Power Point to accompany Genetics From Genes to

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Power. Point to accompany Genetics: From Genes to Genomes Fourth Edition Leland H. Hartwell, Leroy Hood, Michael L. Goldberg, Ann E. Reynolds, and Lee M. Silver Prepared by Mary A. Bedell University of Georgia Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition 1

PART IV How Genes Travel on Chromosomes 13 CHAPTER Chromosomal Rearrangements and Changes in Chromosome Number CHAPTER OUTLINE § § § 13. 1 Rearrangements of DNA Sequences 13. 2 Transposable Genetic Elements 13. 3 Rearrangements and Evolution: A Speculative Comprehensive Example 13. 4 Changes in Chromosome Number 13. 5 Emergent Technologies: Beyond the Karyotype Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 2

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 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 3

Deletions: origin and detection Symbols for a deletion are Del or Df (i. e. Del/+ or Df/+ is a deletion heterozygote and Del/Del or Df/Df is a deletion homozygote) Fig. 13. 2 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 6

Heterozygosity for deletions may have phenotypic consequences With some genes, an abnormal phenotype can be caused by an imbalance in gene dosage (i. e. 2 copies vs. 1 copy of an autosomal gene) In humans, deletion heterozygotes with loss of >3% of genome are not viable Fig. 13. 3 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 7

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, genetic map distances in deletion heterozygotes will not be accurate Fig. 13. 4 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 8

In deletion heterozygotes, 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, the mutant gene must lie inside the deleted region • If the phenotype is wild-type, the mutant gene must lie outside the deleted region Fig. 13. 5 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 9

Polytene chromosomes in the salivary glands of Drosophila larvae In Drosophila, interphase chromosomes replicate 10 times without going through mitosis • Each chromosome has 210 double helices Banding patterns are reproducible and provide detailed physical guide to gene mapping • Total ~5000 bands, size of each band is 3 -150 kb Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 Fig. 13. 6 a 10

Deletion loops also form in polytene chromosomes of Drosophila deletion heterozygotes In Drosophila, homologous chromosomes pair with each other during interphase Comparison of banding patterns in polytene chromosomes of a deletion heterozygote can reveal the position of deletion Fig. 13. 7 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 11

Using deletions to assign genes to bands on Drosophila polytene chromosomes Complementation tests with several deletions used to determine the locations of white (w), roughest (rst), and facet (fa) genes Fig. 13. 8 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 12

In situ hybridization as a tool for locating genes at the molecular level A DNA probe containing the white gene hybridizes to the tip of the Drosophila wild-type polytene X chromosome Fig. 13. 9 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 13

Characterizing deletions with in situ hybridization to polytene chromosomes Labeled DNA probe hybridizes to the wild-type chromosome but not to the deletion chromosome Fig. 13. 9 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 14

Diagnosing Di. George syndrome by fluorescence in situ hybridization (FISH) Di. George syndrome in humans: • Accounts for 5% of all congenital heart defects • Affected people are heterozygous for a 22 q 11 deletion FISH on human metaphase chromosomes Green dots; control probe for chromosome 22 Red dot; probe from 22 q 11 region Fig. 13. 10 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 15

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 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 16

Chromosome breakage can produce duplications According to one scenario, nontandem duplications could be produced by insertion of a fragment elsewhere on the homologous chromosome Fig. 13. 11 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 18

Different kinds of duplication loops in duplication heterozygotes (Dp/+) Different configurations can occur in prophase I of meiosis Fig. 13. 11 c Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 19

Duplication heterozygosity can cause visible phenotypes Increased gene dosage can result in a mutant phenotype Fig. 13. 12 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 20

For rare genes, survival requires exactly two copies Fig. 13. 12 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 21

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 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 22

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 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 23

Chromosome breakage can produce inversions (In) Pericentric inversion – centromere is within the inverted segment Paracentric inversion – centromere is not within the inverted segment Fig. 13. 14 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 24

Intrachromosomal recombination can also produce inversions Recombination occurs between related sequences that are in opposite orientations on the same chromosome Fig. 13. 14 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 25

