm oirn gdsisplay 3 Chromosomal aberations/ rearrangements Chromosomal abberations/ rearrangements deletion Duplication Inversion translocation. Chromosomal abberations/ rearrangements • For chromosomal rearrangement to occur, there has to be two or more double-stranded breaks in the chromosomes of a cell. • DSBs are potentially lethal, unless they are repaired by repair enzymes. Chromosomal rearrangements • If the two ends of the same break are rejoined, the original DNA order is restored. • If the ends of two different breaks are joined together, results in a chromosomal rearrangement. • The only chromosomal rearrangements that survive meiosis are those that produce DNA molecules that have one centromere and two telomeres. • acentric chromosome: Without a centromere • Do not get dragged to either pole at anaphase of mitosis or meiosis Chromosomal • Are not incorporated into either progeny nucleus. rearrangements Therefore acentric chromosomes are not inherited. Chromosomal Re-arragements • Dicentric chromosome: With two centromere • pulled simultaneously to opposite poles at anaphase, forming an anaphase bridge. • Generally do not get incorporated into either progeny cell. • A chromosome lacking a telomere, cannot replicate properly Chromosomal • The larger the segment Re-arragements that is lost or duplicated, the more chance, that it will cause phenotypic abnormalities. 44200_15_p481-520 3/12/04 1:06 PM Page 497 15.2 Changes in chromosome structure 497 mosomal rearrangements by breakage can be induced same relative positions on the homologs, crossing-over artificially by using ionizing radiation. This kind of radia- can produce aberrant chromosomes. Deletions, duplica- tion, particularly X rays and gamma rays, is highly ener- tions, inversions, and translocations can all be produced getic and causes numerous double-stranded breaks in by such crossing-over (see Figure 15-19, right side). DNA. There are two general types of rearrangements, bal- To understand how chromosomal rearrangements anced and unbalanced. Balanced rearrangements change are produced by breakage, several points should be kept the chromosomal gene order but do not remove or du- in mind: plicate any DNA. The two simple classes of balanced re- arrangements are inversions and reciprocal transloca- 1. Each chromosome is a single double-stranded DNA tions. An inversion is a rearrangement in which an molecule. internal segment of a chromosome has been broken 2. The first event in the production of a chromosomal twice, flipped 180 degrees, and rejoined. rearrangement is the generation of two or more double-stranded breaks in the chromosomes of a cell ABCD (see Figure 15-19, top row at left). 3. Double-stranded breaks are potentially lethal, unless they are repaired. ACBD 4. Repair systems in the cell correct the double-stranded breaks by joining broken ends back together (see A reciprocal translocation is a rearrangement in which Chapter 14 for a detailed discussion of DNA repair). two nonhomologous chromosomes are each broken once, 5. If the two ends of the same break are rejoined, the creating acentric fragments, which then trade places: original DNA order is restored. If the ends of two different breaks are joined together, however, one Break result is one or another type of chromosomal Break rearrangement. 6. The only chromosomal rearrangements that survive Reciprocal meiosis are those that produce DNA molecules that translocation have one centromere and two telomeres. If a rearrangement produces a chromosome that lacks a Sometimes the DNA breaks that precede the forma- centromere, such an acentric chromosome will not be tion of a rearrangement occur genes. When they do, dragged to either pole at anaphase of mitosis or within they disrupt gene function because part of the gene moves meiosis and will not be incorporated into either to a new location and no complete transcript can be made. progeny nucleus. Therefore acentric chromosomes are In addition, the DNA sequences on either side of the re- not inherited. If a rearrangement produces a joined ends of a rearranged chromosome are ones that are chromosome with two centromeres (a dicentric), it not normally juxtaposed. Sometimes the junction occurs will often be pulled simultaneously to opposite poles in such a way that fusion produces a nonfunctional hybrid at anaphase, forming an anaphase bridge. Anaphase gene composed of parts of two other genes. bridge chromosomes typically will not be incorporated Chromosomal Deletionschange the gene dosage into either progeny cell. If a chromosome break Unbalanced rearrangements of a chromosome segment. As with aneuploidy for whole produces a chromosome lacking a telomere, that chromosomes, the loss of one copy of a segment or the ad- chromosome cannot replicate properly. Recall from • A Kind of Unbalanceddition of an rearrangements extra copy can disrupt normal gene balance. Chapter 7 that telomeres are needed to prime proper The two simple classes of unbalanced rearrangements are DNA replication at the ends (see Figure 7-24). deletions and duplications. A deletion is the loss of a seg- 7. If a rearrangement duplicates or deletes a segment of ment within one chromosome arm and the juxtaposition a chromosome, gene• balanceA deletion may be affected. is The the lossof the twoof segments a segment on either side of thewithin deleted segment, larger the segment that is lost or duplicated, the more as in this example, which shows loss of segment C–D: likely it is that gene imbalanceone will chromosome cause phenotypic abnormalities. ABCED Another important cause of rearrangements is crossing-over between repetitive DNA segments. In or- ganisms with repeated• shortthey DNA sequencesdo not within revert one ABE chromosome or on different chromosomes there is am- biguity about which of the repeats will pair with each A duplication is the repetition of a segment of a other at meiosis. If sequences pair up that are not in the chromosome arm. In the simplest type of duplication, • change the gene dosage of a chromosome segment. VVaarriaiattioionnss inin CChhrroommoossoommee SSttrruuccttuurree:: DDeelelettioionnss ! TThhee eeffffeecctt ooff aa ddeelelettioionn ddeeppeennddss oonn wwhhaatt wwaass ddeeleletteedd.. – A deletion in one allele of a homozygous wild- type organism may give a normal phenotype " while the same deletion in the wild-type allele of a heterozygote would produce a mutant phenotype. – Deletion of the centromere results in an acentric chromosome that is lost, usually with serious or lethal consequences. " No known living human has an entire autosome deleted from the genome. Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings 6 Deletion Causative Agents heat radiation viruses Transposable errors in chemicals elements recombination Terminal Deletions Off the End Intercalary Deletions From the Middle Recognizing Deletions Terminal Intercalary Homologous Pairs? Intercalary Hemizygous Terminal Hemizygous: gene is present in a single dose. Deletions …result in partial monosomy, …the organism is monosomic for the portion of the chromosome that is deleted e.g terminal deletion of the small arm (petite arm) of chromosome 5, Cri-du-chat Syndrome (46, -5p) Chromosomal Duplication • A duplication is the repetition of a segment of a chromosome44200_15_p481-520 3/12/04 1:06arm PM Page 498 • the duplicate segment can attach at a different 498 position on the Chaptersame 15 • Large-Scale Chromosomal Changes chromosome, or on a different the two segments are adjacent to each other (a tandem A B CEFD Normal sequence chromosomeduplication),. as in this duplication of segment C: A BCEDF Paracentric ABCED ADC B E F Pericentric ABCCDEBecause inversions are balanced rearrangements, they do not change the overall amount of genetic material, so they do not result in gene imbalance. Individuals with in- However, the duplicate segment can end up at a differ- versions are generally normal, if there are no breaks within ent position on the same chromosome, or even on a dif- genes. A break that disrupts a gene produces a mutation ferent chromosome. that may be detectable as an abnormal phenotype. If the The following sections consider the properties of gene has an essential function, then the breakpoint acts as these balanced and unbalanced rearrangements. a lethal mutation linked to the inversion. In such a case, the inversion cannot be bred to homozygosity. However, Inversions many inversions can be made homozygous, and further- more, inversions can be detected in haploid organisms. In Inversions are of two basic types. If the centromere is these cases, the breakpoints of the inversion are clearly not outside the inversion, the inversion is said to be paracen- in essential regions. Some of the possible consequences of tric. Inversions spanning the centromere are pericentric. inversion at the DNA level are shown in Figure 15-20. Breakpoints between genes Normal sequence A P BC D 5´ 3´ 3´ 5´ P PP Breaks in DNA A P BC D 5´ 3´ 5´ 3´ 5´ 3´ 3´ 5´ 3´ 5´ 3´ 5´ P P P Inverted alignment A P CBP P D 5´ 3´ 5´ 3´ 5´ 3´ 3´ 5´ 3´ 5´ 3´ 5´ P Joining of breaks to complete inversion A P CBP P D 5´ 3´ 3´ 5´ P Inversion One breakpoint between genes One within gene C (C disrupted) Figure 15-20 Effects of inversions at the DNA level. A P “C ”“P B P C ” D 5´ 3´ Genes are represented by A, 3´ 5´ B, C, and D. Template strand P is dark green; nontemplate Inversion strand is light green; jagged lines indicate where breaks Breakpoints in genes A and D in the DNA produced gene Creating gene fusions fusions (A with D) after A D P C P B P A D inversion and rejoining.