Download Chromosomes and Genetics

Human Chromosomes
• We have 46 chromosomes, or 23
pairs.
• 44 of them are called autosomes
and are numbered 1 through 22.
Chromosome 1 is the longest, 22
is the shortest.
• The other 2 chromosomes are the
sex chromosomes: the X
chromosome and the Y
chromosome.
• Males have and X and a Y;
females have 2 X’s: XY vs. XX.
Sex Determination
• The basic rule: if the Y chromosome is present, the person is male. If
absent, the person is female.
• The Y chromosome has the main sex-determining gene on it, called SRY.
• About 4 weeks after fertilization, an embryo that contains the SRY gene
develops testes, the primary male sex organ. The testes secrete the
hormone testosterone. Testosterone signals the other cells of the embryo
to develop in the male pattern.
• If the embryo does not have the SRY gene, it develops ovaries instead,
which secrete estrogen and causes development in the female pattern.
A few oddities
•
It is possible to be XY and female. Two ways this can happen:
•
1. the SRY gene can be inactivated by a mutation. If SRY doesn’t work, testes
don’t develop and the embryo develops as a normal female.
•
2. In a condition called “androgen insensitivity”, the person is XY with a
functional SRY gene, but her cells lack the testosterone receptor protein, so the
cells don’t ever get the message that the testosterone is sending. Testes develop in
the abdominal cavity, and no ovaries, fallopian tubes, or uterus develop. At
puberty, the internal testes secrete testosterone, which gets converted into
estrogen and the body develops as a normal (but sterile) adult female.
Hermaphrodites
In some cases, androgen insensitivity is only partial: the cells respond a
little bit to testosterone produced by the testes. The embryo develops
with ambiguous genitalia, neither completely male not completely female.
Such a person is sometimes called a “hermaphrodite”.
Another condition, congenital adrenal dysplasia, causes the adrenal glands
to produce an abnormally large amount of testosterone in a female
embryo, This can also cause development of ambiguous genitalia, a
hermaphrodite.
• Another rare condition: a chimera occurs when two separate embryos
fuse together. This can result in a person with some XX cells and some XY
cells. Such a person can have both testes and ovaries, a “true”
hermaphrodite. This condition is extremely rare: more people say they
have it than actually do.
Chromosome Variations
•
•
•
Changes in number and structure are
possible: first look at number
variations.
Aneuploidy: having an extra or
missing chromosome– is fairly
common in sperm and eggs. Nondisjunction in meiosis causes
chromosomes to not separate equally
into the gametes.
The rate of non-disjunction in males
is constant: 1-2% of sperm have an
extra of missing chromosome. But in
females, the rate increases marked
with age. This is illustrated by the
frequency of Down syndrome births
at different ages of mother. Down
syndrome is the most frequent result
of non-disjunction.
Chromosome Number Variations
•
•
•
•
•
•
Except for the X and Y, humans don’t survive with only 1
copy of any chromosome. Also, 3 copies is lethal in most
cases. Aneuploidy is a major cause of spontaneous
abortion in early pregnancy.
Down Syndrome is the most common human aneuploidy.
It is also called trisomy-21, meaning 3 copies of
chromosome number 21.
People with Down’s have a characteristic appearance:
flattened face, turned up nose, epicanthal folds at the
outer corners of the eyes. In most cases the diagnosis is
made immediately at birth. Heart defects, protruding
tongue, and mental retardation are also found in most
people with Down’s. Occurs about 1 in 1000 births.
There are also translocational and mosaic forms of Down
syndrome.
Translocational involves a chromosome structure
change (2 chromosomes get hooked together) and is
inherited. With translocational Down’s, if one child in a
family has it, others are likely to also get it. Occurs in
about 5% of Down’s cases.
Mosaic Down’s means having some cells with
trisomy 21 and other cells normal. The person’s physical
appearance and mental condition depends on exactly
which cells are which. About 3% of all Down syndrome
cases.
