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Chapter 5.
The Chromosomal Basis of Mendelism
1. Chromosome
2. The Chromosome Theory of Heredity
3. Sex-linked Genes in Human Beings
4. Sex Chromosomes and Sex Determination
5. Dosage Compensation of X-linked Genes
1
What causes organisms to develop as males or
females?
Why are there only two sexual phenotypes?
Is the sex of an organism determined by its genes?
Male and female Drosophila. The male has white eyes because it carries a
mutation on its X chromosome
2
1. Chromosomes
Each species has a characteristic set of chromosomes.
chromatin The complex of DNA and proteins in
eukaryotic chromosomes; originally named because of the
readiness with which it stains with certain dyes.
euchromatin Genetic material that is not stained so
intensely by certain dyes during interphase and that
comprises many different kinds of genes.
heterochromatin Chromatin staining darkly even during
interphase, often containing repetitive DNA with few genes.
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http://www.bu.edu/histology/i/20104loa.jpg
Chromosome Number
Within a species, the number of chromosomes is
almost always an even multiple of a basic number.
In human beings, for example, the basic number is 23;
mature eggs and sperm have this number of
chromosomes.
Most other types of human cells have twice as many
(46), although a few kinds, such as some liver cells,
have four times (92) the basic number.
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Chromosome Number
The haploid, or basic, chromosome number (n)
defines a set of chromosomes called the haploid
genome.
Most somatic cells contain two of each of the
chromosomes in this set and are therefore diploid
(2n).
Cells with four of each chromosome are tetraploid
(4n), those with eight of each are octaploid (8n),
and so on.
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The basic number of chromosomes varies among
species.
Chromosome number is unrelated to the size or
biological complexity of an organism, with most
species containing between 10 and 40 chromosomes
in their genomes
The muntjac, a tiny Asian deer, has only three
chromosomes in its genome, whereas some species of
ferns have many hundreds.
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The record for minimum number of
chromosomes belongs to a subspecies of the ant
Myrmecia pilosula, in which females have a single pair
of chromosomes. This species reproduces by a process
called haplodiploidy, in which fertilized eggs (diploid)
become females, while unfertilized eggs (haploid)
develop into males. Hence, the males of this group of
ants have, in each of their cells, a single chromosome.
The record for maximum number of
chromosomes is found in the fern family.
Ophioglossum reticulatum. This fern has roughly 630
pairs of chromosomes or 1260 chromosomes per cell.
The fact that these cells can accurately segregate
these enormous numbers of chromosomes during
mitosis is truly remarkable.
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Sex chromosome
In some animal species
such as grasshoppers
females have one more
chromosome than
males.
called the X
chromosome
Females of these
species have two X
chromosomes, and
males have only one
(XO).
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Sex chromosome
During meiosis in the
male, the solitary X
chromosome moves
independently of all the
other chromosomes and
is incorporated into half
the sperm; the other
half receive no X
chromosome.
11
In many other animals,
including human
beings, males and
females have the
same number of
chromosomes
Y is much shorter than
the X
12
If fertilization were to occur randomly, approximately
half the zygotes would be XX and the other half would
be XY, leading to a 1:1 sex ratio at conception
However, in human beings, Y-bearing sperm have a
fertilization advantage, and the zygotic sex ratio is
about 1.3:1.
During development, the excess of males is diminished
by differential viability of XX and XY embryos, and at
birth, males are only slightly more numerous than
females (sex ratio 1.07:1).
By the age of reproduction, the excess of males is
essentially eliminated and the sex ratio is very close to
1:1.
13
Human X and Y chromosomes. The terminal regions
are common to both sex chromosomes.
The X and Y chromosomes are called sex
chromosomes. All the other chromosomes in the
genome are called autosomes.
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2. The Chromosome Theory of Heredity
By 1910 many biologists suspected that genes were
situated on chromosomes, but they did not have
definitive proof.
Thomas H. Morgan discovered a particular eye color
mutation in the fruit fly
reproduced quickly and prolifically and was inexpensive
to rear in the laboratory. Only four pairs of
chromosome.
The X and Y chromosomes were morphologically
distinguishable from each other and from each of the
autosomes.
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Experimental evidence linking the inheritance of genes
to chromosomes
Morgan's experiments commenced with his discovery of
a mutant male fly that had white eyes instead of the red
eyes of wild-type flies.
When this male was crossed to wild-type females, all the
progeny had red eyes, indicating that white was
recessive to red.
When these progeny were intercrossed with each other,
Morgan observed a peculiar segregation pattern
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Experimental evidence linking the inheritance of genes
to chromosomes
The transmission of the
mutant condition in
association with sex
suggested that the gene
for eye color was present
on the X chromosome
but not on the Y
chromosome.
17
Hemizygote : an organism that
has only one copy of a gene
Morgan carried out
additional experiments to
confirm the elements of his
hypothesis.
Cross between a
heterozygous female and
a hemizygous mutant male.
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he crossed white-eyed
females to red-eyed males.
This time, all the daughters
had red eyes, and all the sons
had white eyes.
