1. chromosomal mutations
Changes in chromosome number
Changes in chromosome structure
Chromosome testing
Karyotyping
High resolution analysis
Postnatal genetic testing

2. I. Chromosomal Mutations
possibly affecting more than one gene (multi-gene level)
Changes in NUMBER
Monoploid number (2n – 1)
Euploidy (multiples of n)
Polyploid (3n, 4n, 5n…)
Triploid, tetraploid, pentaploid, hexaploid

3. 1. Polyploidy Usually lethal in mammals
Does occur in some animals - Reproduction via parthenogenesis, Flatworms, leeches, brine shrimp, lizards, salamanders, salmonids
Polyploidy in plants: much more common because it can be tolerated by plants, can reproduce asexually…
Important role in the evolution of plants –
wheat: 2n = 14, 28, 42
chrysanthemum: 2n = 18, 36, 54, 72, 90

5. sympatric speciation:
e.g. polyploidy in
plants..
Autopolyploidy: due to meiosis error. Offspring can self fertilize.
Allopolyploidy:
2 different species mating, produce a hybrid that is polyploid:
The hybrid is fertile because the polyploid condition provides the homologous chromosomes for pairing during meiosis…

6. Endopolyploidy only certain cells in the organism are polyploid
Liver cells, plant tissue (stem),
larval gut tissue (mosquitos)

7. 2. Aneuploidy – the total # is not an exact multiple of a set (2n +/- x)
Caused by Nondisjunction = failure of normal chromatid division during meiosis, two chromosomes go to one pole, none in the other.
Results in the wrong number of chromosomes.
Results in a gene imbalance

8. Fertilization of one of these affected gametes produces a zygote w/ either 3 members (trisomy) or only one member (monosomy) of the chromosome.

9. gene imbalance - THE problem
Aneuploids are more abnormal than polyploids, why? (polyploid plants are completely viable and usually bigger, whereas in Drosophila the only aneuploids that survive are trisomics and monosomics for chromosome 4, the smallest chromosome)
Normal physiology of a cell depends on the proper ratio of gene products in the euploid cell.
The amount of expression is correlated with the number of genes in a cell
If 3 copies present: 150% of the normal amount of protein will be made
If 1 copy present: 50% of the normal amount of protein will be made

10. Nondisjunction responsible for Turner’s syndrome and Kleinfelter’s syndrome…
Turner’s syndrome produces sterile females with a normal # of autosomes and 1 X chromosome (XO). These are the only human monosomics that survive…
Klienfelter’s syndrome individuals are trisomic: XXY, they are sterile males that are typically tall, and thin and some degree of mental retardation.
XYY – trisomic males have mild mental retardation

11. Aneuploid Conditions in Humans Condition Frequency syndrome Trisomy-21
1/800
Down
Trisomy-18
1/6,000
Edward
Trisomy-13
1/15,000
Patau
XXY
1/1,000
Klinefelter
XYY
Jacobs
XXX
1/1,500
Superfemale X
1/5,000
Turner
Inherited disorders associated with aneuploidy. Trisomies and variations in the sex chromosomes result in mental retardation, organ defects, sexual immaturity, etc.

12. Trisomy 21, abnormal creases
Trisomy 18, diaphragmatic hernia
Turner’s syndrome, developmental abnormality
polydactyly

13. Why is monosomy so bad?
Monosomics for all human autosomes die in utero
Any deleterious recessive alleles present on monosomic autosome will be automatically expressed

14. B. Changes in chromosome structure
A) Deletions
B) Duplications
C) Inversion
D) Translocation

15. Deletion loop

16. 1. Deletions Spontaneous breakage and rejoining
Interstitial deletion
Terminal deletion
Crossing over between repetitive DNA
Region w/centromere usually maintained during division, the other part will be lost

17. Multigenic deletions
If both homologs have the same deletion then it will be lethal
If only on one homolog, the deletion can “uncover” lethal recessives in the heterozygous condition
Psuedodominance = when recessive alleles are expressed due to a deletion event