Phenotypic effects of inversions Most inversions do not result in an abnormal phenotype Abnormal phenotypes can occur if: • Inversion disrupts a gene (Fig. 13. 14 c) • Inversion places a gene in chromosomal environment that alters its expression § i. e. Gene is placed near regulatory sequences for other genes or near heterochromatin (PEV, chapter 12) Inversions can act as crossover suppressors • In inversion heterozygotes, no viable offspring are produced that carry chromosomes resulting from recombination in inverted region Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 26

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 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 28

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. 13. 16 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 29

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. 16 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 30

Balancer chromosomes are useful tools for genetic analysis Balancer chromosomes have a dominant visible marker and multiple, 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 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 31

Summary of phenotypic and genetic effects of inversions Inversions don't add or remove DNA, but can disrupt a gene or alter expression of a gene In inversion heterozygotes, recombination within inverted segment results in genetically unbalanced gametes Balancer chromosomes with inversions are useful genetic tools Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 32

Translocations attach part of one chromosome to another chromosome Reciprocal translocation (Fig. 13. 18) • Two different chromosomes each have a chromosome break • Reciprocal exchange of fragments – each fragment replaces the fragment on the other chromosome Robertsonian translocation (Fig. 13. 19) • Chromosomal breaks occur at or near centromeres of two acrocentric chromosomes • Generates one large metacentric chromosome and one small chromosome, which is usually lost Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 33

Two chromosome breaks can produce a reciprocal translocation Fig. 13. 18 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 34

Chromosome painting reveals a reciprocal translocation Translocated chromosomes are stained red and green Non-translocated chromosomes are stained entirely red or entirely green Fig. 13. 18 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 35

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. 13. 20) Defects that are observed in translocation heterozygotes • Unbalanced gametes are produced, which results in reduced fertility (Fig. 13. 21) • Genetic map distance are altered because of pseudolinkage Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 37

A reciprocal translocation is the basis for chronic myelogenous leukemia Fig. 13. 20 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 38

In a translocation homozygote, chromosomes segregate normally during meiosis I If the breakpoints of a reciprocal translocation do not affect gene function, there are no genetic consequences in homozygotes Fig. 13. 21 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 39

Chromosome pairing in a translocation heterozygote In a translocation heterozygote, 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 structure Three segregation patterns are possible (Fig. 13. 21 c) Fig. 13. 21 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 40

Three chromosome segregation patterns are possible in a translocation heterozygote Balanced gametes are produced only by alternate segregation, and not by adjacent-1 or adjacent-2 segregation Fig. 13. 21 c Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 41

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. 13. 21 d Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 42

Pseudolinkage is observed in heterozygotes with reciprocal translocations In non-translocation heterozygotes, there are only two possible segregation patterns • With all offspring viable, Mendel's law of independent assortment would be observed with unlinked genes In a reciprocal translocation heterozygote, only the alternate segregation pattern results in viable progeny • In outcrosses, genes located on the nonhomologous chromosomes would behave as if they are linked Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 43

Down syndrome arising from a Robertsonian translocation between chromosomes 21 and 14 14 q 21 q translocation heterozygote Three chromosome segregation patterns Fig. 13. 22 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 44

Transposable elements (TEs) are movable genetic elements TEs are any segment of DNA that evolves the ability to move from place to place within a genome Marcus Rhoades (1930 s) and Barbara Mc. Clintock (1950 s) inferred existence of TEs from genetic studies of corn TEs have now been found in all organisms • Previously considered to be selfish DNA – carried no genetic information useful to host • Now known that some TEs have evolved functions that are beneficial to host • TE length ranges from 50 bp to 10 kb • TEs can be present in hundreds of thousands of copies per genome Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 45

Barbara Mc. Clintock: Discoverer of transposable elements Received Nobel Prize in 1983 Fig. 13. 23 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 46

TEs can move to many locations in a genome In situ hybridization for the copia TE in Drosophila Fig. 13. 24 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 47

