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How Genes Travel on Chromosomes

and Changes in
Chromosome Number

 Rearrangements of DNA Sequences

Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 13



Figure 13.1 Comparing the mouse and human
Mouse chromosome 1 contains large blocks of
sequences found on human chromosomes 1, 2, 5, 6,
8, 13, and 18 (portrayed in different colors).
Arrows indicate the relative orientations of sequence
blocks from the same human chromosome.


Two main themes underlying the observations on
chromosomal changes
1. Karyotypes generally remain constant within a species
• Most genetic imbalances result in a selective disadvantage

2. Related species usually have different karyotypes
• Closely-related species differ by only a few rearrangements
• Distantly-related species differ by many rearrangements
• Correlation between karyotypic rearrangements and speciation


Chromosomal rearrangements

Table 13.1


Changes in chromosome number


FOCUS ON!! • on heritable rearrangements that can be transmitted through the germ line from one generation to the next • the genomes of somatic cells can undergo changes in nucleotide number or order.6 REARRANGEMENTS OF DNA SEQUENCES • All chromosomal rearrangements alter DNA sequence. .

whereas large deletions can generate chromosomes lacking tens or even hundreds of genes . from faulty meiotic or mitotic recombination.1) Deletions: origin and detection • deletions remove one or more contiguous base pairs of DNA from a chromosome • errors in replication. • exposure to X-rays or other chromosome-damaging agents that break the DNA backbone • Small only one gene.

e.2 with a deletion. The two PCR primers shown will amplify a larger PCR product from wild-type DNA than from DNA Fig. 13.8 Symbols for a deletion are Del or Df (i. 8 . Del/+ or Df/+ is a deletion heterozygote and Del/Del or Df/Df is a deletion homozygote) b) One way to detect deletions is by PCR.

• Very large deletions are visible at the relatively low resolution of a karyotype .9 • Most point mutations would not cause such changes as in the PCR detected mutations • Larger deletions are sometimes identifiable because they affect the expression of two or more adjacent genes.

3 . deletion heterozygotes with loss of >3% of genome are not viable Fig. 2 copies vs. an abnormal phenotype can be caused by an imbalance in gene dosage (i. 1 copy of an autosomal gene) • In humans. 13.e.10 Heterozygosity for deletions may have phenotypic consequences • With some genes.

.11 • Del/ + individual is known as a deletion heterozygote • Even small deletions can be harmful in heterozygotes. This imbalance in gene dosage changes the phenotypic effects. ▫ a relatively small deletion from the short arm of chromosome 5 have cri du chat syndrome Why should heterozygosity for a deletion have harmful consequences when the Del/+ individual has at least one wild-type copy of all of its genes? gene dosage —the number of times a given gene is present in the cell nucleus—can create a genetic imbalance.

• Decrease in gene dosage are noticeable but not catastrophic for some genes ▫ Drosophila containing only one copy of the wild-type Notch gene have visible wing abnormalities but otherwise seem to function normally . the normal diploid level of gene expression is essential to individual survival. fewer than two copies of such a gene results in lethality.12 • Some rare genes.

▫ Thus. a cell without any wild-type protein may divide out of control and generate a tumor. individuals born heterozygous for certain deletions have a greatly increased risk of losing both copies of certain genes and developing cancer. .13 • ANOTHER REASON why heterozygosity for a deletion can be harmful • If the gene encodes a protein that helps control cell division. the most malignant form of eye cancer Reveal heterozygosity for deletions on chromosome 13 Cells from the retinal tumors of these same patients have a mutation in the remaining copy of the RB gene on the nondeleted chromosome 13. Retinoblastoma (RB).

14 Deletion loops form in the chromosomes of deletion heterozygotes • Recombination between homologs can occur only at regions of similarity • No recombination can occur within a deletion loop • Consequently.4 . 13. genetic map distances in deletion heterozygotes will not be accurate Fig.

Fig.5 The deletion has thus “uncovered” the scarlet (st) mutation. . the mutant gene must lie outside the deleted region A fly of genotype st/Del displays the recessive scarlet eye color. 13. pseudodominance can "uncover" a recessive mutation • Similar to a complementation test • Examine phenotype of a heterozygote for recessive allele and deletion: • If the phenotype is mutant.15 In deletion heterozygotes. the mutant gene must lie inside the deleted region • If the phenotype is wild-type.

control probe for chromosome 22 Red dot.10 . probe from 22q11 region Fig. 13.16 Diagnosing DiGeorge syndrome by fluorescence in situ hybridization (FISH) DiGeorge syndrome in humans: • Accounts for 5% of all congenital heart defects • Affected people are heterozygous for a 22q11 deletion FISH on human metaphase chromosomes Green dots.

17 Summary of phenotypic and genetic effects of deletions Homozygosity or heterozygosity for deletions can be lethal or harmful • Depends on size of deletions and affected genes In deletion heterozygotes. deletions reveal the effects of recessive mutations • Deletions can be used to map and identify genes .

