BL 414 Genetics
Spring 2006
Study Guide for Test 3
Chapter 8: Chromosomes
karyotype: representation of the chromosomes in the metaphase stage of mitosis, by
arranging the pairs of homologous chromosomes in order of size, with the sex
chromosomes placed at the bottom right of the page
Chromosomes stained with Giesma exhibit characteristic banding patterns, dark bands
are called G bands, contain heterochromatin (highly repetitive DNA) and are gene poor.
In between the dark bands are the interbands, called R-bands – these contain
euchromatin and are gene-rich.
-the dark and light segments due to differential staining are used to identify specific
locations on each chromosome
A more recent technique for labeling chromosomes is “chromosome painting” which is
done by hybridization of fluorescently labeled chromosome specific DNA with
metaphase chromosomes – this results in a karyotype that is color-coded for each
homologous chromosome pair
The human karyotype contains 22 pairs of autosomes and 2 sex chromosomes, with a
total of 46 individual chromosomes. Human chromosomes are identified by their
karyotype number 1-22 or as the X or Y chromosome. The chromosomes are also placed
in groups A-G according to their size.
Smaller regions within chromosomes are identified by location on the arm on either side
of the centromere and the labeling of bands. The shorter arm is called the p arm and the
longer arm is the q arm. More specific location is given by the number for the region,
subregion, band and interband. See Figure 8.3 for these designations. For example, the
gene for Rh blood group is located near 1p36.2, which is on the p arm of chromosome 1,
the second band in subregion 36.
Nomenclature used in describing chromosomes and chromosomal abnormalities,
particularly alterations in the structure of the chromosome – which could be seen in the
karyotype as a change from normal banding patterns on chromosomes:
ter: the terminal portion of a chromosome, pter: terminal portion of p arm, qter: terminal
portion of q arm – could be used to indicate a deletion, inversion or duplication
+: indicates an extra chromosome or part of a chromosome – for example +21 means an
extra copy of chromosome 21, also known as trisomy 21 or Down syndrome
-: indicates a missing chromosome or part of a chromosome
mos: mosaic – an individual with more than one genetic makeup in different tissues or
cells of that individual
dup: duplication – a region of the chromosome is present twice
dirdup: direct duplication – the duplicated region is in the same direction as the original
copy, also called tandem duplication if they are next to each other in the same direction
tandem duplications lead to further multiplication of copies through uneven crossing
over, in which chromosomes line up in a slightly shifted alignment and crossover takes
places between identical copies at different positions on the chromosome – see Figure
8.16
invdup: inverted duplication – the second copy of a gene is in the reverse direction of the
first copy
del: deletion – a segment of the chromosome is missing – one or more genes may be
missing
inv: inversion – the linear order of a group of genes is the reverse of the normal order
t: translocation – a interchange of segments of chromosomes that are not homologous
rcp: reciprocal translocation – the parts are reciprocally exchanged – if reciprocal
translocation occurs in only one pair of chromosomes and the other chromosomes are
normal, the organism will be semisterile, that is only half of its gametes will have the full
complement of genes in the genome: see Figure 8.24 and 8.25
rob: Robertsonian translocation – the centromeres of two nonhomologous acrocentric
chromosomes become fuse to from a single centromere of a single chromosome – this
can occur with chromosome 21, which could lead to Down syndrome in the children of
parents with a Robertsonian translocation (about 3% of Down syndrome patients have
been found to have a parent with a Robertsonian translocation
r: Ring chromosome – a chromosome whose ends are joined, lacks telomere, rare
i: Isochromosome – a chromosome with two identical arms containing homologous
genes
Classification of chromosomes by the relative position of the centromere:
Metacentric chromosome: centromere in the middle of the two arms – appears as a Vshape during anaphase
Submetacentric chromosome: centromere is off-center appears as a J-shape during
anaphase
Acrocentric chromosome: centromere is very close to one end appears as an I-shape
during anaphase
Acentric chromosome: lacking a centromere: lost during cell division because it does
not attach to a spindle
Dicentric chromosome: has two centromeres: often lost during cell division because it
will have problems separating into one or the other daughter cell – it may create a bridge
between the daughter cells, not reach the nucleus of either daughter cell, or break and the
daughter cells will have broken copies of the chromosome.
Dosage compensation: Human females have two copies of X and males have one copy.