Mammals have two major classes of TEs Long interspersed elements (LINEs) • Main LINE in humans is L 1 § Up to 6. 4 kb in length § 20, 000 copies in human genome Short, interspersed elements (SINEs) • Main SINE in humans is Alu § 0. 28 kb in length § 300, 000 copies in human genome, dispersed at ~ 10 kb intervals L 1 and Alu sequences make up 7% of the human genome Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 48

TEs in the corn genome Mottling of kernels caused by movements of a TE into and out of a pigment gene Fig. 13. 25 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 49

Two groups of TEs Retroposons • Move via reverse transcription of an RNA intermediate § e. g. copia elements in Drosophila, L 1 and Alu in humans Transposons • Move directly without being transcribed into RNA § e. g. TEs studied by Mc. Clintock in corn, P elements in Drosophila Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 50

Two kinds of retroposons Both types carry a gene for reverse transcriptase Has poly. A tail at 3'end of an RNA-like DNA strand Has long terminal repeats (LTRs) oriented in the same direction on either side of element Fig. 13. 26 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 51

Evidence that retroposons move via RNA intermediates Experiment done with Ty 1 retroposon of yeast Ty 1 with an intron cloned into a plasmid All new insertions of this Ty 1 into the yeast genome lacked the intron The intron must have been removed by splicing from an RNA Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 Fig. 13. 26 b 52

How retroposons move Reverse transcriptase makes a double-stranded retroposon c. DNA Staggered cut is made in genomic target site Retroposon c. DNA inserts into target site Sticky ends of target site are filled in, creating two copies of the 5 bp target site Original copy remains while new copy inserts into another genomic location Fig. 13. 26 c Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 53

Transposon structure Most transposons contain: • Inverted repeats (IRs) of 10 -200 bp long at each end • Gene encoding transposase, which recognizes the IRs and cuts at border between the IR and genomic DNA Fig. 13. 27 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 54

P elements in Drosophila melanogaster Most laboratory strains of D. melanogaster are M strains • Isolated in early 1900 s • Have no P elements Natural populations of D. melanogaster are P strains • Isolated since 1950 • Have many copies of P elements Hybrid dysgenesis - cross P male with M female • Offspring are sterile, have high levels of mutation, and chromosome breaks • Elevated levels of P element transposition Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 55

Genomes often contain defective copies of TEs Many TEs sustain deletions during the process of transposition or after transposition • Deletion of promoter for retroposon transcription • Deletion of reverse transcriptase gene or transposase gene • Deletion of IRs • Most SINEs and LINEs in human genome are defective Autonomous TEs – nondeleted TEs that can transpose on their own Nonautonomous TEs – defective TEs that can transpose only if transposase activity expressed from intact TE Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 57

TEs can disrupt genes and alter genomes TE insertion can result in altered phenotype • TE can insert within coding region of a gene • TE can insert near a gene and affect its expression • Examples: Drosophila white gene (Fig. 13. 28), wrinkled peas studied by Mendel, hemophilia in humans caused by Alu insertion into clotting factor IX TEs can trigger spontaneous chromosomal rearrangements • Unequal crossing over between TEs (Fig. 13. 29 a) Gene relocation due to transposition • Formation of composite TE (Fig. 13. 29 b) Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 58

Spontaneous mutations in the white gene of Drosophila arising from TE insertions Eye color phenotype depends on the TE involved (pogo, copia, roo, and Doc) and where it inserts Fig. 13. 28 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 59

Unequal crossing-over between TEs Can occur between TEs found in slightly different locations on homologous chromosomes Fig. 13. 29 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 60

Two transposons can form a large, composite transposon Composite transposons • Can occur when two copies of a TE integrate in nearby locations on the same chromosome • Transposase can recognize outermost IR sequences and move intervening sequences to a different location • Can move up to 400 kb of DNA • Mediates transfer of drug resistance genes between different strains and species of bacteria (discussed in Chapter 14) Fig. 13. 29 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 61

Rearrangements and evolution: A speculative comprehensive example Deletions • May move the coding region of one gene closer to regulatory sequences of another gene • Timing or tissue-specificity of expression may be altered Duplications • One copy of the gene retains original function and the new copy evolves new functions • Generation of multi-gene families Inversions • Crossover suppression can ensure that beneficial alleles of closely-linked genes do not separate by recombination Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 62

