Peter J Russell CHAPTER 21 Chromosomal Mutations edited

Peter J. Russell CHAPTER 21 Chromosomal Mutations edited by Yue-Wen Wang Ph. D. Dept. of Agronomy, 台大農藝系 NTU 遺傳學 601 20000 1

Types of Chromosomal Mutations 1. Variations in chromosome structure or number can arise spontaneously or be induced by chemicals or radiation. Chromosomal mutation can be detected by: a. Genetic analysis (observing changes in linkage). b. Microscopic examination of eukaryotic chromosomes at mitosis and meiosis (karyotype analysis). 2. Chromosomal aberrations contribute significantly to human miscarriages, stillbirths and genetic disorders. a. About 1⁄2 of spontaneous abortions result from major chromosomal mutations. b. Visible chromosomal mutations occur in about 6/1, 000 live births. c. About 11% of men with fertility problems, and 6% of those institutionalized with mental deficiencies have chromosomal mutations. 台大農藝系 遺傳學 601 20000 2

Variations in Chromosome Structure 1. Mutations involving changes in chromosome structure occur in four common types: a. Deletions. b. Duplications. c. Inversions (changing orientation of a DNA segment). d. Translocations (moving a DNA segment). 2. All chromosome structure mutations begin with a break in the DNA, leaving ends that are not protected by telomeres, but are “sticky” and may adhere to other broken ends. 3. Polytene chromosomes (bundles of chromatids produced by DNA synthesis without mitosis or meiosis) are useful for studying chromosome structure mutations. a. Polytene chromosomes are easily detectable microscopically. b. Homologs are tightly paired, joined at the centromeres by a proteinaceous chromocenter. c. Detailed banding patterns are characterized for the four polytene chromosomes, with each band averaging 30 kb of DNA, enough to encode 台大農藝系 遺傳學 601 20000 several genes. 3

Deletion 1. In a deletion, part of a chromosome is missing (Figure 21. 1). a. Deletions start with chromosomal breaks induced by: i. Heat or radiation (especially ionizing). ii. Viruses. iii. Chemicals. iv. Transposable elements. v. Errors in recombination. b. Deletions do not revert, because the DNA is missing. 2. The effect of a deletion depends on what was deleted. a. 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. b. 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. ) c. Large deletions can be detected by unpaired loops seen in karyotype analysis (Figure 21. 2). 台大農藝系 遺傳學 601 20000 4

Fig. 21. 1 A deletion of a chromosome segment Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 5

Fig. 21. 2 Cytological effects of meiosis of heterozygosity for a deletion Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 6

3. Deletion mapping can indicate the physical location of a gene on the chromosome, because deletion of the dominant allele in a heterozygote results in the recessive phenotype. a. Expression of the recessive trait caused by the absence of a dominant allele is called pseudodominance. b. Demerec and Hoover (1936) studied a fly strain heterozygous for the X-linked recessive mutations y, ac and sc (Figure 21. 3). i. Genetic analysis shows the 3 loci linked at the left end of the X chromosome. ii. Deletion experiments correlate the deleted DNA with loss of dominant alleles and the appearance of pseudodominance. iii. This technique was used to produce the detailed physical map of Drosophila polytene chromosomes. 台大農藝系 遺傳學 601 20000 7

Fig. 21. 3 Use of deletions to determine the physical locations of genes on Drosophila polytene chromosomes Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 8

4. Human disorders caused by large chromosomal deletions are generally seen in heterozygotes, since homozygotes usually die. Examples include: a. Cri-du-chat (“cry of the cat”) syndrome, resulting from deletion of part of the short arm of chromosome 5 (Figure 21. 4). b. Prader-Willi syndrome, occurring in heterozygotes with part of the long arm of one chromosome 15 homolog deleted. The deletion results in feeding difficulties, poor male sexual development, behavioral problems and mental retardation. 台大農藝系 遺傳學 601 20000 9

