Download Genetics- Part 1- Genes

Genetics- Part 1- Genes
Mendel
Mendel was an Austrian monk who taught natural science and worked on plant breeding
experiments.
He developed a basic understanding of genetics and inheritance.
Mendel’s Work
It took him 2 years to select the pea plant as his subject.
He collected data for 10 years.
His sample sizes were large; he tabulated results from 28,000 pea plants.
He replicated his experiments.
He analyzed his data with statistics (probability theory).
Characteristics of Garden Peas:
Peas are easy to grow, and take little space.
They are inexpensive.
They have a short generation time compared to large animals so that a large number of
offspring can be obtained in a short amount of time.
They have some distinct characteristics that are easy to recognize. These characteristics
can be used when trying to determine patterns of inheritance.
They are easily self-fertilized or cross fertilized.
Traits Studied by Mendel
smooth or wrinkled seeds
yellow or green seeds
red or white flowers
inflated or constricted pods
green or yellow pods
axial or terminal flowers
tall or dwarf plants
Mendels Crosses
Mendel used pure-breeding individuals in the first (P1) generation.
P1
yellow X green

F1
F2
all yellow

3/4 yellow, 1/4 green
Conclusions from Mendel's Crosses
The F1 generation showed only one character that was present in the P1. The other
character reappeared in the F2 (25%).
The sex of the parent did not matter.
The traits did not blend.
Mendel concluded that the F1 plants must contain 2 discrete factors, one for each
character. The character that was seen in the F1 is called dominant. The character not
seen in the F1 is called recessive.
Letters Can Represent Genes
The characteristics studied by Mendel were due to single genes. On the pair of
chromosomes diagrammed below, the letter "A" represents a gene for yellow seeds. The
letter "a" on the homologous chromosome represents a gene for green seeds. By
convention, upper case letters are used to represent dominant genes and lower case letters
are used for recessive genes.
Because individuals are diploid, two letters can be used to represent the genetic makeup
of an individual. In the case of seed color, the following three gene combinations are
possible: AA, Aa, and aa.
Heterozygote (also called hybrid) refers to an individual that has two different forms of
the gene. Example: Aa
Homozygote refers to an individual that has two identical genes. Example: AA or aa
A hybrid is a heterozygote. Example: Aa
Principle of Segregation
Mendel’s principle of segregation states that paired factors (genes) separate during
gamete formation (meiosis). Because the pair of genes (Aa, AA, or aa) separate, one
daughter cell will contain one gene and the other will contain the other gene. (See
diagram above.)
Gametes
Because pairs of chromosomes separate during meiosis I, gametes are haploid, that is,
they carry only one copy of each chromosome. An Aa individual therefore produces two
kinds of gametes: A and a.
Below: An "AA" individual produces all "A" gametes. Similarly, an "aa" individual
produces all "a" gametes.
Individual (genotype)
Type of gametes produced
AA
all gametes will contain an "A"
Aa
1/2 will contain "A" and 1/2 will contain "a"
aa
all "a" gametes
Punnett Squares
Suppose that an "Aa" individual is crossed with another "Aa" individual. One will
produce "A" eggs and "a" eggs. The other will produce "A" sperm and "a" sperm. What
are all of the possible combinations of eggs and sperm? A Punnett square can be used to
show all of these combinations.
The Punnett square in the diagram below is used to show between two Aa individuals.
The square below is used for this cross: AA X Aa.
One half of the offspring produced by this cross will be AA, the other half will be Aa.
The cross can also be written as shown below because the AA parent can produce only
one kind of gamete (all A).
A Closer look at Mendel’s Crosses (One Gene Locus)
Y = yellow y = green
P1
F1
YY X yy

Yy
Yy X Yy
 A cross between two individuals that are heterozygous for a
trait is called a monohybrid cross.
F2 The above cross is illustrated below.
Genotype and Phenotype
The genetic makeup of P1 plants was different from that of F1 because the P1 plants were
true breeding and the F1 plants were not. The genetic makeup of an individual is referred
to as its genotype. Because the plants are diploid, two letters can be used to write the
genotype. In this case, the genotype of the P1 plants was YY; the genotype of the F1
plants was Yy.
The characteristics of an individual are its phenotpye. This word refers to what the
individual looks like so ddjectives are used to write the phenotype. For example,
"yellow" or "tall" are phenotypes. The yellow P1 plants looked like the F1; they had the
same phenotype but different genotypes.
An individual with a recessive phenotype has two recessive genes. A dominant
phenotype results from either one or two dominant genes. In the cross above, YY or Yy
are yellow; yy is green. The phenotype ratio in the F2 is 3 yellow:1 green. The genotype
ratio is 1YY:2Yy:1yy.
Genotype Phenotype
AA or Aa
Yellow
aa
Green
Other Crosses
S = smooth s = wrinkled
P1
F1
SS X ss

Ss
Ss X Ss
F2 genotype ratio = 1:2:1 (1SS : 2Ss : 1ss)
phenotype ratio = 3:1 (3Smooth : 1 wrinkled)
F = full f = constricted
P1
F1
FF X ff

Ff
Ff X Ff
F2 genotype ratio = 1:2:1 (1FF : 2Ff : 1ff)
phenotype ratio = 3:1 (3full: 1 constricted)
Alleles and Loci
An allele is a gene that has more than one form. Each of the forms is referred to as an
allele. For example, the gene for red flowers and the gene for white flowers are two
different alleles.
