1. BIOL 2416 Chapter 16: Chromosomal Changes

2. Chromosomal Mutations
Changes in
Chromosome number
Chromosome structure
Induced by
Chemicals
radiation
Detected by
Genetic analysis (linkage studies)
Microscopic analysis
Karyotyping
Seen in 6/1000 of live births
Contribute significantly to
½ of miscarriages
Stillbirths
Genetic disorders
Seen in 11% of men with fertility problems
Seen in 6% of people institutionalized with mental deficiencies

3. Changes in Chromosome Structure
4 kinds:
Deletions
Duplications
Inversions
re-attaching DNA in opposite orientation
Translocation
moving DNA piece from one chromosome to another
Often studied using Drosophila polytene chromosomes
Chromatid bundles produced by DNA replication without mitosis/meiosis cell division
Tightly paired at centromeres
Easy to see banding patterns
All begin with a break in the DNA
Leaves sticky ends not protected by telomeres
Induced by:
Heat or radiation (especially ionizing)
Viruses
Chemicals
Transposable elements
Errors in recombination (Xover)

5. Deletions Among most devastating mutations (cannot recover lost piece)
Effect depends on actual deletion:
AA mutates to Aa (still normal)
Aa mutates to aa (abnormal)
Loss of centromere means acentric chromosomal piece will be lost during cell division
Detected by unpaired loops in karyotypes
Common disorders:
Cri-du-chat Syndrome (chromosome 5 piece deleted)
cat’s cry, microcephaly; round face; hypertelorism; micrognathia; prominent nasal bridge; epicanthic folds; hypotonia; severe psychomotor retardation
Prader-Willi Syndrome (paternal chromosome 15 piece deleted)
developmental delay, cryptorchidism (small or undescended testes), hyperphagia obesity (never feel full – can’t quit eating), short stature, mild retardation
Angelman Syndrome (maternal chromosome 15 piece deleted)
seizures, severe mental retardation, inappropriate laughter, a characteristic face that is small with a large mouth and prominent chin, fair skin,hair and eyes

6. Duplications Can be: Probably result from unequal Xing over
Tandem (adjacent)
Reverse tandem (adjacent in opposite order)
Terminal (at end of chromosome)
Probably result from unequal Xing over
Similar sequences elsewhere in chromosome)
Also seen as unpaired loops
Can result in multi-gene families (Hb alpha vs. beta)
E.g. Drosophila bar eye shape allele (slit-like rather than oval)
Resembles incompletely dominant mutation
Small X-chromosome segment (16A) duplicated
Female heterozygotes have kidney-shaped eyes (medium # of eye segments)
Hemizygous males have slits (low # of eye segments)

7. Inversions Cut and paste back in opposite orientation
Pericentric: include centromere
Paracentric: exclude centromere
Shows up as inversion loop
Usually no lost DNA, but can cause problems if breakpoint falls in regulatory/gene region
Xover of inverted region can compound problems:
Can cause imbalance in number of genes in gametes - some deleted, some duplicated
Sometimes acentric (no centromere) or dicentric (2 centromeres) pieces are formed

9. Translocations Change in location of a chromosome segment
Intrachromosomal - within same chromosome
Interchromosomal - between two chromosomes
Called reciprocal if exchanged
Can be balanced (even swap)
or unbalanced
Gametes can be affected
Homozygous for translocation means altered gene linkage
Nonreciprocal: often result in unbalanced duplications or deletions in gametes after segregation
E.g. familial Down’s syndrome: long arm of #21 translocates to and travels with long arm of #14 or #15; one gamete has no copies of #21 while the other has two copies of #21; fusion of gamete with two copies of #21 with a normal gamete (one copy of #21) results in Down’s syndrome (< 5% of cases).
Reciprocal: heterozygotes have trouble pairing homologues at metaphase (cross-like arrangements)
Often see inviable gametes with duplications/deletions

11. Diseases caused by translocations
Familial Down’s syndrome
Cancer
Reciprocal translocation involving #9 and #22: Philadelphia Chromosome
AML, CML
Proto-oncogene convereted to c-abl oncogene
Reciprocal translocation involving #8 and #14
Burkitt’s Lymphoma
infertility

13. Position effects
Inversions or translocations may move gene(s) from transcribed euchromatin to untranscribed heterochromatin
E.g. white eye locus in Drosophila
Inversion moves w+ (red) gene from euchromatin on the X chromosome to heterochromatin (essentially becomes w (white) allele)
Affected cells in hemizygous w+ males or w+/w females will show up as white; eyes will be red with white spots
Or duplications may alter expression patterns of genes differently depending on where they are located
E.g. Bar locus in Drosophila
The greater the number of ADJACENT duplicated 16A regions within the Bar gene on a given chromosome, the lower the number of eye facets (3/1)
The same number of duplicate 16A regions spread out evenly over two chromosomes results in more eye facets (2/2)

14. Fragile sites
Narrowings or unstained chromosome areas (gaps) are prone to breakage
Over 40 human fragile sites known
E.g. Fragile X Syndrome
Xq27.3 tends to break
Causes retardation in 80% of fragile X males
Only 33% of female heterozygote carriers show mild retardation
Caused by tandem CGG repeats inside the FMR-1 gene at the fragile X site; disease caused by amplification above a threshold number of repeats
Other triplet repeat diseases are myotonic dystrophy, spinobulbar muscular distrophy (Kennedy’s disease) and Huntington’s disease.

15. Changes in chromosome number
Euploid = 1 complete set of chromosomes, or exact multiples of complete sets (e.g. 1n, 2n, etc)
Monoploidy or polyploidy = change in numbers of whole sets of chromosomes
Aneuploid = change in numbers of individual chromosomes, so chromosome number is no longer an exact multiple of the haploid set

16. Aneuploidy Autosomal aneuploidy not well tolerated in animals
Can occur due to nondisjunction
(disjoin = to separate, non = not happening)
Already seen earlier with sex chromosomes
Autosomal aneuploidy not well tolerated in animals
E.g. trisomy 21 (non-familial Down’s syndrome):
Higher risk of nondisjunction in moms over 35
Moderate mental retardation, short, epicanthal folds, short/broad hands, heart problems, higher chance of acute leukemia, GI problems, lower life expectancy
E.g. trisomy 13 (Patau), trisomy 18 (Edwards)

17. Monoploidy and polyploidy
Both are cases of euploidy (have complete sets of chromosomes)
Monoploidy = 1n
Rare in adult diploids because of recessive lethal mutations
Although male bees, wasps and ants develop from unfertilized haploid eggs and are monoploid
Polyploidy = 3n or more
More common in plants due to self-fertilization
Autoplyploid = all chromosomes sets from same species (e.g. seedless fruits)
Allopolyploid = from different species
Salmon is polyploid
Almost all animals and plants have polyploid tissues/cells: e.g. endosperm and mammalian liver tissue
Euploidy is lethal in most animals, but common in plants (has played role in speciation)
Polyploidy results from
Meiotic division without cytokinesis
Nondisjunction of ALL chromosomes
Fusion of e.g. diploid + haploid > polyploid