Duplication 1. Duplications result from doubling of chromosomal segments, and occur in a range of sizes and locations (Figure 21. 5). a. Tandem duplications are adjacent to each other. b. Reverse tandem duplications result in genes arranged in the opposite order of the original. c. Tandem duplication at the end of a chromosome is a terminal tandem duplication (Figure 21. 6). d. Heterozygous duplications result in unpaired loops, and may be detected cytologically. 台大農藝系 遺傳學 601 20000 10

Fig. 21. 5 Duplication, with a chromosome segment repeated Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 11

Fig. 21. 6 Forms of chromosome duplications are tandem, reverse tandem, and terminal tandem duplications Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 12

2. An example is the Drosophila eye shape allele, Bar, that reduces the number of eye facets, giving the eye a slit-like rather than oval appearance (Figure 21. 7). a. The Bar allele resembles an incompletely dominant mutation: i. Females heterozygous for Bar have a kidney-shaped eye that is larger and more faceted than in a female homozygous for Bar. ii. Males hemizygous for Bar have slit-like eyes like those of a Bar/Bar female. b. Cytological examination of polytene chromosomes showed that the Bar allele results from duplication of a small segment (16 A) of the X chromosome. 台大農藝系 遺傳學 601 20000 13

Fig. 21. 7 Chromosome constitutions of Drosophila strains Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 14

3. Duplications like Bar probably result from unequal crossing-over, perhaps due to similar DNA sequences in neighboring chromosome regions (Figure 21. 8). 4. Bar homozygote parents (Bar/Bar X Bar/Y) sometimes produce offspring that do not show the Bar phenotype: a. About 1 in 1, 600 progeny flies will have wild-type eyes. b. About 1 in 1, 600 will have double-Bar eyes, with 3 copies of the 16 A sequence and eyes even more reduced than Bar. c. Unequal crossing-over would account for these results. 5. Multigene families result from duplications. Hemoglobin (Hb) is an example: a. Each Hb contains two copies of two subunits (e. g. , 2 α-globins and 2 βglobins), and the identity of the subunits changes with the organism’s developmental stage. b. Genes for the α-type polypeptides are clustered together on 1 chromosome, and those for β-type polypeptides are clustered on another. c. α-type genes have similar sequences, as do β-type. They probably result from duplication and subsequent sequence divergence. 台大農藝系 遺傳學 601 20000 15

Fig. 21. 8 Unequal crossing-over and the Bar mutant of Drosophila Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 16

Inversion Animation: Crossing-over in an Inversion Heterozygote 1. Inversion results when a chromosome segment excises and reintegrates oriented 1800 from the original orientation. There are two types (Figure 21. 9): a. Pericentric inversions include the centromere. b. Paracentric inversions do not include the centromere. 2. Inversions generally do not result in lost DNA, but phenotypes can arise if the breakpoints are in genes or regulatory regions. 3. Linked genes are often inverted together. For example: a. If a normal chromosome has the gene order ABCDEFGH, inversion of the BCE) segment would give the gene order ADCBEFGH. i. A fly homozygous for the inversion (ADCBEFGH/ADCBEFGH) will have normal crossing over and meiosis, and no problems with gene duplications or deletions. ii. A heterozygote (ABCDEFGH/ADCBEFGH) suffers serious genetic consequences due to unequal crossover. 台大農藝系 遺傳學 601 20000 17

Fig. 21. 9 Inversions Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 18

4. Different recombinant chromosomes are produced by crossover in a heterozygote, depending on centromere involvement: a. Paracentric inversions (no centromere) result in visible inversion loops between homologous chromosomes (Figures 21. 10 and 21. 11). i. Crossover in the inversion region results in unbalanced sets of genes, and gametes or zygotes derived from recombined chromatids may be inviable due to abnormal gene dose. ii. Without crossover in the looped region, gametes receive complete sets of genes (two gametes with normal and two with inversions) and are viable. iii. Effects of a single crossover within an inverted segment in a heterozygote include: (1) Joining of homologous regions of two chromatids to produce a dicentric bridge, and corresponding loss of an acentric fragment. (2) During anaphase the two centromeres of the dicentric chromosome migrate towards opposite poles, causing the bridge to break, and producing two chromatids with deletions. (3) The second meiotic division distributes one chromatid to each gamete: (a) Two gametes carry normal sets of genes (one in the normal order and the other in inverted order). (b) Two gametes are missing many genes, and are inviable. (4) Female mammals often shunt dicentric chromosomes or acentric 台大農藝系 遺傳學 601 20000 fragments to the polar bodies, so fertility may not be so reduced. 19