A locus (plural: loci) is the location of a gene on a chromosome. The gene for red flowers
and the gene for white flowers are two different alleles at the same locus. A single
chromosome can have a gene for white flowers or a gene for red flowers but not both.
There are two loci illustrated below, one is for flower color and the other is for stem
length. Flower color has five alleles and stem length has two.
Application
Sickle-cell anemia is an abnormality of hemoglobin, the molecule that carries oxygen in
our blood. Red blood cells of affected individuals often become distorted in shape, they
then may break down or clog blood vessels causing pain, poor circulation, jaundice,
anemia, internal hemorrhaging, low resistance, and damage to internal organs.
This condition is caused by a recessive gene.
A = normal hemoglobin
a = sickle-cell hemoglobin
AA = normal
Aa = normal (called sickle-cell trait)
aa = sickle-cell anemia
A man with sickle-cell trait marries a normal woman. What is the probability that their
children will have sickle-cell trait?
If both parents have sickle-cell trait, what percentage of their children will:
have a normal phenotype?
have sickle-cell trait?
have sickle-cell anemia?
Testcross - One Locus
let A = red
a = white
Is a red flower AA or Aa?
Solution: cross it with aa
P1
A? X aa
The A? individual can produce these kinds of gametes: "A" and "?"
gametes: A, ? and a
F1
Aa and ?a
If the ?a individual is red, then ? = A. If it is white, then ? = a.
Should There Be Fewer Recessive Alleles?
The population model described above predicts that gene frequencies will not change
from one generation to the next even if there are more recessive alleles.
There is sometimes a misconception among students beginning to study genetics that
dominant traits are more common than recessive traits. Sometimes this is true, sometimes
it is not. For some traits, the dominant is more common; for other traits, the recessive is
more common. For example, blood type O is recessive and is the most common type of
blood. Huntington's disease (a disease of the nervous system) is caused by a dominant
gene and the normal gene is recessive. Fortunately, most people are recessive; the
dominant is uncommon.
The misconception comes from the observation that in a cross of Aa X Aa, 3/4 of the
offspring will show the dominant characteristic. However, the 3:1 ratio comes only if the
parents are both Aa. If there are many recessive genes in a population, then most matings
are likely to be aa X aa and most offspring will be aa.
In nature, natural selection may favor one- either the dominant or the recessive- and that
one will become more common over time. Other forces such as genetic drift may also
cause one or the other allele to become more common. In the absence of forces that
change gene frequencies, there is no reason to expect dominant genes to be more
common.
Probability
Multiplicative Rule
The probability of two or more independent events occurring is equal to the product of
their probabilities.
Example: What is the probability of tossing a coin two times and getting a heads both
times?
Solution: The probability of getting a heads on one coin is 1/2. The probability of getting
a heads on the second coin does not depend on the outcome of the first coin, so the
multiplicative rule is used. The probability of getting a heads on two coins is 1/2 X 1/2 =
1/4.
Additive Rule
The probability of two or more mutually exclusive events occurring is equal to the sum
of their probabilities.
What is the probability that a student will get an “A” or a “B” in a class if students
generally earn the following grades:
A = 10% (or 0.10)
B = 35% (or 0.35)
C = 45%
D = 10%
Solution: In this example, the two outcomes (getting an "A" or getting a "B") are
mutually exclusive because you can only get one or the other. The additive rule is used to
determine the overall probability of getting an "A" or a "B". 10% + 35% = 45% (or 0.10
+ 0.35 = 0.45).
Consider Two Loci at the Same Time
Independent Assortment
Genes that are on different chromosomes assort independently. The following are four
different metaphase I allignment patterns that are possible for a hypothetical species with
a diploid chromosome number of 6.
The alignment pattern shown in the diagram below will produce Sy and sY gametes.
The alignment pattern shown in this diagram will produce SY and sy gametes.
Both of the patterns illustrated above are possible because S and Y are located on
different chromosomes.
Possible Gametes for Several Different Genotypes
The table below shows the kinds of gametes that can be produced by several different
kinds of genotypes. Each gene locus (A and B) is on a different chromosome.
Individual
AABB
AABb
AaBB
AaBb
Aabb
AAbb
aaBB
aaBb
aabb
Gametes
AB
AB, Ab
AB, aB
AB, Ab, aB, ab
Ab, ab
Ab
aB
aB, ab
ab
Genotypes and Phenotypes
let A = red, a = white
let B = smooth, b = wrinkled
The table below shows possible genotypes and phenotypes.
Genotype
AABB
AABb
AaBB
AaBb
Aabb
AAbb
aaBB
aaBb
aabb
Phenotype
red, smooth
red, smooth
red, smooth
red, smooth
red, wrinkled
red, wrinkled
white, smooth
white, smooth
white, wrinkled
Linkage
In peas, the locus for seed texture (smooth or wrinkled) and seed color (yellow or green)
are on two different chromosomes so they assort independently.
