Chromosome Mutation Relocation of Genetic Material Mutations change: 1) Amount of genetic material 2) Location of genetic material Specific Types of Changes: - Deletions and Duplications - Change (up or down) in chromosome # (individual chromosomes or whole sets of chromosomes - Translocations (balanced or unbalanced) - Inversions (pericentric or paracentric) Relocation of Genetic Material how do chromosome rearrangements occur? how can we detect them what are their genetic and phenotypic consequences?

Mechanisms of Chromosome Rearrangements Breakage and rejoining (can be between genes or within one or more genes) Breakage by DNA damage (e.g. irradiation), or errors in mitosis, or after chromosome fusions which create dicentric chromosomes (breaks during next mitosis) Rejoining during attempts to repair damage Position and number of breaks and the process of rejoining determines the type of rearrangement Deletion, Deletion + duplication, inversion, reciprocal translocation, non-reciprocal translocation Individuals carrying deletion + duplication, reciprocal translocation, or non-reciprocal translocation, can produce gametes with unbalanced rearrangements (later) - balanced rearrangements = no loss or gain of genetic material - unbalanced rearrangements = gain or loss or both Translocation chromosomes containing more than 1 centromere typically are unstable (dicentric chromosomes) and undergo repeated anaphase bridge-breakage-fusion cycles (later) Chromosome derivative containing no centromere are usually lost (sometimes a new centromere forms...

Mechanisms of Chromosome Rearrangements Mechanism: physical or chemical breakage and rejoining Rejoining wrong ends together: - DNA is folded - folds bring different segments together

Mechanisms of Chromosome Rearrangements Unequal homologous recombination (unequal crossovers) between repetitive DNA on same chromosome, homologous chromosomes, non-homologous chromosomes Repeats can be the highly repetitive DNA (Transposon or genes) or large genome duplications called “segmental duplications” - large, relatively recent duplications of non-repetitive DNA Same chromosome = deletions; which piece is lost depends on where centromere is relative to the repeats. Or, = inversion - depends on whether repeats are direct or inverted Homologous chromosomes = deletion duplication Non-homologous chromosomes = reciprocal translocations

Inversion loop at meiosis in an Inversion Heterozygotes

Inversion loop at meiosis in an Inversion Heterozygotes

Generation of acentric and dicentric chromosomes by meiotic recombination in inversion heterozygotes

Decrease in RF in Paracentric Inversion Heterozygotes 50 cM 10 cM 30 cM in WT 10 cM u v w x y ~ fewer crossovers < 10 cM ~ no crossovers ~ 0 cM < 20 cM u x w v y Paracentric inversion

Pericentric Inversions Detect by inversion loops and reduction in RF in crosses Recombination within loop produces duplication + deletion gametes Essentially complete linkage within the duplication, increase in linkage for genes at the borders of the duplication…

Translocation Heterozygotes allow detection of translocations cytologically and genetically Quadravalent in Cross-shape forms at meiosis Segregation patterns produce either viable or duplication + deletion gametes here, ½ of gametes are duplication deletion independently of recombination semisterility Compare/contrast consequences of inversions to translocations in crosses involving heterozygotes - reduction in number of viable progeny - which progeny genotypes are missing - what if the inversion heterozygote is only heterozygous for markers within the inversion?

Application of Inversion or Translocation Rearrangements Disease gene mapping – example NF1 gene responsible for neurofibromatosis - used rearrangement breakpoint mapping Create strains carrying duplication or deletions Small inversions or translocations can result in viable progeny Balancer Chromosomes in Drosophila Prevent recombination anywhere on a chromosome in a inversion heterozygote

Deletions Deletions can be small – single gene – or larger – multigene - single gene deletions create null alleles - best for deducing function of the gene from the mutant phenotype multigene deletions can be recessive or dominant lethal dependent on affect on gene dosage recessive multigene deletions can reveal presence of recessive point mutations in that region (see deletion mapping, later) Detect deletions cytologically – deletion loops in meiosis or polytenes Detect recessive deletions phenotypically – recessive point mutations in that region will all be expressed when combined with the deletion Use of deletions in gene mapping…

Drosophila Polytene Chromosomes allow deletion loops to be visualized

Using multigene deletions for mapping the location of point mutants pn mutation is expressed in progeny from cross of pn mutant with 264-38 Fa mutation is expressed in progeny from all crosses except those involving 258-11 and 258-14 Determine results for w and rst for yourself – which crosses produce progeny expressing these recessive phenotypes?

Human diseases associated with deletions 1% of institutionalized mental retardation patients Characteristic facial appearance, cry in newborns, microcephaly, other physically apparent and physiological features Due to deletion of genes associated with 5p15.2 through 5p15.3 Most are spontaneous deletions during gametogenesis Heritable form from heterozygous parents carrying a small translocation involving the end of chromosome 5 - adjacent 1 segregation leads duplication or deletion of this region

Conceptions involving chromosome abnormalities are relatively common 7.5 up to 15% of all Conceptions! Conceptions involving chromosome abnormalities are relatively common