Some Sex Chromosome Aneuploidies
• Non-disjunction can also result in
a person with 2 X’s and a Y:
47,XXY. This is called Klinefelter
Syndrome.
• The Y chromosome makes a
person with Klinefelter’s male:
possessing testes.
• Symptoms: female body hair
pattern, breast development,
sterile, can be some
developmental delay or
retardation, especially for verbal
skills.
• Often not diagnosed, or
diagnosed only accidentally.
• Most symptoms are helped by
testosterone treatment.
Turner Syndrome
• Also called XO, because people
with Turner’s have only 1 X
chromosome: 45, X.
• No Y means Turner’s people are
female. However, no ovaries
develop, so they don’t undergo
the body changes of puberty and
they are sterile.
• Hormone treatment cures all but
the sterility.
• Other symptoms: short stature,
webbed skin and low hairline at
the neck, some oddities of spatial
perception. Not retarded.
Other Number Variations
• Triplo-X, having 3 X chromosomes. No Y
chromosome means female. Many with this
syndrome are undiagnosed because they have no
symptoms. Some have slight social and
developmental problems, especially languagerelated. Occasional fertility problems, but many have
normal fertility. Not well studied.
• XYY: having 2 Y chromosomes plus an X. Male
because they have a Y. Many are never diagnosed
due to a lack of symptoms. Tend to be taller, more
physically active, slightly retarded, prone to acne.
Chromosome Structure Variations
•
•
•
•
Chromosomes can be broken by X-rays and by
certain chemicals. The broken ends spontaneously
rejoin, but if there are multiple breaks, the ends
join at random. This leads to alterations in
chromosome structure.
Problems with structural changes: breaking the
chromosome often means breaking a gene. Since
most genes are necessary for life, many
chromosome breaks are lethal or cause serious
defects.
Also, chromosomes with structural variations
often have trouble going through meiosis, giving
embryos with missing or extra large regions of the
chromosomes. This condition is aneuploidy, just
like the chromosome number variations, and it is
often lethal.
The major categories: duplication (an extra copy of
a region of chromosome), deletion (missing a
region of chromosome), inversion (part of the
chromosome is inserted backwards, and
translocation (two different chromosomes switch
pieces).
Structure Variation Examples
•
•
•
There are lots of ways chromosomes can
change structure, so the syndromes are
not as well defined as with number
variations.
Cri-du-chat syndrome comes from a
deletion of one end of chromosome 5, so
the person only has 1 copy of all the genes
on this end of the chromosome. The
name means “cat’s cry”, because their cry
sounds vaguely like a cat’s meow. People
with this condition are severely retarded,
as well as having a variety of physical
problems.
Translocational Down syndrome is caused
by most of chromosome 21 becoming
joined with chromosome 14. Some
children of a person with this
translocation will inherit the translocation
as well as 2 normal chromosome 21’s.
This results in trisomy-21: having 3 copies
of the chromosome, which gives Down
syndrome.
Sex-linked Genes
• Genes on the X chromosome are called “sex-linked”, because they
expressed more often in males than in females
• There are very few genes on the Y chromosome.
• Since males only have one X chromosome, all genes on it, whether
dominant or recessive, are expressed.
• In contrast, a mutant gene on an X chromosome in a female is usually
covered up by the normal allele on the other X. Most mutations are
recessive. So, most people with sex-linked genetic conditions are male.
• Another fact about sex-linked genes. Males produce ½ their sperm with
their X chromosome, and half with their Y chromosome. The X-bearing
sperm lead to daughters and the Y-bearing sperm lead to sons. So, sons
get their only X from their mothers, and the father’s X goes only to
daughters.
• The Y chromosome is passed from father to son.
Colorblindness
• We have 3 color receptors in the
retinas of our eyes. They respond
best to red, green, and blue light.
• Each receptor is made by a gene.
The blue receptor is on an
autosome, while the red and
green receptors are on the X
chromosome (sex-linked).
• Most colorblind people are
males, who have mutated,
inactive versions of either the red
or the green (sometimes both)
color receptors. Most females
with a mutant receptor gene are
heterozygous: the normal version
of the receptor genes gives them
normal color vision.