Suppose that they are on the same chromosome as indicated in the diagram below.
Independent assortment will not occur because the "S" gene is on the same chromosome
as the "y" gene. Similarly, the "s" gene is on the same chromosome as the "Y" gene.
Unless crossing-over occurs, "S" will always be found with a "y" and "s" will be found if
there is a "Y".
Mendel studied seven different characteristics in peas. Each of these characteristics are
on different chromosomes, so they assort independently.
Example: Two Gene Loci
Let S = smooth, s = wrinkled
Let Y = yellow, y = green
P1 SMOOTH, YELLOW X wrinkled, green
genotypes: SSYY ssyy
gametes: SY sy

F1 SMOOTH, YELLOW X SMOOTH YELLOW
genotypes: SsYy X SsYy  
  
gametes: SY, Sy, sY, sy

F2
Mendel's Results
SMOOTH, YELLOW 315
SMOOTH, green
108
wrinkled, YELLOW 101
wrinkled, green
32
556
A general rule for dihybrid crosses (AaBb X AaBb)
TRAIT 1, TRAIT 2 X trait 1, trait 2
(upper case traits are dominant)
9 - TRAIT 1 and TRAIT 2 expressed (A-B-)
3 - TRAIT 1 expressed (A-bb)
3 - TRAIT 2 expressed (aaB-)
1 - No dominant traits expressed (all aabb)
A dihybrid cross is two monohybrid crosses
Remember that each of the individual traits in the dihybrid cross above behaves as a
monohybrid cross, that is, they will produce a 3:1 phenotype ratio in the offspring.
SMOOTH X wrinkled
Refer to the F2 data for the SMOOTH, YELLOW X wrinkled, green cross above.
The number of smooth offspring was 315 + 108 = 423.
The number of wrinkled was 101 + 32 = 133.
The ratio of smooth to wrinkled is therefore 423:133 or approximately 3:1.
YELLOW X green
yellow = 315 + 101 = 416
green = 108 + 32 = 140
ratio = 416:140 or approximately 3:1
Combining Probabilities
9:3:3:1 can be obtained in a dihybrid cross by first calculating probabilities for two
monohybrid crosses and then combining their probabilities.
probability of round = 3/4
probability of wrinkled = 1/4
probability of yellow = 3/4
probability of green = 1/4
probability of round and yellow = 3/4 X 3/4 = 9/16
probability of round and green = 3/4 X 1/4 = 3/16
probability of wrinkled and yellow = 1/4 X 3/4 = 3/16
probability of wrinkled and green = 1/4 X 1/4 = 1/16
Other Crosses
The following steps can be used to determine the expected number of offspring from any
cross.
1. Determine the kinds of gametes that can be produced by each parent.
2. Determine all of the possible combinations of gametes that can be produced. A Punnett
square may be useful for this.
If you use a Punnett square, the gametes of one parent are written across the top and the
gametes of the other parent written on one side. The number of cells in the square is
therefore equal to the number of gametes that one parent can produce multiplied by the
number of gametes that the other parent can produce.
Example:
Let T = tall, t = short
F = inflated, f = constricted
List the phenotypes produced by the following cross:
TtFf X ttFf
Step 1: List the kind of gametes produced by each parent.
TtFf can produced TF, Tf, tF and tf.
ttFf can produce tF and tf.
Step 2: Construct a Punnett square.
The Punnett square above shows that eight different genotypes are produced. The
phenotype for each is listed in the table below.
Genotype
tTFF, tTFf, tTfF
tTff
ttFF, ttFf, ttfF
ttff
Phenotype
tall, inflated
tall constricted
short inflated
short, constricted
Test Cross - Two Loci
Y = yellow
y = green
R = red
r = white
What is the genotype of a plant with yellow seeds and red flowers?
In the cross below, the symbols "-" and "?" represent unknown alleles. "-" is either "Y"
or "y". "?" is either "R" or "r".
The genotype of a plant with yellow seeds and red flowers is "Y-R?".
Cross it with yyrr to find out the "-" and "?" alleles.
Y-R? X yyrr
gametes: YR, Y?, -R, -? (parent 1) and yr (parent 2)
If the unknown alleles (- and ?) are recessive, the phenotype ratio will be 1:1:1:1.
Incomplete (Partial) Dominance
In the cases that are discussed above, blending does not occur. Flowers are either red or
white but are never pink. Seeds are either yellow or green but not yellowish-green. In
these cases, if a dominant gene is present, it is expressed. Some genes, however are
neither dominant nor recessive and when mixed, blending occurs.
Example: Snapdragons
A = Red flowers
A' = white flowers
A heterozygote (AA') is pink.
Codominance and Multiple Alleles- Example: ABO blood group
Up to this point, we have discussed two possible alleles for any gene locus. For example,
at the flower color locus, there is either the red or the white allele (A or a). With human
blood types, there are three alleles: A, B, or O. This is referred to as multiple alleles.