Fig. 21. 10 Consequences of crossing-over in a paracentric inversion Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 20

Fig. 21. 11 Meiotic products resulting from a single crossover within a heterozygous, pericentric inversion loop Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 21

b. Pericentric inversions that undergo a single crossover will result in: i. Two viable gametes, one with genes in normal order, the other with the inversion. ii. Two inviable gametes, each with some genes deleted and others duplicated. c. Some crossover events within the inversion loop do not affect gamete viabiity Examples: i. A double crossover close together involving the same two chromatids (a 2 -strand double crossover). ii. Changes where duplicated and deleted segments do not affect gene expression (e. g. , very small segments). iii. In mammals, inverted segments may remain unpaired, and so avoid crossing-over. 台大農藝系 遺傳學 601 20000 22

Translocation Animation: Meiosis in a Translocation Heterozygote 1. A change in location of a chromosome segment is a translocation. No DNA is lost or gained. Simple translocations are of two types (Figure 21. 12): a. Intrachromosomal, with a change of position within the same chromosome. b. Interchromosomal, with transfer of the segment to a nonhomologous chromosome. i. If a segment is transferred from one chromosome to another, it is nonreciprocal. ii. If segments are exchanged, it is reciprocal. 2. Gamete formation is affected by translocations. a. In homozygotes with the same translocation on both chromosomes, altered gene linkage is seen. b. Gametes produced with chromosomal translocations often have unbalanced duplications and/or deletions and are inviable, or produce disorders like familial Down syndrome. c. Strains homozygous for a reciprocal translocation form normal gametes. 台大農藝系 遺傳學 601 20000 23

Fig. 21. 12 Translocations Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 24

d. Strains heterozygous for a reciprocal translocation must pair a set of normal chromosomes (N) with a set of translocated ones (T). i. Result is a cross-like configuration in meiotic prophase I of four associated chromosomes, each partially homologous to two others in the group (Figure 21. 13). ii. Anaphase I segregation may occur in three different ways (crossover will not be considered). (1) Alternate segregation moves alternate centromeres to the same poles (e. g. , N 1 and N 2 one direction, T 1 and T 2 the other). Gametes are viable, with either normal or translocated chromosomes. (2) Adjacent 1 segregation moves adjacent nonhomologous centromeres to the same pole (e. g. , N 1 and T 2 one direction, N 2 and T 1 the other). Gametes are inviable due to gene duplications and deletions. (3) Adjacent 2 segregation is rare, moving different pairs of adjacent homologous centromeres to the same pole (N 1 and T 1 one direction, N 2 and T 2 the other). These gametes are usually inviable. iii. Thus, heterozygotes for a reciprocal translocation are considered semi 台大農藝系 遺傳學 601 20000 -sterile. 25

Fig. 21. 13 Meiosis in a translocation heterozygote in which no crossover occurs Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 26

3. Animal gametes with large duplications or deletions may function, but the zygote generally dies. Small duplications or deletions may be viable. Plant pollen with duplications or deletions is usually nonfunctional. 4. Some tumors have chromosomal abnormalities (either in number or structure) early in inception, and develop more mutations over time that often correlate with progression to uncontrolled growth. Examples: a. Chronic myelogenous leukemia (CML) involves a reciprocal translocation of chromosomes 9 and 22. i. Myeloblasts (stem cells of white blood cells) replicate uncontrollably. ii. 90% of CML patients have the Philadelphia chromosome (Ph 1) reciprocal translocation. iii. The reciprocal translocation causes transition from a differentiated cell to a tumor cell, by translocating a proto-oncogene from chromosome 9 to chromosome 22, and probably converting it to the c-abl oncogene. iv. The hybrid gene arrangement causes expression of a leukemia-producing gene product. b. Burkitt lymphoma (BL) involves a reciprocal translocation of chromosomes 8 and 14. 台大農藝系 遺傳學 601 20000 27