.18 2) Types of duplications (Dp) • Duplications increase the number of copies of a particular chromosomal region. either in the same order or in reverse order In nontandem (or dispersed ) duplications. the two or more copies of a region are not adjacent to each other and may lie far apart on the same chromosome or on different chromosomes. repeats of a region lie adjacent to each other. In tandem duplications.

nontandem duplications could be produced by insertion of a fragment elsewhere on the homologous chromosome Fig.11b . unequal crossing-over. or errors in DNA replication • According to one scenario. 13.19 Chromosome breakage can produce duplications • Duplications arise by chromosomal breakage and faulty repair.

the repeated bands form a duplication loop —a bulge in the Dp -bearing chromosome that has no similar region with which to pair in the unduplicated normal homologous • chromosome.20 • Most duplications have no obvious phenotypic consequences • can be detected only by cytological or molecular means • During the prophase of meiosis I in heterozygotes for such duplications ( Dp/ +). .

13.21 Different kinds of duplication loops in duplication heterozygotes (Dp/+) Different configurations can occur in prophase I of meiosis Fig.11c .

13. Fig.12a .22 Duplication heterozygosity can cause visible phenotypes Increased gene dosage can result in a mutant phenotype Most duplications have no obvious phenotypic consequences and can be detected only by cytological or molecular means.

heterozygosity for duplications covering more than 5% of the haploid genome is most often lethal.23 For rare genes.12b . 13. • In humans. survival requires exactly two copies • In a very large duplication have additive deleterious effects that risk survival. Fig.

24 Unequal crossing-over can increase or decrease copy number Genotype of X chromosome Phenotype Out-of-register pairing during meiosis can occur in a Bar-eyed female Fig.13 . 13.

25 Summary of phenotypic and genetic effects of duplications • Novel phenotypes may occur because of increased gene copy number or because of altered expression in new chromosomal environment • Homozygosity or heterozygosity for a duplication can be lethal or harmful • Depends on size of duplication and affected genes • Unequal crossing-over between duplicated regions on homologous chromosomes can result in increased and decreased copy number .

14a .26 3) Chromosome breakage can produce inversions (In) • The half-circle rotation of a chromosomal region known as an inversion ( In ) Pericentric inversion – centromere is within the inverted segment Paracentric inversion – centromere is not within the inverted segment radiation produces two double-strand breaks in a chromosome’s DNA Fig. 13.

13.27 Intrachromosomal recombination can also produce inversions Recombination occurs between related sequences that are in opposite orientations on the same chromosome Fig.14b .

13. chapter 12) Inversions can act as crossover suppressors • In inversion heterozygotes.28 Phenotypic effects of inversions Most inversions do not result in an abnormal phenotype Abnormal phenotypes can occur if: • Inversion disrupts a gene (Fig. no viable offspring are produced that carry chromosomes resulting from recombination in inverted region .e.14c) • Inversion places a gene in chromosomal environment that alters its expression  i. Gene is placed near regulatory sequences for other genes or near heterochromatin (PEV.

29 Inversions can disrupt a gene Fig.14c . 13.

30 Inversion loops form in inversion heterozygotes • Formation of inversion loop allows tightest possible alignment of homologous regions • Crossing over within the inversion loop produces aberrant recombinant chromatids Fig. 13.15 .

13.31 Why pericentric inversion heterozygotes produce few if any recombinant progeny • Each recombinant chromatid has a centromere. but each will be genetically unbalanced • Zygotes formed from union of normal gametes with gametes carrying these recombinant chromatids will be nonviable Fig.16a .

32 Why paracentric inversion heterozygotes produce few if any recombinant progeny One recombinant chromatid lacks a centromere and the other recombinant chromatid has two centromeres Zygotes formed from union of normal gametes with gametes carrying the broken dicentric recombinant chromatids will be nonviable Fig. 13.16b .

Thin white lines mark locations of inversion breakpoints. (A) A single crossover event within the inverted segment results in the formation of chromosomes with deletions and zero (acentric) centromeres or duplications and two (dicentric) centromeres. heterochromatin is shown in gray. and centromeres are depicted as circles. Euchromatin is shown in blue. In(1)dl-49.Consequences of a single or double crossover between a WT X chromosome and an X chromosome carrying a single inversion. 1. . neither of which will segregate properly during meiosis. and yellow crosses/thin lines mark locations of crossover events. (B) A double crossover within an inverted segment results in intact chromosomes with one centromere that will segregate properly during meiosis.33 Fig.

. inversions act as crossover suppressors.34 whether an inversion is pericentric or paracentric. only gametes containing chromosomes that did not recombine within the inversion loop can yield viable progeny. crossing-over within the inversion loop of an inversion heterozygote has the same effect: • formation of recombinant gametes that after fertilization prevent the zygote from developing.

overlapping inversions In progeny of crosses of heterozygotes with a marked balancer and a non-inversion chromosome • No viable progeny with recombinants on this chromosome will be produced because of crossover suppression • Progeny that don't carry the marked chromosome must carry the nonrecombined. unmarked chromosome Balancer chromosome Normal chromosome with mutations of interest Fig. 13.17 .35 Balancer chromosomes are useful tools for genetic analysis Balancer chromosomes have a dominant visible marker and multiple.