Inheritance of Colorblindness
• A heterozygous female has
normal color vision. Sons get
their only X from their mother.
So, ½ of the sons of a
heterozygous mother are
colorblind, and ½ are normal.
• A colorblind male will give his X to
his daughters only. If the mother
is homozygous normal, all of the
children will be normal. However,
the daughters will heterozygous
carriers of the trait, and ½ of their
sons will be colorblind.
Hemophilia
•
Hemophilia is a disease in which the blood does not clot when exposed to air.
People with hemophilia can easily bleed to death from very minor wounds.
Hemophilia is another sex-linked trait.
•
Hemophilia is treated by injecting the proper clotting proteins, isolated from the
blood of normal people. In the early 1980’s, the blood supply was contaminated
by HIV, the AIDS virus, and many hemophiliacs contracted AIDS at that time.
•
Queen Victoria of England, who lived through most of the 1800’s, apparently had a
mutation on one of her X chromosomes that caused many of her descendants to
have hemophilia. Most importantly, Alexis, son of the Czar of Russia had it, which
contributed to the Russian Revolution and the rise of communism.
Sex-Influenced Traits
•
•
•
•
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Some traits appear to be specific to
one sex, but are not sex-linked: their
genes are not on the X chromosome.
Such a trait is called sex-influenced.
More specifically, a trait that is
dominant in one sex but recessive in
the other is a sex-influenced trait.
The best human example is male
pattern baldness.
Baldness is dominant in males:
heterozygotes and homozygotes both
become bald. In females, baldness is
recessive: only homozygotes (which
are relatively rare) become bald.
Also, females tend to lose hair more
evenly than men, giving a sparse hair
pattern rather than completely
baldness.
BUT: this may be an
oversimplification.
Types of Chromosomal Mutations
1. Variations in chromosome structure or number can arise
spontaneously or be induced by chemicals or radiation.
Chromosomal mutation can be detected by:
a. Genetic analysis (observing changes in linkage).
b. Microscopic examination of eukaryotic chromosomes at mitosis
and meiosis (karyotype analysis).
2. Chromosomal aberrations contribute significantly to human
miscarriages, stillbirths and genetic disorders.
a. About 1⁄2 of spontaneous abortions result from major
chromosomal mutations.
b. Visible chromosomal mutations occur in about 6/1,000 live births.
c. About 11% of men with fertility problems, and 6% of those
institutionalized with mental deficiencies have chromosomal
mutations.
Variations in Chromosome Structure
1. Mutations involving changes in chromosome structure occur in four
common types:
a. Deletions.
b. Duplications.
c. Inversions (changing orientation of a DNA segment).
d. Translocations (moving a DNA segment).
2. All chromosome structure mutations begin with a break in the DNA,
leaving ends that are not protected by telomeres, but are “sticky” and
may adhere to other broken ends.
3. Polytene chromosomes (bundles of chromatids produced by DNA
synthesis without mitosis or meiosis) are useful for studying
chromosome structure mutations (Figure 17.1).
a. Polytene chromosomes are easily detectable microscopically.
b. Homologs are tightly paired, joined at the centromeres by a proteinaceous
chromocenter.
c. Detailed banding patterns are characterized for the four polytene
chromosomes, with each band averaging 30 kb of DNA, enough to encode
several genes.
Fig. 17.1 Diagram of the complete set of Drosophila polytene chromosomes in a single
salivary gland cell
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Deletion
1. In a deletion, part of a chromosome is missing.
a. Deletions start with chromosomal breaks induced by:
i. Heat or radiation (especially ionizing).
ii. Viruses.
iii. Chemicals.
iv.Transposable elements.
v. Errors in recombination.
b. Deletions do not revert, because the DNA is missing.