Fig. 21. 14 Origin of the Philadelphia chromosome in chronic myelogenous leukemia (CML) by a reciprocal translocation involving chromosomes 9 and 22 Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 28

Position Effect 1. Sometimes inversions or translocations change phenotypic expression of genes by the position effect, for example by moving a gene from euchromatin to heterochromatin (transcription generally occurs in euchromatin but not heterochromatin). 2. An example is the white-eye (w) locus in Drosophila: a. An inversion moves the w gene from a euchromatin region of the X chromosome to a position in heterochromatin. b. In a w+ male, or a w+/w female, where w is involved in the inversion, the eyes will have white spots resulting from the cells where the w allele was moved and inactivated. 3. The Bar eye in Drosophila shows a different kind of position effect. a. Recall that different alleles are produced by duplication of the 16 A region of the X chromosome (Figure 21. 7). i. Wild-type has one copy of the 16 A segment. ii. Bar has two copies of 16 A. iii. double-Bar has three copies of 16 A. b. Different combinations of locations may be tested for this allele. For example: i. Flies that are Bar/Bar have four copies of the 16 A segment (two on each chromosome). ii. Flies that are double-Bar/+ also have four copies of the 16 A segment (three on one chromosome and one on the other). iii. Sturtevant (1925) showed that these arrangements do not produce the same phenotype: (1) Bar/Bar flies have an average of 68 eye facets, while double-Bar/ + has only 45. (2) In some way, the three adjacent 16 A segments exert a greater effect on eye development than the same number of segments on different chromosomes, indicating that position can affect gene expression. 台大農藝系 遺傳學 601 20000 29

Fig. 21. 15 Position effect and Bar eye in Drosophila Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 30

Fragile Sites and Fragile X Syndrome 1. Chromosomes in cultured human cells develop narrowings or unstained areas (gaps) called fragile sites; over 40 human fragile sites are known. 2. A well-known example is fragile X syndrome, in which a region at position Xq 27. 3 is prone to breakage and mental retardation may result. a. Fragile X syndrome has an incidence in the U. S. of about 1/1, 250 in males, and 1/2, 500 in females (heterozygotes). b. Inheritance follows Mendelian patterns, but only 80% of males with a fragile X chromosome are mentally retarded. The 20% with fragile X chromosome but a normal phenotype are called normal transmitting males. i. A normal transmitting male can pass the chromosome to his daughter(s). ii. Sons of those daughters frequently show mental retardation. c. About 33% of carrier (heterozygous) females show mild mental retardation. i. Sons of carrier females have a 50% chance of inheriting the fragile X. ii. Daughters of carrier females have a 50% chance of being carriers. 台大農藝系 遺傳學 601 20000 31

Fig. 21. 16 Diagram of a human X chromosome showing the location of the fragile site responsible for fragile X syndrome Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 32

d. Molecular analysis shows a repeated 3 -bp sequence, CGG, in the FMR-1 (fragile X mental retardation-1) gene, at the fragile X site. i. Normal individuals have 6– 54 CGG repeats, with an average of 29. ii. Normal transmitting carrier males, their daughters and some other carrier females have 55– 200 copies, but do not show symptoms. iii. Individuals with fragile X syndrome have 200– 1, 300 copies, indicating that tandem amplification of this sequence is tolerated until a threshold number of copies is reached. iv. Amplification of CGG repeats occurs only in females, perhaps during a slipped mispairing process during DNA replication. v. The function of the FMR-1 gene is unknown. It encodes a protein of unidentified function. 3. There are other examples of triplet repeat amplifications that cause disease above a threshold number of copies. In these examples, amplification can occur in both sexes. a. Myotonic dystrophy. b. Spinobulbar muscular atrophy (Kennedy disease). c. Huntington disease. 台大農藝系 遺傳學 601 20000 33

Variations in Chromosome Number 1. An organism or cell is euploid when it has one complete set of chromosomes, or exact multiples of complete sets. Eukaryotes that are normally haploid or diploid are euploid, as are organisms with variable numbers of chromosome sets. 2. Aneuploidy results from variations in the number of individual chromosomes (not sets), so that the chromosome number is not an exact multiple of the haploid set of chromosomes. 台大農藝系 遺傳學 601 20000 34