So if there is no compensation for the difference in amount of X genes, males will
express half of much from genes on X as females do, or looking at it the other way,
females will express twice as much as males. This would not work well in an organism,
because the level of gene expression is very important to normal function. This is why
dosage compensation is necessary - there needs to be something to equalize the
expression of X genes in males and females.
X-inactivation: In humans this is accomplished by inactivating one of the X
chromosomes in every cell of females. During early embryonic development one X is
randomly inactivated. All descendant cells of this embryonic cells keep the same X
inactivated.
The X-inactivation initiates at the XIC “X-inactivation center” near the centromere –
the chromosome condenses, is coated with an RNA transcript called Xist that is essential
for X-inactivation, and heavy methylation occurs along the chromosome
In some cells, the inactivated X chromosome is visible as a densely staining Barr body
in the cell nucleus
For this reason, human females are mosaic for X-linked genes because in different cells
and tissues of a human individual, the maternal or paternal X chromosome may be the
active copy and therefore different alleles of X-linked genes will be expressed throughout
her cells
There are a few genes in X that are not silenced by gene inactivation
Some of these have homologs in the Y chromosome – and they can undergo crossover
during meiosis – therefore they do not behave as X-linked genes but behave as autosomal
genes and are said to show pseudoautosomal inheritance – the regions of the X and Y
chromosomes on which they reside, PARp and PARq, are called pseudoautosomal
regions
Polyploidy in plants
Many plants species have genomes composed of multiple complete sets of chromosomes
The number of single chromosomes of each types is called the monoploid chromosome
set. A diploid species has two copies of the monoploid set, triploid has three copies,
tetraploid has four copies of the monoploid set, hexaploid – 6 copies, octoploid – 8
copies, decaploid – 10 copies. The chromosome number present in the gametes of a
species is the haploid number and is one-half of the number of chromosomes in the
somatic cells.
Autopolyploidy refers to the case where all of the chromosomes in the species derive
from a single ancestral species. Allopolyploidy is the case where complete sets of
chromosomes have come from two or more different ancestral species.
Polyploidy can arise sexually from unreduced gametes or asexually by means of
endoreduplication in which a cell undergoes chromosome replication but not
chromosome separation or cytoplasmic division. See Figure 8.32
Ch. 11 – see chapter outline
Ch. 14 DNA mutations and repair – see Types of Mutations chart
Sources of mutations
Replication slippage – responsible for triplet expansion, which are large tracts of
trinucleotide repeats – see Figure 14.8
Triplet expansion diseases: genetic diseases caused by a disruption in the gene
expression due to a long triplet repeat region – e.g. Fragile X syndrome, which causes
mental retardation. In Fragile X, the protein FMR1 is not produced in adequate amounts,
causing problems in nervous system development and learning
Anticipation: because the number of repeats increases from generation to generation,
there is in an increase in the severity of the disease in each successive generation
Transposable elements, or transposons: large sequences of DNA move throughout the
genome – their insertion into sites within chromosomes may disrupt the activity or
regulation of genes in the insertion site
Cut-and-paste elements: transposable elements that insert by a nicking the target DNA,
leaving overhanging DNA, and subsequent insertion and relegation
LTR retrotransposons: use an RNA transcript as an intermediate, and have long
terminal repeats at both ends
Non-LTR retrotranposons: use an RNA transcript as an intermediate, but do not have
long terminal repeats at both ends – LINE and SINE elements are this type of transposon
and they are the most abundant types of transposons in mammals
There are many copies of transposons in the human genome but they do not seem to be
transpositionally active. They may have function during organismic stress (such as heat
or starvation) because SINE elements are known to be transcribed when an organism is
under stress, and they promote protein production under stressful conditions.
Studies of sequence similarities and changes in the transposon repeats can indicate the
activity of transposition and it appears that only 1 in 600 new mutations in humans are
due to transpositions, whereas the number is 1 in 10 for mice. Therefore, transposition
does not appear to be a major source of mutation in humans.