Rearrangements and evolution: A speculative comprehensive example (cont) Translocations • Robertsonian translocations can lead to reproductive isolation and speciation § e. g. Two populations of mice on the island of Madeira (Fig. 13. 30) Transpositions • Create novel mutations, duplications, inversions that affect gene functions in beneficial ways Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 63

Rapid chromosomal evolution in house mice on the island of Madeira One population of mice introduced to island in 1400 s Two populations evolved different sets of Robertsonian translocations, hybrid offspring are sterile Fig. 13. 30 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 64

Aneuploidy is the loss or gain of one or more chromosomes Aneuploids – individuals whose chromosome number is not an exact multiple of the haploid number (n) for that species • Monosomic – individuals that lack one chromosome from the normal diploid number (2 n – 1) • Trisomic – individuals that have one chromosome in addition to the normal diploid number (2 n + 1) • Tetrasomic – organisms with four copies of a particular chromosome (2 n + 2) Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 65

Deleterious effects of autosomal aneuploidy in humans Most autosomal aneuploidies and trisomies are lethal and result in spontaneous abortion Trisomy 21 (Down syndrome) is the most frequently observed autosomal trisomy • Majority of Down syndrome results from nondisjunction during maternal meiosis I (Fig. 13. 32 a) Individuals with monosomy 21 survive for only a short time after birth Two autosomal trisomies allow birth, but cause severe developmental abnormalities and early death • Trisomy 18 causes Edwards syndrome • Trisomy 13 cause Patau syndrome Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 66

X chromosome aneuploidies X-inactivation results in dosage compensation for most genes on the X chromosome • Some genes on X chromosome escape inactivation • X reactivation occurs in oogonia so that every mature ovum receives an active X XXY individuals – Klinefelter syndrome (see Fig. 13. 31) • Some X-linked genes expressed at twice the normal level and result in skeletal abnormalities, long limbs, and sterility XO individuals – Turner syndrome • Sterility may be caused by decreased dosage of X-linked genes in oogonia Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 67

Humans tolerate X chromosome aneuploidy because of X inactivation Fig. 13. 31 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 68

Aneuploidy is caused by nondisjunction Nondisjunction is the failure of chromosomes to segregate normally and can occur during either meiosis I or meiosis II Fig. 13. 32 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 69

Aneuploids beget aneuploid progeny Offspring of fertile aneuploids have an extremely high chance of aneuploidy because of production of unbalanced gametes Fig. 13. 32 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 70

Mistakes in chromosome segregation can occur in somatic cells Mitotic nondisjunction – failure of sister chromatids to separate during anaphase of mitosis Chromosome loss – lagging chromatid that is not pulled to either spindle pole at mitotic anaphase Mosaic organism • Aneuploid cells can survive and undergo further rounds of mitosis, producing clones of aneuploid cells • Side-by-side existence of aneuploid and normal tissues • e. g. Mitotic nondisjunction of X chromosome § Gynandromorphs in XX Drosophila (Fig. 13. 33 c) § Some cases of Turner and Down syndrome in humans Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 71

Nondisjunction during mitosis can generate clones of aneuploid cells Fig. 13. 33 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 72

Some euploid species are not diploid Euploids carry complete sets of chromosomes • Polyploids – carry ≥ 3 complete sets of chromosomes • Monoploids – 1 x, carry only one set of chromosomes • Triploids – 3 x, three complete sets of chromosomes • Tetraploids – 4 x, four complete sets of chromosomes • Monoploidy and polyploidy rarely observed in animals § Exceptions – in some species of ants and bees, males are monoploid and females are diploid; hermaphroditic worms are polyploid; some fish are tetraploid § Polyploidy in humans is lethal Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 73

Chromosome numbers x = the number of different chromosomes that make up a single, complete set n = number of chromosomes in gametes In diploids, x = n For polyploids, x ≠ n (e. g. bread wheat is hexaploid, x = 7, 6 x = 42, n = 21) Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 74