36 Summary of phenotypic and genetic effects of inversions • Inversions don't add or remove DNA. recombination within inverted segment results in genetically unbalanced gametes (nonviable zygotes) • Geneticists can take advantage of this: ▫ Balancer chromosomes with inversions are useful genetic tools ▫ The production of genetic lines of known composition. . but can disrupt a gene or alter expression of a gene • In inversion heterozygotes.

13.37 4) Translocations attach part of one chromosome to another chromosome Reciprocal translocation (Fig.18) • Two different chromosomes each have a chromosome break • Reciprocal exchange of fragments – each fragment replaces the fragment on the other chromosome Two chromosome breaks can produce a reciprocal translocation .

18b . 13.38 Chromosome painting reveals a reciprocal translocation • Translocated chromosomes are stained red and green • Non-translocated chromosomes are stained entirely red or entirely green Fig.

 15. 21. 13.19) • Chromosomal breaks occur at or near centromeres of two acrocentric chromosomes (13.39 Robertsonian translocations can reshape genomes Robertsonian translocation (Fig.19 . which is usually lost Fig. 13. 14. 22 and the Y chromosome) • Generates one large metacentric chromosome and one small chromosome.

13.20) • Defects that are observed in translocation heterozygotes • Unbalanced gametes are produced. which results in reduced fertility (Fig. 13.40 Phenotypic effects of reciprocal translocations • Most reciprocal translocations don't affect the phenotype because they don't add or remove DNA • Abnormal phenotypes can be caused if translocation breakpoint disrupts a gene or results in altered expression of a gene • Translocations in somatic cells can result in oncogene activation (Fig.21) • Genetic map distance are altered because of pseudolinkage .

41 How a reciprocal translocation helps cause one kind of leukemia a) Uncontrolled divisions of large. Translocations in somatic cells can result in oncogene activation . dark-staining white blood cells in a leukemia patient (right) produce a higher ratio of white to red blood cells than that in a normal individual (left).

42 A reciprocal translocation is the basis for chronic myelogenous leukemia Fig. 13.20b .

43 DIAGNOSIS AND TREATMENT OF CML • To confirm a diagnosis of myelogenous leukemia ▫ a blood sample from the patient ▫ a pair of PCR primers derived from opposite sides of the breakpoint ▫ The PCR will amplify the region between the primers only if the DNA sample contains the translocation • To monitor the effects of chemotherapy .

even in the absence of growth factor. and this leads to runaway cell division • Gleevec ® ▫ inhibits the enzymatic activity of the protein tyrosine kinase encoded by bcr/c-abl. ▫ 98% of participants experienced a complete disappearance of leukemic blood cells .44 To treat CML • The protein encoded by c-abl is a protein tyrosine kinase. • It is always active. ▫ cell growth and division (active with a growth signal) • the fused protein encoded by bcr/c-abl in cells carrying the translocation is not amenable to regulation. an enzyme that adds phosphate groups to tyrosine amino acids on other proteins.

45 In a translocation homozygote. chromosomes segregate normally during meiosis I If the breakpoints of a reciprocal translocation do not affect gene function.21a . there are no genetic consequences in homozygotes Fig. 13.

13.21c) Fig. the two haploid sets of chromosomes carry different arrangements of DNA • Chromosome pairing during prophase I of meiosis is maximized by formation of a cruciform (crosslike) structure Three segregation patterns are possible (Fig. 13.21b .46 Chromosome pairing in a translocation heterozygote In a translocation heterozygote.

rather than the normal two.47 during prophase of the first meiotic division. the translocated chromosomes and their normal homologs assume a crosslike configuration in which four chromosomes. pair to achieve a maximum of synapsis between similar regions .

and not by adjacent-1 or adjacent-2 segregation Fig.48 Three chromosome segregation patterns are possible in a translocation heterozygote Balanced gametes are produced only by alternate segregation. 13.21 c .

49 Semisterility in a corn plant that is heterozygous for a reciprocal translocation • Slightly less than 50% of gametes arise from alternate segregation and are viable • Unbalanced ovules resulting from adjacent-1 or adjacent-2 segregation are aborted Fig.21d . 13.

Mendel's law of independent assortment would be observed with unlinked genes In a reciprocal translocation heterozygote. genes located on the nonhomologous chromosomes would behave as if they are linked .50 Pseudolinkage is observed in heterozygotes with reciprocal translocations In non-translocation heterozygotes. there are only two possible segregation patterns • With all offspring viable. only the alternate segregation pattern results in viable progeny • In outcrosses.

22 Copyright © The McGraw-Hill Companies. Chapter 13 51 . 4th edition.Down syndrome arising from a Robertsonian translocation between chromosomes 21 and 14 Three chromosome segregation patterns 14q21q translocation heterozygote Fig.. Inc. 13. Permission required to reproduce or display Hartwell et al.