Changes in One or a Few Chromosomes 1. Aneuploidy can occur due to nondisjunction during meiosis. a. Nondisjunction during meiosis I will produce four gametes, two with a chromosome duplicated, and two that are missing that chromosome. i. Fusion of a normal gamete with one containing a chromosomal duplication will produce a zygote with three copies of that chromosome, and two of all others. ii. Fusion of a normal gamete with one missing a chromosome will result in a zygote with only one copy of that chromosome, and two of all others. b. Nondisjunction during meiosis II produces two normal gametes and two that are abnormal (one with two sibling chromosomes, and one with that chromosome missing). i. Fusion of abnormal gametes with normal ones will produce the genotypes discussed above. ii. Normal gametes are also produced, and when fertilized will produce normal zygotes. c. More complex gametic chromosome composition can result when: i. 1 chromosome is involved. ii. Nondisjunction occurs in both meiotic divisions. iii. Nondisjunction occurs in mitosis (result is somatic cells with unusual chromosome complements). 台大農藝系 遺傳學 601 20000 35

2. Autosomal aneuploidy is not well tolerated in animals, and in mammals is detected mainly after spontaneous abortion. Aneuploidy is much better tolerated in plants. There are four main types of aneuploidy (Figure 21. 17): a. Nullisomy involves loss of 1 homologous chromosome pair (the cell is 2 N - 2). b. Monosomy involves loss of a single chromosome (2 N - 1). c. Trisomy involves one extra chromosome, so the cell has three copies of one, and two of all the others (2 N + 1). d. Tetrasomy involves an extra chromosome pair, so the cell has four copies of one, and two of all the others (2 N + 2). 3. More than one chromosome or chromosome pair may be lost or added. Examples: a. A double monosomic aneuploidy has two separate chromosomes present in only one copy each (2 N - 1). b. A double tetrasomic aneuploidy has two chromosomes present in four copies each (2 N + 2). 台大農藝系 遺傳學 601 20000 36

Fig. 21. 17 Normal (theoretical) set of metaphase chromosomes in a diploid (2 N) organism (top) and examples of aneuploidy (bottom) Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 37

4. Some types of aneuploidy have serious meiotic consequences. Examples: a. A monosomic cell (2 N - 1): i. May produce gametes that are N (normal) and N - 1(monosomic). ii. Or, the unpaired chromosome may be lost completely, producing gametes that are all N - 1. b. A trisomic cell (2 N + 1) with the genotype +/+/a, would be an example (assuming that this organism can tolerate trisomy, and no crossing-over occurs) (Figure 21. 18). i. Gametes produced belong to four genotypic classes, in these proportions: (1) Two gametes with genotype +/a. (2) Two gametes with genotype +. (3) One gamete with genotype +/+. (4) One gamete with genotype a. ii. The cross of a +/+/a trisomic to an a/a individual will produce a phenotypic ratio of 5 wild type : 1 mutant (a). 台大農藝系 遺傳學 601 20000 38

Fig. 21. 18 Meiotic segregation possibilities in a trisomic individual Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 39

5. Human examples of aneuploidy in autosomes and sex chromosomes are summarized in Table 21. 1. a. Sex chromosome aneuploidy is found more often than autosome aneuploidy, because lyonization compensates for chromosome dosage. b. Autosomal monosomies are rarely found in humans, presumably because they are lost early in pregnancy. c. Autosomal trisomies account for about half of fetal deaths, and only a few are seen in live births. Most (trisomy-8, -13 and -18) result in early death, with only trisomy-21 (Down syndrome) surviving to adulthood. 台大農藝系 遺傳學 601 20000 40

d. Trisomy-21 occurs in an estimated 3, 510/106 conceptions, and 1, 430/106 births. i. Down syndrome individuals are characterized by: (1) Low IQ. (2) Epicanthal folds over eyes. (3) Short and broad hands. (4) Below-average height. ii. Table 21. 2 shows the correlation of maternal age and probability of trisomy-21. (1) A female fetus before birth produces primary oocytes in her ovaries that stop their development at prophase I of meiosis. (2) After puberty, secondary oocytes develop from the primary ones, entering the second meiotic division but again arresting, this time at metaphase II. (3) If fertilization occurs, the second meiotic division is completed. (4) The probability of nondisjunction increases with length of time the primary oocyte is in the ovary. (5) Amniocentesis or chorionic villus sampling can determine 遺傳學 601 20000 whether the fetus has a normal台大農藝系 complement of chromosomes. 41