Creation and use of monoploid plants Creation of monoploid plants (see Fig. 13. 34 a): • Special treatment of germ cells from diploid species • Rare spontaneous events in large, natural populations • Usually sterile, but can easily be converted to diploid (Fig. 13. 34 c) Uses of monoploid plants (see Fig. 13. 34 b): • Can visualize recessive traits directly, without crosses to homozygosity • Introduce mutations into individual monoploid cells • Select for desirable phenotypes (herbicide resistance) • Hormone treatment to grow cells into monoploid plants Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 75

Colchicine treatment prevents spindle formation and results in doubling of chromosome numbers Fig. 13. 34 c Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 77

Formation of a triploid organism Diploid gametes may arise from 4 x parent or from a diploid with defects in meiosis (defect in spindle or defect at cytokinesis) Fig. 13. 35 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 78

Meiosis in a triploid organism Regardless of how chromosomes pair, there is no way to ensure that gametes contain a complete balanced set of chromosomes All polyploids with odd numbers of chromosome sets are sterile because they cannot produce balanced gametes Fig. 13. 35 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 79

Generation of tetraploid (4 x) cells Tetraploid cells occur during mitosis in a diploid when chromosomes fail to separate into two daughter cells • If tetraploidy occurs in gamete precursors, diploid gametes are produced • Union of two diploid gametes produces a tetraploid organism • Autopolyploid – all chromosome sets are derived from the same species Fig. 13. 36 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 80

In a tetraploid, pairing of chromosomes as bivalents generates balanced gametes Four copies of each group of homologs pair two-bytwo to form two bivalents Successful tetraploids produce balanced 2 X gametes and are fertile Fig. 13. 36 b Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 81

Gametes formed by A A a a tetraploids Tetraploids generate unusual Mendelian ratios Fig. 13. 36 c Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 82

Polyploids in agriculture One-third of all known flowering plant species are polyploid Polyploidy often results in increased size and vigor Many polyploid plants have been selected for agricultural cultivation • Tetraploids – alfalfa, coffee, peanuts, Macintosh apples, Bartlett pear • Octaploids – strawberries (Fig. 13. 37) Allopolyploid – hybrids in which chromosome sets come from distinct, but related, species Amphidiploid – has two diploid parental species • e. g. Raphanobrassica – sterile F 1 from crossing cabbages and radishes, has 18 chromosomes (9 from each parent) Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 83

Creation of the allopolyploid Triticale F 1 hybrid of wheat and rye is sterile because there are no pairing partners for the rye chromosomes Fig. 13. 38 a Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 84

Fertile Triticale can be created from infertile F 1 hybrid Triticale Different Triticale hybrids have been generated • Some combine high yield of wheat with ability of rye to grow in unfavorable enviroments • Some combine high level of protein from wheat with high level of lysine from rye Fig. 13. 38 a (cont) Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 85

Emergent technologies: Beyond the karyotype Two main problems with traditional karyotyping • Procedure is tedious and microscopic analysis is subjective • Very low resolution – cannot detect deletions or duplications of < 5 Mb Development of microarray-based technologies • Can scan entire genome for chromosomal rearrangements and aneuploidy • Has much higher accuracy, resolution, and throughput • Comparative genomic hybridization (Fig. 13. 39) § Also called "virtual karyotyping" Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 86

Preparation of microarray and samples for comparative genomic hybridization (CGH) Fig. 13. 39 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 87

Detection of duplications and deletions by CGH After hybridization of DNA samples, analyze microarray for ratio of yellow (control DNA) and orange (test DNA) (c) Incubate microarray with combined samples Fig. 13. 39 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 88

Aneuploidy in the human population Incidence of abnormal phenotypes caused by aberrant chromosome organization or number is 0. 004% Half of spontaneously aborted fetuses have chromosome abnormalities Incidence of abnormal phenotypes caused by single-gene mutations is 0. 010% Table 13. 2 Copyright © The Mc. Graw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al. , 4 th edition, Chapter 13 89