Hot spots of mutation: certain sequences are more likely to undergo mutation:
Mutagens:
Oxidizing agents: deaminates cytosine or adenine – if adenine is deaminated this can
cause an AG transition, if cytosine is deaminated, uracil is made, but there is a cellular
repair mechanism to remove uracils from DNA, involving DNA uracil glycosylase, if
methyl-cytosine is deaminated, thymine is made causing a CT transition,
e.g. nitrous acid
Base analog: increases the rate of base mispairs – can cause transitions,
e.g. 5-Bromodeoxyuridine
alkylating agents: add methyl or larger alkyl group to DNA bases, causes mispairing and
transitions e.g. EMS or nitrogen mustard
Intercalating agents: inserting between the base pairs in DNA – distort the DNA and
cause insertion or deletion of one or a few bases – this could cause a frameshift mutation,
e.g. acridine orange, proflavin
UV radiation: energy absorption from UV light causes chemical reaction linking
pyrimidines together, especially thymines which form covalently bound thymine dimers,
which lead to blockage of DNA replication and RNA transcription, there are cell repair
mechanisms for pyrimidine dimers but they may be overwhelmed in the case of excessive
exposure to UV light
Ionizing radiation e.g. X rays, radioactive material emitting  and  radiation,
Create free radicals which damage tissue and DNA
Ch.15 Cell Cycle and Cancer – refer to powerpoint slides, notes on slides
 Cancer is not one disease, but a collection of diseases united by certain
characteristics:
– Uncontrolled cell proliferation
– Caused by mutations in several genes
– Occurs in somatic cells
– About 99% of cancer is caused by sporadic mutations, and 1% is
caused by inherited mutation
Cancer cells
Normal cells
No contact inhibition – pile up on top Stop growing and dividing upon
of each other in petri dish
contact with others cells – single
sheet on petri dish
No apoptosis
Apoptosis (programmed cell death)
occurs when cell is damaged or
starving
Immortal – cells never cease dividing, Cell senescence occurs - cells stop
generation after generation – this
dividing after several generations
property is necessary for cell lines
Clonal – cells are descendants of a
single ancestral cell
Cells differentiate according to
normal development
The genetics of cancer:
 Cancer results from mutations in somatic cells, so in most cases it is not
hereditary
 When sporadic mutations in several genes governing the cell growth and cell
death occur  cell can become cancerous
 In the small number of cancers that are familial, one mutation is inherited
and others sporadically occur
Mutations of genes involved in the cell cycle cause cancer:
 G1 S transition
 Apoptosis (programmed cell death)
 Tumor-suppressor genes, the most important of which is p53
 Oncogenes and proto-oncogenes
What is the cell cycle?
It’s a division of the lifetime of a cell (between its formation and cell division) into 4
phases including DNA synthesis and mitosis: many genes and proteins, discovered
in yeast studies, are involved in the maintenance and regulation of the cell cycle
 Cyclins are proteins involved in cell-cycle control – their levels of expression
go through regular cycles
 Timing of synthesis and destruction of Cyclin + Cyclin-dependent protein
kinase (Cdk) complexes during cell cycle
 If something is amiss in the cell, it does not proceed through the cell cycle –
growth is arrested at cell cycle checkpoints
 Tumor suppressor protein p53 is involved in the control of DNA damage
 The balance of Bax and Bcl2 proteins determines the fate of a cell (normal,
apoptosis or immortalization)
Cell cycle regulatory genes affected in tumors: tumor-suppressor genes:
Tumor-suppressor genes Alteration
Consequence
p53
p16/p19ARF
Loss of G1/S, S, and
G2/M checkpoint
functions
Mutation
p21
Mutation
Loss of G1/S, and S
checkpoint functions
RB
Mutation
Promotes proliferation
Bax
Mutation
Failure to promote
apoptosis
Bub1p
Mutation
Loss of spindle assembly
checkpoint function
Cell cycle regulatory genes (proto-oncogenes/oncogenes) affected in tumors:
Proto-oncogenes
Alteration
Consequence
Cyclin D`
Cdk4
Amplification or
overexpression
Amplification
Cdk4
Mutation
EGFR (epidermal
Amplification
growth factor)
FGFR (fibroblast
growth-factor receptor)
Ras
Amplification
Ras
Mutation
Bcl2
Overexpression by
translocation next to
strong enhancer
Amplification
Mdm2
Promotes entry into S
phase
Proliferation b/c of
Constitutive activation
of growth factor
pathway
Proliferation from
constitutive growth
signal
Inactivates GTPase –
constitutive activation of
growth factor pathway
Blocks apoptosis
Mimics loss of p53
About 1% of cancer is from familial cancer syndromes – these involve the
inheritance of a mutation in a cancer gene. The incidence and type of cancer
depends on the particular mutation.