Chapter 16Variations in Chromosome Structure and Number

Most human malignant tumors have chromosomal mutations.◦ a. The most common are translocations.◦ b. There is much variation in chromosome

abnormalities, however, and they include simple rearrangements to complex changes in chromosome structure and number.

◦ c. Many tumor types show a variety of mutations.

◦ d. Some, however, are associated with specific chromosomal abnormalities.

Chronic myelogenous leukemia (CML; OMIM 151410) 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 (Ph1) 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 ABL oncogene.

◦ iv. The hybrid gene arrangement causes expression of a leukemia-producing constitutively activated tyrosine kinase. The drug Gleevec blocks the tyrosine kinase, reducing white blood cell proliferation.

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 in heterochromatin).

This is an example of an epigenetic effect since the DNA sequence of the gene is not affected.

An example is the white-eye (w) locus in Drosophila:◦ a. An inversion moves the w1 gene from a

euchromatin region of the X chromosome to a position in heterochromatin.

◦ b. In a w1 male, or a w1/w female, where w1 is involved in the inversion, the eyes will have white spots resulting from the cells where the w1 allele was moved and inactivated.

Chromosomes in cultured human cells develop narrowings or unstained areas (gaps) called fragile sites; over 40 human fragile sites are known.

A well-known example is fragile X syndrome, in which a region at position Xq27.3 is prone to breakage and mental retardation may result.◦ a. Fragile X syndrome has an incidence in the

United States 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

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 to 54 CGG repeats, with an

average of 29.◦ ii. Normal transmitting carrier males, their daughters, and

some other carrier females have 55 to 200 copies but do not show symptoms.

◦ iii. Individuals with fragile X syndrome have 200 to 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 FMR-1 product (FMRP) is an RNA-binding protein. The triplet repeat expansion in FMR-1 affects expression of certain mRNAs, blocking protein synthesis. FMRP is active at synapses in the brain.

◦ vi. In individuals with the full mutation, C nucleotides of the CGG repeats are methylated, silencing the FMR-1 gene and resulting in mental retardation.

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.

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.

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. One chromosome is involved. Ii. Nondisjunction occurs in both meiotic divisions. Iii. Nondisjunction occurs in mitosis (result is somatic cells with unusual

chromosome complements).

Autosomal aneuploidy is not well tolerated in animals, and in mammals it is detected mainly after spontaneous abortion. Aneuploidy is much better tolerated in plants. There are four main types of aneuploidy:◦ a. Nullisomy involves loss of one

homologous chromosome pair (the cell is 2N - 2).

◦ b. Monosomy involves loss of a single chromosome (2N - 1).

◦ c. Trisomy involves one extra chromosome, so the cell has three copies of one chromosome and two of all the others (2N + 1).

◦ d. Tetrasomy involves an extra chromosome pair, so the cell has four copies of one chromosome and two of all the others (2N + 2).

A monosomic cell (2N - 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.

A trisomic cell (2N + 1) with the genotype +/+/a is an example (assuming that this organism can tolerate trisomy, and no crossing-over occurs).◦ 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).

Trisomy-21 occurs in an estimated 3,510/106 conceptions, and 1,430/106 births.◦ a. Down syndrome (OMIM 190685) individuals

are characterized by: i. Low IQ ii. Epicanthal folds over eyes iii. Short and broad hands iv. Below-average height

A female fetus before birth produces primary oocytes in her ovaries that stop their development at prophase I of meiosis.

After puberty, secondary oocytes develop from the primary ones, entering the second meiotic division but again arresting, this time at metaphase II.

If fertilization occurs, the second meiotic division is completed. The probability of nondisjunction increases with the length of

time the primary oocyte is in the ovary. Amniocentesis or chorionic villus sampling can determine

whether the fetus has a normal complement of chromosomes. Additional risks for Down syndrome include:

◦ i. Increased paternal age◦ ii. Smoking in mothers who have an error in meiosis II, especially

if they use oral contraceptives (oral contraceptives alone do not increase risk)

Robertsonian translocation (centric fusion) produces three copies of the long arm of chromosome 21, resulting in familial Down syndrome (Figure 16.18).◦ i. In this nonreciprocal translocation, two nonhomologous acrocentric

(centromeres near end) chromosomes break at centromeres. (1) 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).

(2) The short arms also fuse, forming a reciprocal product that is usually lost within a few cell divisions.

(3) 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.

Trisomy-13◦ Trisomy-13 (Patau syndrome) occurs in 2/104 live births, and most die

within the first 3 months. Characteristics: a. Cleft lip and palate b. Small eyes c. Polydactyly (extra fingers and toes) d. Mental and developmental retardation e. Cardiac and other abnormalities

Trisomy-18◦ 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 16.21): a. Small size with multiple congenital malformations throughout the body. b. Clenched fists. c. Elongated skull. d. Low-set ears. e. Mental and developmental retardation.

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.

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 (3N) zygote.

◦ c. Fusion of two gametes that each have two sets of chromosomes produces a tetraploid (4N) zygote.

◦ d. Polyploidy of somatic cells can result from mitotic nondisjunction of complete chromosome sets.

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. Mutants are easily produced from monoploid individuals since mutants can be isolated directly.

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 (6N); the strawberry is octaploid (8N). v. North American sucker fish, salmon, and some salamanders are polyploid.

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.

Triploids are unstable in meiosis because random segregation means that balanced gametes (either exactly N or exactly 2N) 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.

Polyploidy is more common in plants, probably due to self-fertilization, allowing even-number 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 such as bananas, grapes, and

watermelons (2) Grasses, garden flowers, crop plants, and forest

trees

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 N1 1 N2 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 (2N1 1 2N2). The diploid sets function normally in meiosis, and fertile allotetraploid plants result.

◦ (3) An example of allopolyploidy is that of crosses between cabbages (Brassica oleracea) and radishes (Raphanus sativus), which both have a chromosome number of 18. (a) The F1 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 F1 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 F1 hybrids and are named

Raphanobrassica.

Polyploidy is the rule in agriculture, where polyploids include all commercial grains (e.g., bread wheat, Triticum aestivum, an allohexaploid of three plant species), most crops, and common flowers.