I is dominant to i.
There are two forms of I: IA and IB but only one form of i.
6 possible genotypes, 4 phenotypes:
IAIA and IAi = blood type A
IBIB and IBi = blood type B
IAIB = blood type AB
i i = blood type O
People with blood type A have a specific kind of carbohydrate chain on the surface of
their red blood cell. The carbohydrate chain is attached to a membrane protein or lipid.
Blood type B cells have have a different carbohydrate chain. Type AB cells have both A
and B chains. IA and IB are codominant because both phenotypes are expressed; there is
no blending
Codominance is different than Incomplete dominance (blending).
Pleiotropy
Genes that affect more than one trait are called pleiotropic.
For example, people with Marfan syndrome may be tall, thin, have long legs, arms and
fingers, and may be nearsighted. Their connective tissue is defective. If unrepaired, the
connective tissue surrounding the aorta will eventually rupture and kill the person. All of
these characteristics are due to a single gene.
Epistasis
Alleles at one locus prevent the expression of alleles at another locus. This interaction is
referred to as epistasis.
Example: Flower color in peas
enzyme 1
enzyme 2
AA or Aa
BB or Bb
compound A compound B  red pigment
An individual with AA or Aa genotypes will have red flowers. AA or Aa individuals
could have white flowers if the individual also has a "bb" genotype (example: AAbb). In
this case, the locus for enzyme 2 prevents the expresson of the locus for enzyme 1.
Genomic Imprinting
sometimes an allele is expressed differently if it is inherited from the mother than if it is
inherited from the father.
Example: Huntington's disease is expressed earlier if inherited from the father.
The symptoms of Huntington's disease are caused by a slow deterioration of brain cells
that begins at middle age. It is characterized by involuntary jerking movements of the
body including facial muscles and slurred speech. Later, there is difficulty swallowing,
loss of balance, mood swings, impaired reasoning, and memory loss. The person
eventually dies, usually to pneumonia or heart failure.
Polygenic Inheritance
A polygenic trait is due to more than one gene locus. It involves active and inactive
alleles.
Active alleles function additively.
Example: 3 loci (polygenic)
Height (tallness) in humans is polygenic but the mechanism of gene function or the
number of genes involved is unknown.
Suppose that there are 3 loci with 2 alleles per locus (A, a, B, b, C, c).
Assume that:
Each active allele (upper case letters: A, B, or C) adds 3 inches of height.
The effect of each active allele is equal, A = B = C.
Males (aabbcc) are 5' tall.
Females (aabbcc) are 4'7".
Genotype
Males
Females
aabbcc
5'0"
4'7"
Aabbcc (or aaBbcc etc.)
5'3"
4'10"
AaBbcc etc.
5'6"
5'1"
AaBbCc etc.
5'9"
5'4"
AaBbCC etc.
6'0"
5'7"
AaBBCC etc.
6'3"
5'10"
AABBCC
6'6"
6'1"
The following is a cross between two people of intermediate height.
AaBbCc X AaBbCc
If there is independent assortment, the following gametes will be produced in equal
numbers:
ABC, ABc, AbC, aBC, abC, aBc, Abc, abc
Punnett square analysis:
The Punnett square above can be summarized as follows:
Genotype
Males
Females
Frequency
AABBCC
6'6"
6'1"
1/64
AaBBCC etc.
6'3"
5'10"
6/64
AaBbCC etc.
6'0"
5'7"
15/64
AaBbCc etc.
5'9"
5'4"
20/64
AaBbcc etc.
5'6"
5'1"
15/64
Aabbcc etc.
5'3"
4'10"
6/64
aabbcc
5'0"
4'7"
1/64
The frequency column in the table above can be plotted to produce the graph below.
Variability
Variability results in a bell-shaped curve (see the diagram above).
Traits with many loci produce many categories. In the example above, 3 loci produced 7
possible heights because a person could have anywhere from 0 to 6 active alleles. If a
trait were determined by 4 loci (AABBCCDD for example) there would be 9 possible
categories because a person could have anywhere from 0 to 8 active alleles.
Heritability
Variability in polygenic traits can result from genetics and also from the environment. A
measure of the relative contribution of genetics is called heritability.
A trait with a high heritability is determined mostly by genes. A trait with a low
heritability is determined mostly by the environment.
For example, skin pigmentation (darkness) is determined by 2 or 3 pairs of alleles, but
exposure to sunlight (UV radiation) also causes the skin to darken due to the deposition
of protective pigments.
Examples of polygenic traits
stature
performance on IQ tests
skin color
neural tube defects (spina bifida, anencephaly)
Genetics - Part 2 - Chromosomes
Linkage
Genes on the same chromosome are linked.
Example: Unlinked Genes
G = gray body
g = black (ebony) body
R = red eyes
r = purple eyes
The diagrams below show that the locus for body color (G or g) is on a different
chromosome than the locus for eye color (R or r). These two loci will assort
independently to produce either GR and gr gametes or Gr and gR gametes.
cross: GgRr X ggrr
gametes: GR, Gr, gR, gr X gr
Ratio expected: 1:1:1:1
Example: Linked Genes
Suppose G and R are linked as shown below. If the body color and eye color loci are on
the same chromosome, they will not assort independently unless crossing-over occurs
frequently.
