Changes in chromosome structure that are large enough to be observed microscopically or with cytological methods. Includes changes as major as POLYPLOIDY to less global changes such as chromosome deletions.

Karyotype
metaphase chromosomes from actively growing cells. Arranged in pairs, and by size. Classified according to location of centromere:

• metacentric - centromere approx in the middle
• submetacentric - centromere is displaced to one end, creating a long and short arm
• acrocentric - centromere near one end, creating a long arm and a knob
• telocentric - centromere at or near the end of the chromosome

• Giemsa stain - G bands, A-T rich
• quinacrine mustard - Q bands, fluoresce under UV light
• C bands, regions of heterochromatin near centromere
• R bands, G-C rich

I) CHANGES IN NUMBER, OR SETS, OF CHROMOSOMES
    A) Polyploidy - changes in complete sets of chromosomes (3n, 4n, etc)
        Much more common in plants than animals.
        More likely to have an even number of sets.
        Found in some lower invertebrates.
        One mammal, the red viscacha rat from Argentina.

    B) Aneuploidy - change in the number of chromosomes

• nullisomy - loss of both members of a homologous pair, 2n-2. Humans = 44
• monosomy - loss of a single chromosome, 2n-1. Humans = 45
• trisomy - gain of a single chromosome, 2n+1. Three homologous copies of one chromosome. Humans = 47
• tetrasomy - gain of two homologous chromosomes, 2n+2. Four homologous copies of one chromosome. Humans = 48

    Effects of aneuplody often severe -WHY?
        - gene dosage effect for every gene on the chromosome

    1. Sex-chromosome aneuploids - most common (least deleterious) aneuploidy seen in humans (Ch. 4 text).

• Turner syndrome "XO" 1/3000 female births
• Kleinfelter syndeome, XXY 1/1000 male births
• other combinations

• trisomy 21 or Down syndrome. Most common autosomal defect, 1/700 births.
• primary Down syndrome - three full copies of chr. 21.

Most often due to nondisjunction in the egg. Incidence of nondisjunction increases with mother's age. (Fig 9.23 text)
• familial Down syndrome - 4% of Down cases. The long arm of chr. 21 is attached to another chromosome; a translocation (fig 8.24 text)
• trisomy 18 or Edward syndrome, 1/8000 live births
• trisomy 13 or Patau syndrome, 1/15,000 live births
• trisomy 8, 1/25,000-50,000 live births

• deletion
• duplication
• inversion
• paracentric - centromere is outside of the inversion loop
• pericentric - inverted section contains the centromere
• translocation

Inversion
    Requires two breaks in the same chromosome.
Possible effects:
"position effect", change in gene expression because of change in surrounding DNA.
Reduction in crossover frequency within the inverted region. Must form a loop in order to line up the genes correctly.
If crossing over does occur within the inversion loops, not all the gametes will be viable; may result in a dicentric or acentric chromosome.

Translocation
    Movement of a piece of one chromosome to another. Can also be reciprocal translocation - the ends of two nonhomologous chromosomes are translocated to each other.
Possible efects:
position effects, new linkage rearrangements

Duplication
gene dosage effects

    B) Chromosomal rearrangements in humans

• fragile-X syndrome, 1/1250 males, 1/2000 females. A region at the X-chromosome tip that looks like it is hanging by a thread and breaks off more easily. (fig 8.15 text). Increase in the number of CCG repeats in the FMR-1 gene. Normally 6-50, but increases to 230-2000 copies.

• Cri-du-chat (46, XX or XY, 5p-). Deletion in "p" arm of chromosome 5 (Fig 8.16, text)

    C) Chromosome mutations and cancer
    Are mutations cause or result of cancer?
    Some types of tumors are consistently associated with specific chromosome mutations.
    Deletions, inversions, and translocations assoc. with specific cancers.

    1. deletions - remove "tumor suppressor genes" that control the cell cycle.
    2. inversions, translocations - may disrupt tumor suppressor genes. May cause fusion protein with altered regulation. May transfer a cancer-causing gene to a new location where it is activated by different regulatory sequences.

• Philadelphia chromosome - shortened chromosome 22. 90% of patients with chronic myeloid leukemia. Reciprocal translocation between the long arm of chromosome 22 and the tip of the long arm of chromosome 9. Part of c-ABL from chromosome 9 is fused with the BCR gene from chromosome 22. Fusion protein much more active than the normal protein. Stimulates cell division.

• Burkitt lymphoma - cancer of B lymphocyles. Recip translocation btwn a piece of chromosome 8 and chr. 2, 14, or 22 which carries genes for immune response. The c-MYC gene is now next to a gene for an immunoglobulin protein. c-MYC is expressed in the B cells and stimulates cell division.