2. The effect of a deletion depends on what was deleted.
a. A deletion in one allele of a homozygous wild-type organism may give a normal
phenotype, while the same deletion in the wild-type allele of a heterozygote would
produce a mutant phenotype.
b. Deletion of the centromere results in an acentric chromosome that is lost, usually
with serious or lethal consequences. (No known living human has an entire
autosome deleted from the genome.)
c. Large deletions can be detected by unpaired loops seen in karyotype analysis
(Figure 17.2).
Fig. 17.2 A deletion of a chromosome segment
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Duplication
1. Duplications result from doubling of chromosomal
segments, and occur in a range of sizes and locations
(Figure 17.5).
a. Tandem duplications are adjacent to each other.
b. Reverse tandem duplications result in genes arranged in the
opposite order of the original.
c. Tandem duplication at the end of a chromosome is a terminal
tandem duplication (Figure 17.6).
d. Heterozygous duplications result in unpaired loops, and may be
detected cytologically.
Fig. 17.5 Duplication, with a chromosome segment repeated
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Fig. 17.6 Forms of chromosome duplications are tandem, reverse tandem, and
terminal tandem duplications
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Fig. 17.7 Chromosome constitutions of Drosophila strains
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Chapter 21 slide 25
Multigene families result from duplications. Hemoglobin (Hb)
is an example:
a. Each Hb contains two copies of two subunits (e.g., 2 α-globins and
2 β-globins), and the identity of the subunits changes with the
organism’s developmental stage.
b. Genes for the α-type polypeptides are clustered together on 1
chromosome, and those for β-type polypeptides are clustered on
another.
c. α-type genes have similar sequences, as do β-type. They probably
result from duplication and subsequent sequence divergence.
Fig. 17.8 Inversions
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Chapter 21 slide 27
Different recombinant chromosomes are produced by crossover in a
heterozygote, depending on centromere involvement:
a. Paracentric inversions (no centromere) result in visible inversion loops between
homologous chromosomes (Figures 17.9).
i. Crossover in the inversion region results in unbalanced sets of genes, and
gametes or zygotes derived from recombined chromatids may be inviable
due to abnormal gene dose.
ii. Without crossover in the looped region, gametes receive complete sets of
genes (two gametes with normal and two with inversions) and are viable.
iii. Effects of a single crossover within an inverted segment in a heterozygote
include (Figure 17.10):
(1) Joining of homologous regions of two chromatids to produce a
dicentric bridge, and corresponding loss of an acentric fragment.
(2) During anaphase the two centromeres of the dicentric chromosome
migrate towards opposite poles, causing the bridge to break, and
producing two chromatids with deletions.
(3) The second meiotic division distributes one chromatid to each gamete:
(a) Two gametes carry normal sets of genes (one in the normal order and the other in inverted
order).
(b) Two gametes are missing many genes, and are inviable.
(4) Female mammals often shunt dicentric chromosomes or acentric
fragments to the polar bodies, so fertility may not be so reduced.
Fig. 17.9 Consequences of crossing-over in a paracentric inversion
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Fig. 17.10 Meiotic products resulting from a single crossover within a heterozygous,
pericentric inversion loop
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Chapter 21 slide 30
Fig. 17.11 Translocations
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Chapter 21 slide 31
Fig. 17.12 Meiosis in a translocation heterozygote in which no crossover occurs
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Chapter 21 slide 32
Chromosomal Mutations and Human Tumors
1. 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.
2. Examples of specific abnormalities associated with tumors:
a. Chronic myelogenous leukemia (CML; OMIM 151410) involves a reciprocal
translocation of chromosomes 9 and 22 (Figure 17.13).
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 gene
product.
Fig. 17.13 Origin of the Philadelphia chromosome in chronic myelogenous leukemia
(CML) by a reciprocal translocation involving chromosomes 9 and 22
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Chapter 21 slide 34
b.Burkitt lymphoma (BL) involves a reciprocal
translocation of chromosomes 8 and 14.
i. Induced by a virus, this disease is common in
Africa.
ii. B cells are affected, and secrete antibodies as
they proliferate.
iii. The reciprocal translocation positions the MYC
proto-oncogene next to an active immunoglobulin
gene, resulting in over-expression of MYC and
development of the lymphoma.