In this case, GgRr can produce only two kinds of gametes: GR and gr.
GgRr X ggrr
gametes: GR, gr X gr
If G and R are linked, then whenever you have a G, you have an R. Any gray, purple
offspring (G-rr) would result from crossing over because a Gr gamete is needed.
Suppose out of 100 offspring, you got 46 gray, red, 46 black purple, 4 gray purple and 4
black red. Eight percent of the offspring resulted from crossing over. These offspring are
recombinant.
Crossing Over
Crossing over is more likely to occur between genes that are far apart. The farther apart
genes are, the greater the probability that crossing over will occur between them.
In the example above, we had 8% crossing over.
The percent of recombination (crossing over) can beused as a measure of how far apart
genes are. 1% crossing over = 1 map unit.
Example
G = gray body
g = black (ebony) body
R = red eyes
r = purple eyes
Suppose that G and R are linked (on the same chromosome) in a particular individual and
g and r are also linked
P1 GgRr X ggrr
If there is no crossing-over, possible gametes for the first parent are GR and gr.
If there is crossing-over, possible gametes are gR and Gr.
the following results were obtained:
How far apart are the G and R loci?
Sex Chromosomes
Humans have 23 pairs of chromosomes (46 total) chromosomes. Two of these are called
sex chromosomes, the other 44 are called autosomes.
There are two kinds of sex chromosomes, called the X chromosome and the Y
chromosome. The X chromosome is larger and contains many genes. The Y chromosome
is much smaller and contains very few genes.
Normally, human females have two X chromosomes (XX) and males have one X and one
Y chromosome (XY).
Occasionally, an accident happens in which a person is born with too many or too few
sex chromosomes. In these cases, the person will be male if they inherit a Y chromosome
and female if they do not.
Examples of four different possibilities that produce males are shown below. The last
three are abnormal.
XY
XXY
XXXY
XYY
Examples of four different possibilities that produce females are shown below. Normal
females are XX.
X
XX
XXX
XXXX
The cross below shows that normal females produce eggs that have one X chromosome.
Half of the sperm produced by normal males have an X chromosome and the other half
have a Y chromosome.
XX x XY

This analysis shows that half of the offspring are expected to be male, half are expected
to be female.
X-Linkage
Morgan (Columbia U):
P1
F1
F2
red-eyed X white-eyed

all red-eyed
3:1 (red:white) but all white were male
explanation:
These genes are found on the X chromosome but not on the Y chromosome. An XrY
male will therefore have red eyes. Details of this cross are below.
P1
XRXR
female
X
XrY
male
gametes: XR (female) and Xr, Y (male)
The offspring produced from the above cross are crossed with each other (below):
XRXr X XRY

gametes: XR and Xr (from female); XR and Y (from male)
F1
F2:
Notice that there are three possible genotypes for females and two possible genotypes for
males.
Females
Males
Genotypes
Phenotypes
Genotypes
Phenotypes
XRXR
red
XRY
red
r
white
R
r
X X
red
r
r
white
XX
XY
X-Linked Inheritance
Males inherit their X chromosome from their mother. Their Y chromosome comes from
their father. A male, therefore, cannot pass an X-linked trait to his sons. Males inherit all
of their X-linked traits from their mother.
If a male inherits an X-linked recessive trait, it will be expressed because males do not
have a homologous X chromosome.
Females can be carriers of X-linked traits without expressing them because they might
carry the dominant allele on the other X chromosome. For example, the following
genotype will have a dominant phenotype: XAXa.
Inactivation
Inactivation occurs early in embryonic development (12-16 days).
In females, each cell normally contains two X chromosomes. The X chromosome that is
inactivated is determined randomly.
Once inactivation occurs, all daughter cells of a particular cell have the same X
chromosome inactivated.
All of the "pink" chromosomes in the drawing below (left side of diagram) have been
inactivated. All future cells produced by this cell will have the pink chromosome
inactivated. In the diagram on the right, all of the blue chromosomes have been
inactivated. All future generations of this cell will have the blue chromosome inactivated.
Females are therefore mosaics with respect to the X chromosome. Patches of body cells
will have the maternally inherited X chromosome inactivated and other patches will have
the paternally inherited one inactivated.
Example of Mosaicism: Calico Cats
A calico cat has patches of orange and patches of black
X = orange
X1 = black
MALES:
XY = orange
X1Y = black
FEMALES:
XX = orange
X1 X1 = black
X X1 = orange or black patches
All cells descended from an X1 cell (X is inactive) are orange-yellow.
All cells descended from an X cell (X1 is inactive) are black.
Human Example - Anhydrotic Dysplasia
Anhydrotic dysplasia is a disease that results in the absence of sweat glands.
It is inherited as an X-linked recessive disease.
Let X = normal sweat glands and X' = absence of sweat glands. Normal males are XY.
Affected males are X'Y and do not have sweat glands.