18. “partial monosomy”
Caused by a heterozygous deletion of the tip of the p arm of chromosome #5 – phenotype: distinctive cat-like cry made by infants, microencephaly & moon-like face

19. 2. Duplications
Extra copy of some particular region… Rare, and difficult to detect
Usually due to unequal crossing over during meiosis, or through replication error prior to meiosis
Not as problematic as deletions, but some problems are associated:
Bar eye in Drosophila (gene imbalance)

21. 3. Inversions Region breaks, rotates 180 degrees and rejoins
Generally viable, and show no abnormalities at the phenotypic level
Paired homologs form an
During synapsis, one chromosome must twist into a loop to pair up w/the genes on the other…

22. Types of inversions
1) Paracentric – centromere outside of the inversion
Cross over products: dicentric and acentric chromosome
2) Paricentric – inversion spans centromere
Cross over products: duplication, and deletion

23. During meiosis, homologs still pair up, even w/inversions
-Inversion loop makes this possible

24. Crossing over produces affected chromatids:
Duplication &
Deletion events

26. 4. Translocation-movement of chromosomal fragments to a new location.
Semisterility = an organism that is heterozygous for a reciprocal translocation usually produces about half as many offspring as normal
due to difficulty in chromosome segregation in meiosis.
Translocation cross = because of the translocations, the pairing of homologous regions leads to the unusual structure that contains four pairs of sister chromatids.

27. Nonreciprocal translocation – (unbalanced)
Centromeric regions of two nonhomologous acrocentric chromosomes become fused to form single centromere.
-Down Syndrome
chromosome 21 & 14 rearrangement leads to familial Down Syndrome. The heterozygote is normal, the 3 chromosomes must separate during meiosis (only 2/6 are normal, the rest either monosomic or trisomic)
-Cancer
(CML) type of leukemia, translocation between chromosome 9 & 22, leads to the movement of a gene where it will be overexpressed

29. Fragile sites – susceptible to breakage
Fragile X syndrome
Most common form of inherited mental retardation (1/4000 males, 1/8000 females)
FMR1 gene, has several trinucleotide repeats CGG in the 5’UTR region
Normal individuals = 6 to 54 repeats
Affected individuals = >230 repeats, region becomes modified (bases are highly methylated & gene NOT expressed)
Link between fragile sites & cancer
Chromosome #3 FRA3B region, FHIT gene often altered or missing in tumor cells taken from individuals w/ cancer

30. II. Chromosome Testing Chromosomes: Karyotyping
High resolution chromosome analysis

31. A. karyotyping
adding a dye to metaphasic chromosomes; different dyes that affect different areas of the chromosomes are used for a range of identification purposes.
Giemsa dye is effective because it markedly stains the bands on a chromosome; Each chromosome can then be identified by its banding pattern
Amniocentesis
Chorionic Villi Biopsy

32. Prenatal genetic testing cont.
Maternal Serum & Amniotic fluid
Alpha-fetoprotein (AFP)
Unconjugated estriol (uE3)
Dimeric inhibin A (DIA)
Fetal cell sorting

33. B. High resolution chromosome analysis
SKY – uses probes. Each of the individual probes complementary to a unique region of one chromosome - together, all of the probes make up a collection of DNA that is complementary to all of the chromosomes within the human genome.
Each probe is labeled with a fluorescent color that is designated for a specific chromosome..
the probes hybridize, the fluorescent probes essentially paint the full set of chromosomes, can be analyzed to determine whether any of them exhibits translocations or other structural abnormalities.

35. 2) In situ hybridization – used to map specific deletions & insertions
No binding, deleted

36. (FISH) analysis of a normal individual (D) and patient with a chromosome 22 deletion using a probe for the UFD1 gene. The patient has only one copy of UFD1 seen in blue (white arrows). Chromosome 22 was labeled with a red fluorescent marker (yellow arrows).