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Chapter 21 slide 35
Position Effect
1. 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).
2. This is an example of an epigenetic effect since the DNA sequence of the
gene is not affected.
3. An example is the white-eye (w) locus in Drosophila:
a. An inversion moves the w+ gene from a euchromatin region of the X
chromosome to a position in heterochromatin.
b. In a w+ male, or a w+/w female, where w+ is involved in the inversion, the eyes
will have white spots resulting from the cells where the w+ allele was moved and
inactivated.
4. Position effects are associated with some human diseases. Aniridia (“without
iris,” OMIM 106210) is an example.
a. Aniridia is severe hypoplasia of the iris, usually associated with cataracts and
clouding of the cornea.
b. The cause of aniridia is early termination of eye development, resulting from lost
function of the PAX6 gene by deletion, mutation, or translocation.
Fragile Sites and Fragile X Syndrome
1. Chromosomes in cultured human cells develop narrowings or unstained
areas (gaps) called fragile sites; over 40 human fragile sites are known.
2. 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
(Figure 17.14).
a. Fragile X syndrome has an incidence in the U.S. of about 1/1,250 in males,
and 1/2,500 in females (heterozygotes) (Figure 17.15).
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.
c. About 33% of carrier (heterozygous) females show mild mental retardation.
i. Sons of carrier females have a 50% chance of inheriting the fragile X.
ii. Daughters of carrier females have a 50% chance of being carriers.
Fig. 17.14 Diagram of a human X chromosome showing the location of the fragile site
responsible for fragile X syndrome
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Variations in Chromosome Number
1. 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.
2. 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.
Changes in One or a Few Chromosomes
1. 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. 1 chromosome is involved.
ii. Nondisjunction occurs in both meiotic divisions.
iii. Nondisjunction occurs in mitosis (result is somatic cells with unusual
chromosome complements).
2. Autosomal aneuploidy is not well tolerated in animals, and in mammals
is detected mainly after spontaneous abortion. Aneuploidy is much
better tolerated in plants. There are four main types of aneuploidy
(Figure 17.16):
a. Nullisomy involves loss of 1 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, and two of all the others (2N + 1).
d. Tetrasomy involves an extra chromosome pair, so the cell has four
copies of one, and two of all the others (2N + 2).
3. More than one chromosome or chromosome pair may be lost or added.
Examples:
a. A double monosomic aneuploidy has two separate chromosomes
present in only one copy each (2N - 1 - 1).
b. A double tetrasomic aneuploidy has two chromosomes present in four
copies each (2N + 2 + 2).
Fig. 17.16 Normal (theoretical) set of metaphase chromosomes in a diploid (2N)
organism (top) and examples of aneuploidy (bottom)
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Chapter 21 slide 42
Fig. 17.17 Meiotic segregation possibilities in a trisomic individual
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
5. Human examples of aneuploidy in autosomes and sex chromosomes are
summarized in Table 17.1.
a. Sex chromosome aneuploidy is found more often than autosome
aneuploidy, because lyonization compensates for chromosome dosage.
b. Autosomal monosomies are rarely found in humans, presumably because
they are lost early in pregnancy.
c. Autosomal trisomies account for about half of fetal deaths, and only a
few are seen in live births. Most (trisomy-8, -13 and -18) result in early
death, with only trisomy-21 (Down syndrome) surviving to adulthood.
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Chapter 21 slide 44
e. Trisomy-13 (Patau syndrome) occurs in 2/104 live births, and most die
within the first 3 months. Characteristics include (Figure 17.21):
i. Cleft lip and palate.
ii. Small eyes.
iii. Polydactyly (extra fingers and toes).
iv. Mental and developmental retardation.
v. Cardiac and other abnormalities.
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Chapter 21 slide 45
f. 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 17.22):
i. Small size with multiple congenital malformations throughout the
body.
ii. Clenched fists.
iii. Elongated skull.
iv. Low-set ears.
v. Mental and developmental retardation.
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Chapter 21 slide 46