When he intercrossed these
progeny, Morgan observed the
expected segregation: half the
progeny of each sex had
white eyes, and the other half
had red eyes.
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Chromosomes as Arrays of Genes
Morgan and his students soon identified other Xlinked genes in Drosophila. In each case, simple
breeding experiments demonstrated that recessive
mutations of these genes were transmitted along with
the X chromosome.
Morgan's research group also identified genes that
were not on the X chromosome.
These genes followed the Mendelian Principle of
Segregation, but they did not segregate with sex, as
the gene for eye color did.
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Morgan's students were able to
show that genes were indeed
situated at different sites, or loci
(from the Latin word for “place”;
singular; locus), on a linear
structure.
all genes were located on
chromosomes and Mendel's
principles could be explained by
the transmissional properties of
chromosomes during
reproduction. This idea, called
the Chromosome Theory of
Heredity,
21
Nondisjunction as proof of the chromosome theory
Bridges performed one of Morgan's experiments on a
larger scale.
He crossed white-eyed female Drosophila to red-eyed
males and examined many F1 progeny.
Although as expected, nearly all the F1 flies were either
red-eyed females or white-eyed males, Bridges found a
few exceptional flies—white-eyed females and red-eyed
males.
22
Nondisjunction as proof of the chromosome theory
white-eyed females and
red-eyed males.
The exceptional males all
proved to be sterile;
however, the exceptional
females were fertile
23
Nondisjunction as proof of the chromosome theory
Bridges explained these results by proposing that the
exceptional F1 flies were the result of abnormal X
chromosome behavior during meiosis in the females of
the P generation.
Ordinarily, the X chromosomes in these females should
disjoin, or separate from each other, during meiosis.
Occasionally, however, they might fail to separate,
producing an egg with two X chromosomes or an egg
with no X chromosome at all.
24
Nondisjunction as proof of the chromosome theory
nondisjunction Failure of disjunction or separation of
homologous chromosomes in mitosis or meiosis,
resulting in too many chromosomes in some daughter
cells and too few in others.
Examples: In meiosis, both members of a pair of
chromosomes go to one pole so that the other pole does
not receive either of them; in mitosis, both sister
chromatids go to the same pole.
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The chromosomal basis of Mendel’s principles of
segregation and independent assortment
Mendel established two principles of genetic transmission:
(1) the alleles of a gene segregate from each other
(2) the alleles of different genes assort independently.
The finding that genes are located on chromosomes made
it possible to explain these principles (as well as
exceptions to them) in terms of the meiotic behavior of
chromosomes.
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The Principle of Segregation
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The Principle of Independent Assortment
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The Principle of Independent Assortment
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3. Sex-Linked Genes in Human Beings
• Because males only need to inherit one X chromosome
to exhibit an X-linked trait, there are a preponderance of
males who are afflicted with recessive sex-linked
disorders.
Some X-linked diseases are:
• Hemophilia characterized by excessive bleeding
because of a lack of a critical bloodclotting factor.
-female??
• Color blindness caused by faulty red-green perception
through red or green color receptors in the retina.
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Sex-linked gene in human beings
Hemophilia, an x-linked blood-clotting disorder
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Color blindness, an X-linked vision disorder
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• Mental retardation due to fragile X syndrome,
associated with a constriction in the long arm of the X
chromosome; this anomaly is caused by a long section of
DNA containing repeats of a short nucleotide sequence.
1/2000
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Genes on the human Y chromosome
- 250 genes
- more than people expected why?
Several of the genes on the human Y chromosome seem
to be required for male fertility.
Obviously, a mutation in such a gene will interfere with a
man's ability to reproduce.
By comparison, it has identified more than 1000 genes
on the human X chromosome.
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Genes on both the X and Y chromosomes
- mostly near the ends of the short arms
- pseudoautosomal genes
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4. Sex Chromosomes & Sex Determination
In the animal kingdom, sex is perhaps the most
conspicuous phenotype.
Animals with distinct males and females are sexually
dimorphic. Sometimes this dimorphism is established by
environmental factors.
In one species of turtles, for example, sex is determined
by temperature. Eggs that have been incubated above
30°C hatch into females, whereas eggs that have been
incubated at a lower temperature hatch into males.
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Sex determination in human beings
The discovery that human females are XX and that
human males are XY suggested that sex might be
determined by the number of X chromosomes or by the
presence or absence of a Y chromosome.
As we now know, the second hypothesis is correct. In
humans and other placental mammals, maleness is due
to a dominant effect of the Y chromosome
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Sex determination in human beings
The evidence for this fact comes from the study of
individuals with an abnormal number of sex
chromosomes. XO animals develop as females, and XXY
animals develop as males.
The dominant effect of the Y chromosome is manifested
early in development, when it directs the primordial
gonads to develop into testes.
Once the testes have formed, they secrete testosterone,
a hormone that stimulates the development of male
secondary sexual characteristics.
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Researchers have shown that the testis-determining
factor (TDF) is the product of a gene called SRY (for
s ex-determining r egion Y ), which is located just
outside the pseudoautosomal region in the short arm of
the Y chromosome.