Normal females are XX, heterozygous females are XX' and have patches of skin with
sweat glands and patches of skin without sweat glands. Females that are X'X' do not have
sweat glands.
Genetics - Part 3 - Human Genetics
Introduction
This chapter is a review of patterns of inheritance in humans including a review of
genetic diseases.
The genetic diseases are divided into two categories: chromosomal abnormalities and
gene abnormalities. Chromosomal abnormalities are caused by cells that have extra or
missing chromosomes or parts of chromosomes. Gene abnormalities (gene mutations)
occur when the genetic instructions stored in the DNA are altered so that the protein
product coded for by the gene is less functional or nonfunctional.
Prenatal Diagnosis
The techniques listed below enable physicians to diagnose many kinds of genetic
abnormalities by examining some of the cells from the developing fetus.
Amniocentesis
The fetus is surrounded by a layer of liquid called amniotic fluid. Amniocentesis is a
technique in which a sample of amniotic fluid is removed and cells that it contains are
grown on a culture dish. Because these cells are of fetal origin, any chromosomal
abnormalities present in the fetus will also be present in the cells.
In addition to chromosomal analysis, a number of biochemical tests can be done on the
fluid to determine if any problems exist.
Amniocentesis cannot be done until the 14th to 16th week of pregnancy. Cells must then
be cultured on a laboratory culture dish for 2 weeks to obtain sufficient numbers of cells.
The risk of inducing a spontaneous abortion by this procedure is 0.5 to 1% above the
background rate of spontaneous abortion.
Chorionic Villi Sampling
Chorionic villi sampling is a procedure in which a small amount of the placenta is
removed.
It is normally done during the 10th to 12th week but it can be done as early as the 5th
week of pregnancy. Karyotype analysis can be performed on these cells immediately
after sampling.
Although Chorionic villi sampling can be performed earlier in the pregnancy than
amniocentesis, the risk of inducing a spontaneous abortion is 1 to 2% higher than the
background rate.
Karyotypes
Karyotypes are prepared using cells from amniocentesis, chorionic villi sampling, or
white blood cells.
Cells are photographed while dividing. cells are normally stained so that banding patterns
appear on the chromosomes. The bands make it easier to identify the chromosomes.
Banding patterns are not visible in the photograph below due to the staining technique.
Pictures of the chromosomes are cut out and arranged in pairs according to size and
banding patterns.
Karyotypes can be used to determine if there is an abnormality in chromosome number or
structure.
Nondisjunction
Nondisjunction occurs when chromosomes fail to "disjoin" during meiosis or mitosis.
Meiosis
Metaphase I
Anaphase I
The probability of nondisjunction increases with age. It increases rapidly after age 35
years in women and after 55 years in men.
Aneuploidy
Cells that have extra chromosomes or chromosomes missing are aneuploid. Two types of
aneuploidy are discussed below.
Monosomy refers to a condition in which there is one chromosome is missing. It is
abbreviated 2N - 1. For example, monosomy X is a condition in which cells have only
one X chromosome.
A trisomy has one extra chromosome and is abbreviated 2N + 1. Trisomy 21 is an
example of a trisomy in which cells have an extra chromosome 21.
Monosomies and trisomies usually result from nondisjunction during meiosis but can
also occur in mitosis. They are more common in meiosis 1 than meiosis 2.
They are generally lethal except monosomy X (female with one X chromosome) and
trisomy 21 (Down’s Syndrome).
Affected indivisuals have a distinctive set of physical and mental characteristics called a
syndrome. For example, trisomy 21 is Down syndrome.
Oogenesis is more likely to continue than spermatogenesis when a chromosomal
abnormality occurs. As a result, 80% to 90% of aneuploid (extra chromosomes or
chromosomes missing) fetuses are due to errors in meiosis I of the female.
Incidence of Genetic Abnormalities
Maternal Age
At 25 years, 17% of secondary oocytes may have chromosomal abnormalities. At 40
years, up to 74% may contain abnormalities.
Spontaneous Abortion (Miscarriage)
Two-thirds of all pregnancies are lost. These miscarriages are called spontaneous
abortions.
Genetic mutation causes an estimated 60% of these spontaneous abortions.
Autosomal Abnormalities
Nine percent of spontaneous abortions are trisomy 13, 18, or 21; but 0.1% of newborns
have these trisomies.
Down Syndrome
Down syndrome is trisomy 21. It is characterized by mental retardation, an abnormal
pattern of palm creases, a flat face, sparse, straight hair, and short stature. People with
Down syndrome have a high risk of having cardiac anomalies, leukemia, cataracts, and
digestive blockages.
Life expectancy of Down syndrome individuals is in the middle teens but some live much
longer.
The gene responsible for Alzheimer’s is on chromosome 21. Down’s are at increased risk
for developing Alzheimer’s.
Down Syndrome is associated with maternal age. Older women, particularly those older
than 40, are more likely to have a Down Syndrome child.
During meiosis, the two chromosomes might align so that each daughter cell receives one
chromosome 21 as shown below. This will produce a normal egg.
.
Mosaic Down Syndrome
Some of the cells of mosaic Down's sydrome are trisomy 21 but others are normal.