Animation: Down Syndrome Caused by a Robertsonian Translocation iii. Robertsonian translocation (centric fusion) produces three copies of the long arm of chromosome 21, resulting in familial Down syndrome. (1) In this nonreciprocal translocation, two nonhomologous acrocentric (centromeres near end) chromosomes break at centromeres. (a) Both long arms become attached to the same centromere, creating a chromosome with the long arm of chromosome 21 and the long arm of chromosome 14 (or 15). (b) The short arms also fuse, forming a reciprocal product that is usually lost within a few cell divisions. (c) The heterozygous carrier of this chromosome is phenotypically normal, since the two copies of each major chromosome arm supply two copies of all essential genes. 台大農藝系 遺傳學 601 20000 43

Fig. 21. 20 Robertsonian translocation Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 44

(2) Mating of a heterozygous carrier and a normal individual has a high risk of Down syndrome offspring. (a)The normal parent produces normal gametes, with one copy each of chromosomes 14 and 21. (b) The heterozygous carrier parent produces three reciprocal pairs of gametes, each produced by different segregation of the three chromosomes involved. (c)Theoretically, the zygotes produced would be: (i) 1⁄6 with normal chromosomes 14 and 21 (like 1 parent). (ii) 1⁄6 heterozygous carriers with normal phenotype (like other parent). (iii) 1⁄6 inviable due to monosomy of chromosome 14. (iv) 1⁄6 inviable due to monosomy of chromosome 21. (v) 1⁄6 inviable due to trisomy of chromosome 14. (vi) 1⁄6 with trisomy of chromosome 21. These individuals have a normal chromosome number (46) but three copies of the long arm of chromosome 21, sufficient to cause Down syndrome. (vii) In summary, 1⁄2 the zygotes are inviable, and 1⁄3 of the live offspring are predicted to have Down syndrome, although the actual birth rate is lower 台大農藝系 遺傳學 601 20000 45

Fig. 21 The three segregation patterns of a heterozygous Robertsonian translocation involving the human chromosomes 14 and 21 Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 46

e. Trisomy-13 (Patau syndrome) occurs in 2/104 live births, and most die within the first 3 months. Characteristics include (Figure 21. 22): i. Cleft lip and palate. ii. Small eyes. iii. Polydactyly (extra fingers and toes). iv. Mental and developmental retardation. v. Cardiac and other abnormalities. 台大農藝系 遺傳學 601 20000 47

f. Trisomy-18 (Edwards syndrome) occurs in 2. 5/104 live births, and 90% die within 6 months. About 80% of Edwards syndrome infants are female. Characteristics include (Figure 21. 19): i. Small size with multiple congenital malformations throughout the body. ii. Clenched fists. iii. Elongated skull. iv. Low-set ears. v. Mental and developmental retardation. 台大農藝系 遺傳學 601 20000 48

Changes in Complete Sets of Chromosomes 1. Monoploidy and polyploidy involve complete sets of chromosomes, and so both are cases of euploidy. Euploidy is lethal in most animal species, but often tolerated in plants, where it has played a role in speciation and diversification. 2. Monoploidy and polyploidy can result when either round of meiotic division lacks cytokinesis, or when meiotic nondisjunction occurs for all chromosomes. a. Complete nondisjunction at meiosis I will produce 1⁄2 gametes with normal chromosomes, 1⁄4 with two sets of chromosomes and 1⁄4 with no chromosomes. b. A gamete with two sets of chromosomes fused with a normal gamete produces a triploid (3 N) zygote. c. Fusion of two gametes that each have two sets of chromosomes produces a tetraploid (4 N) zygote. d. Polyploidy of somatic cells can result from mitotic nondisjunction of complete chromosome sets. 台大農藝系 遺傳學 601 20000 49