The discovery of SRY was made possible by the
identification of unusual individuals whose sex was
inconsistent with their chromosome constitution—XX
males and XY females
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1/20000
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Testosterone is a hormone that binds to receptors in many
kinds of cells. Once bound, the hormone–receptor
complex transmits a signal to the nucleus, instructing the
cell in how to differentiate.
If the testosterone signaling system fails, these
characteristics do not appear and the individual develops
as a female.
One reason for failure is an inability to make the
testosterone receptor
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Testicular feminization
43
Testicular feminization
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Sex determination in Drosophila
The Y chromosome in Drosophila—unlike that in
humans—plays no role in sex determination. Instead, the
sex of the fly is determined by the ratio of X
chromosomes to autosomes.
Normal diploid flies have three pairs of autosomes + XX
or XY, Three pairs of autosomes: AA
A: represents one haploid set of autosomes.
Y chromosome for male fertility.
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Sex determination in Drosophila
-the ratio of X’s to A’s:
1.0 ~ greater, female
0.5~1.0, both sexes
0.5 or less, male
46
Sex determination in other animals
In both Drosophila and human beings, males produce
two kinds of gametes, X-bearing and Y-bearing.
For this reason, they are referred to as the
heterogametic sex; in these species females are the
homogametic sex.
In birds, butterflies, and some reptiles, this situation is
reversed.
Males are homogametic (usually denoted ZZ) and
females are heterogametic (ZW).
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Sex determination in other animals
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In a haplo-diplo system of sex determination, eggs are
produced through meiosis in the queen, and sperm are
produced through mitosis in the male.
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Hermaphrodites
Hermaphrodites have both male and female sex organs.
Many species of fish are hermaphroditic.
Some start out as one sex and then, in response to
stimuli in their environment, switch to the other.
Other species have both testes and ovaries at the same
time (but seldom fertilize themselves).
Like those reptiles and fishes whose sex is determined by
incubation temperature, hermaphroditic fishes have no
sex chromosomes.
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5. Dosage Compensation of X-Linked Genes
Animal development is usually sensitive to an imbalance
in the number of genes. Normally, each gene is present in
two copies.
Departures from this condition, either up or down, can
cause abnormal phenotypes, and sometimes even death.
Females with two X chromosomes and males with only
one. In these species, how is the numerical difference of
X-linked genes accommodated?
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Dosage Compensation of X-Linked Genes
three mechanisms may compensate for this difference:
(1) each X-linked gene could work twice as hard in males
as it does in females, or
(2) one copy of each X-linked gene could be inactivated in
females, or
(3) each X-linked gene could work half as hard in females
as it does in males.
Extensive research has shown that all three mechanisms
are utilized, the first in Drosophila, the second in
mammals, and the third in the nematode (see Chapter21)
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Hyperactivation of X-linked Genes in Male Drosophila
In Drosophila, dosage compensation of X-linked genes is
achieved by an increase in the activity of these genes in
males.
This phenomenon, called hyperactivation, involves a
complex of different proteins that binds to many sites on
the X chromosome in males and triggers a doubling of
gene activity
When this protein complex does not bind, as is the case
in females, hyperactivation of X-linked genes does not
occur. In this way, total X-linked gene activity in males
and females is approximately equalized.
53
Inactivation of X-linked Genes in Female Mammals
In placental mammals, dosage compensation of X-linked
genes is achieved by the inactivation of one of the
female's X chromosomes
the inactivation event occurs when the mouse embryo
consists of a few thousand cells.
At this time, each cell makes an independent decision to
silence one of its X chromosomes.
The chromosome to be inactivated is chosen at random;
once chosen, however, it remains inactivated in all the
descendants of that cell.
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Thus, female mammals are genetic
mosaics containing two types of cell
lineages; the maternally inherited X
chromosome is inactivated in roughly
half of these cells, and the paternally
inherited X is inactivated in the other
half. A female that is heterozygous for
an X-linked gene is therefore able to
show two different phenotypes.
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Inactivation of X-linked Genes in Female Mammals
An X chromosome that has been inactivated does not look
or act like other chromosomes.
Chemical analyses show that its DNA is modified by the
addition of numerous methyl groups.
In addition, it condenses into a darkly staining structure
called a Barr body
This structure becomes attached to the inner surface of
the nuclear membrane, where it replicates out of step
with the other chromosomes in the cell.
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Inactivation of X-linked Genes in Female Mammals
The inactivated X chromosome remains in this altered
state in all the somatic tissues.
In the germ tissues it is reactivated, perhaps because two
copies of some X-linked genes are needed for the
successful completion of oogenesis.
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Mechanism of x chromosome inactivation
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Inactivation of X-linked Genes in Female Mammals
Cytological studies have identified human beings with
more than two X chromosomes (see Chapter 6).
For the most part, these people are phenotypically normal
females, apparently because all but one of their X
chromosomes is inactivated.
Often all the inactivated X's congeal into a single Barr
body. These observations suggest that cells may have a
limited amount of some factor needed to prevent Xinactivation.
Once this factor has been used to keep one X
chromosome active, all the others quietly succumb to the
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inactivation process.