This is due to nondisjunction that occurs during mitosis (after fertilization).
Mosaic Down Syndrome is likely to be less severe because some of the cells are normal.
Trisomy 18 (Edward Syndrome)
The incidence of Trisomy 18 is approximately 1 out of every 3000 live births.
Trisomy 18 is associated with mental and physical retardation, skull and facial
abnormalities, defects in all organ systems, and poor muscle tone.
Mean survival is 2 to 4 months. Less than 10% survive to 1 year; a few survive to their
20s or 30s.
Trisomy 13 (Patau Syndrome)
The incidence of Trisomy 13 is is approximately 1 out of 16,000 live births.
Trisomy 13 produces mental and physical retardation, skull and facial abnormalities, and
defects in all organ systems. It is also associated with a left lip, a large, triangular nose,
and extra digits.
Eighty percent die in the first month, five to ten percent live past the first year.
Polyploidy
Polyploidy is a condition in which there is more than 2 sets of chromosomes.
Triploids (3N), tetraploids (4N), pentaploids (5N) etc. are polyploids.
Polyploidy in Plants
Polyploidy is a major evolutionary mechanism in plants. Approximately 47% of all
flowering plants are polyploid.
Some examples of polyploid plant species are corn, wheat, cotton, sugarcane, apples,
bananas, watermelons, and many flowers.
Polyploid plants are often more vigorous than the diploid parent species.
Polyploid plants are fertile.
Polyploidy in Humans
Polyploids have defects in nearly all organs.
Most die as embryos or fetuses. Occasionally an infant survives for a few days.
Abnormalities of the Sex Chromosomes
Turner Syndrome - XO
Characteristics of Turner syndrome include the following:
Sexually underdeveloped
Short stature
Folds of skin on the back of the neck
Wide-spaced nipples
Narrow aorta
Pigmented moles
97% die before birth
Malformed elbows
Infertile
Normal Intelligence
The incidence of Turner syndrome is 1 in 2000 female births.
Turner syndrome individuals that are treated with hormones lead fairly normal lives.
XXX - Triple-X Syndrome (also XXXX and XXXXX)
Triple-X individuals are tall and thin and have menstrual irregularities. Their IQ is in the
normal range but it is slightly reduced.
The incidence of Triple-X Syndrome is 1 in 1,500 female births.
Additional X chromosomes are associated with an increased mental handicap.
XXY - Klinefelter Syndrome (also XXXY)
Males with two or more X chromosomes have Klinefelter Syndrome.
The incidence of Klinefelter Syndrome is 1 in 1000 male births.
Symptoms include reduced sexual maturity and secondary sexual characteristics, breast
swelling, and no sperm. Klinefelter males are slow to learn and individuals with
additional X’s (XXXY) may be mentally retarded.
XYY - Jacob Syndrome(anti-social man syndrome)
XYY males are tall, have acne, speech, and reading problems.
Although there are a disproportionate number in penal institutions, 96% of Jacob's
Syndrome men are normal.
In the early 1970’s screening began in hospitals in England, Canada, Denmark and US.
Families with XYY boys were offered "anticipatory guidance". These types of programs
were stopped because they were self-fulfilling prophesies.
Other Chromosomal Abnormalities
Deletions
Deletions are fragments of chromosomes that are missing. They are usually lethal when
homozygous and cause abnormalities when heterozygous.
Radiation, viruses, chemicals, and unequal crossing-over may cause them.
Cri du Chat Syndrome
Cri du chat syndrome is due to a deletion of a portion of chromosome 5.
Cri du chat individuals are mentally retarded.
"Cri du chat" is French for "cry of the cat". The infants cry sounds like a cat.
Duplication
A chromosome segment that is repeated is called a duplication.
It can be due to unequal crossing over which produces a deletion on one chromosome and
a duplication on the other.
Often, multiple copies of genes from duplication can mutate without harming the
individual because they still have one good copy of the gene. This type of mutation may
be a source of variation for species. For example, the gene for human globin has given
rise to several different genes that produce similar types of proteins. The different globins
produced by these genes have very similar amino acid sequences.
An example of a family of genes that have been produced by duplication is the beta
globin family. This family contains five functioning genes and a pseudogene.
Epsilon globin
G-gamma globin
A-gamma globin
delta globin
beta globin
a pseudogene
All of these genes have similar amino acid sequences due to their evolution from the
same ancestral gene.
Some families of genes contain hundreds of genes.
Repeated Sequences
Repeated sequences are short segments of DNA that are repeated hundreds or thousands
of times. For example: In the segment of DNA illustrated below, CCG is repeated several
times.
The cause is unknown.
Fragile X Syndrome
This is the second most common cause of mental retardation (Down Syndrome is first).
The characteristic long, narrow face becomes more pronounced with age.
The symptoms of fragile-X syndrome appear to be caused by an abnormal number of
repeats (CCG) on the X chromosome. Normal DNA has 6 - 50 copies of "CCG" at the
locus in question. Carrier males have 50 - 230 copies. This is referred to as a premutation
(pre-fragile-X). The full mutation involves more than 230 repeats of CCG.