Fig. 21. 24 Variations in number of complete chromosome sets Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings. 台大農藝系 遺傳學 601 20000 50

3. Monoploidy is rare in adults of diploid species due to recessive lethal mutations. a. Males of some species (e. g. , wasps, ants and bees) develop from unfertilized eggs and are monoploid. b. Plant experiments often use monoploids. i. Haploid cells are isolated from plant anthers and grown into monoploid cultures. ii. Colchicine (which inhibits mitotic spindle formation) allows chromosome number to double, producing completely homozygous diploid breeding lines. iii. Mutant genes are easily identified in monoploid organisms. 台大農藝系 遺傳學 601 20000 51

4. Polyploidy involves three or more sets of chromosomes, and may occur naturally (e. g. , by breakdown of the mitotic spindle), or by induction (e. g. , with chemicals such as colchicine). a. Nearly all plants and animals probably have some polyploid tissues. Examples: i. Plant endosperm is triploid. ii. Liver of mammals (and perhaps other vertebrates) is polyploid. iii. Giant abdominal neuron of Aplysia has about 75, 000 copies of the genome. iv. Wheat is hexaploid (6 N) and the strawberry is octaploid (8 N). v. North American sucker fish, salmon and some salamanders are polyploid. b. There are two classes of polyploids based on the number of chromosome sets: i. Even-number polyploids are more likely to be at least partially fertile, because the potential exists for equal segregation of homologs during meiosis. ii. Odd-number polyploids will always have unpaired chromosomes. Balanced gametes are rare and these organisms are usually sterile or have increased zygote death. 台大農藝系 遺傳學 601 20000 52

c. Triploids are unstable in meiosis, because random segregation means that balanced gametes (either exactly N or exactly 2 N) are rare. i. The probability of a triploid organism producing a haploid gamete is (1⁄2)n, where n is the number of chromosomes. ii. Triploidy is always lethal in humans, accounting for 15– 20% of spontaneous abortions and 1/104 live births, with most dying in the first month. iii. Tetraploidy in humans is also lethal, usually before birth, accounting for 5% of spontaneous abortions. d. Polyploidy is more common in plants, probably due to selffertilization, allowing an even-number of polyploids to produce fertile gametes and reproduce. Plant polyploidy occurs in two types: i. Autopolyploidy results when all sets of chromosomes are from the same species, usually due to meiotic error. Fusion of a diploid gamete with a haploid one produces a triploid organism. Examples include: (1) “Seedless” fruits like bananas, grapes and watermelons. (2) Grasses, garden flowers, crop plants and forest trees. 台大農藝系 遺傳學 601 20000 53

ii. Allopolyploidy results when the chromosomes are from two different organisms, typically from the fusion of haploid gametes followed by chromosome doubling. For example: (1) Fusion of haploid gametes from plant 1 and plant 2 produces an N 1 + N 2 hybrid plant. No chromosomal pairing occurs at meiosis, viable gametes are not produced and the plants are sterile. (2) Rarely, division error doubles the chromosome sets (2 N 1 + 2 N 2). The diploid sets function normally in meiosis, and fertile allotetraploid plants result. (3) An example is crosses between cabbages (Brassica oleracea) and radishes (Raphanus sativus), which both have a chromosome number of 18. (a) The F 1 hybrids have 9 chromosomes from each parent, and have a morphology intermediate between cabbages and radishes. They are mostly sterile. (b) A few seeds, some fertile, can be produced by the F 1 through meiotic errors. (i) Somatic cells in the resulting plants have 36 chromosomes, a full diploid set from both cabbages and radishes. (ii) These fully fertile plants look much like the F 1 hybrids, and are named Raphanobrassica. (4) Polyploidy is the rule in agriculture, where polyploids include all commercial grains (e. g. , bread wheat, Triticum aestivum, an 台大農藝系 601 20000 allohexaploid of three plant species), most遺傳學 crops and common flowers. 54