The chance of being affected increases in successive generations because extra copies of
CCG are added during the gamete-formation process.
Females are more likely to add repeats than males. At most, males pass on 230 repeats to
their children but females pass on more than 230 repeats.
Mental problems are more common if the fragile X is inherited from the mother. This is
an example of genomic imprinting discussed in the previous chapter. Fragile-X is more
common in males because males inherit their X chromosome from their mother.
The repeats cause the X to have a thread-like portion. It is called a fragile site because it
breaks if cultured under certain conditions in the laboratory.
Translocation
Chromosomes that break usually rejoin at the same place but sometimes the broken ends
rejoin in different places.
Translocation is the movement of a chromosome or part of a chromosome to another
(nonhomologous) chromosome.
Inversion
A segment of a chromosome may become turned around forming an inversion.
This can cause altered gene activity, a loss of crossing-over, or a duplication/deletion if
crossing-over does occur.
Pedigrees
It is often easy to visualize relationships within an extended family by using symbols to
represent people and relationships. A family tree which uses these symbols is called a
pedigree. A sample pedigree is below.
In a pedigree, squares represent males and circles represent females. Horizontal lines
connecting a male and female represent mating. Vertical lines extending downward from
a couple represent their children. Subsequent generations are therefore written underneath
the parental generations and the oldest individuals are found at the top of the pedigree.
If the purpose of a pedigree is to analyze the pattern of inheritance of a particular trait, it
is customary to shade in the symbol of all individuals that possess this trait.
In the pedigree above, the grandparents had two children, a son and a daughter. The son
had the trait in question. One of his four children also had the trait.
Autosomal Recessive
Characteristics of autosomal recessive inheritance
It often skips generations; children that have the trait can have parents that do not.
Heterozygotes (carriers) do not have the trait. People with the trait have two copies of the
genes.
If both parents are have the trait, all offspring will.
Males and females are affected equally.
Inbreeding results in a greater-than-expected number of rare autosomal recessive
phenotypes.
Cystic Fibrosis
Thick mucous forms in the digestive tract and lungs of people with CF. As a result, they
have difficult breathing and are susceptible to lung infections.
The median life expectancy for babies born with cystic fibrosis is 32 years.
The gene that causes the disease is on chromosome 7. One particular mutation of this
allele causes 70-75% of the cases.
It is somewhat difficult to detect prenatally.
Gene therapy may be a possibility in the future. The normal gene was inserted into cells
in laboratory cultures.
Viruses have been engineered to deliver the gene. An aerosol spray is used to deliver the
virus to the lungs.
There has been some success reported in treating human patients in 1994.
Cystic fibrosis is the most common lethal genetic disease among Caucasians in the US.
One in 25 is a carrier; one in 2500 is affected.
Tay Sachs
A fatty substance builds up in the neurons (nerve cells) of people with Tay Sachs. This
causes a gradual paralysis and loss of nervous function that leads to death by age 4 or 5.
It is due to a single defective enzyme which normally digests the fatty material.
Heterozygotes (Aa) are not affected and are resistant to tuberculosis.
Prenatal diagnosis is available.
It is a common genetic disease among the Jewish population in the US (central and
eastern European descent). Up to 11% are carriers. It is also common in people of
French-Canadian or Cajun descent.
PKU - Phenylketonuria
PKU is a recessive genetic disease in which the person does not have the ability to break
down the amino acid phenylalanine. The level of phenylalanine in the persons blood
builds up and interferes with the development of the nervous system.
Children that are raised on a phenylalanine-restricted diet may develop normally but
children that are not raised on a special diet will become severely mentally retarded. The
diet should be followed for life because high phenylalanine levels affect cognitive
functioning.
Genetic screening is the routine testing of individuals for specific genotypes. Newborns
in U.S. hospitals are screened for PKU.
PKU women must resume the diet several months before conception
The incidence of PKU in the United States is 1 in 13,500 to 1 in 19,000.
Sickle-Cell Anemia
Sickle-cell anemia is an abnormality of hemoglobin, the molecule that carries oxygen in
our blood. Hemoglobin is contained within red blood cells. When the oxygen
concentration in the hemoglobin molecules becomes low, the molecules stick together
forming long rods that distort the cell (picture below). The cells break down or clog blood
vessels causing pain, poor circulation, jaundice, anemia, internal hemorrhaging, low
resistance, and damage to internal organs. Death usually occurs before age 50.
Heterozygotes (carriers) are not affected with anemia and are resistant to malaria.
Eight to ten percent of African Americans carry the allele (have sickle-cell trait)..
Autosomal Dominant
Severe dominant diseases are rare because carriers die before they get a chance to
reproduce and pass on the disease to their offspring.
Heterozygotes (Aa) have the trait.
Children with the trait have at least one parent that has the trait.
Two parents with the trait can produce a child that does not have the trait.
Both males and females are affected equally.
Huntington’s Disease
The brain cells of Huntington's victims slowly degenerate, producing jerking muscles,
slurred speech, swallowing difficulty, loss of balance, mood swings, reasoning and
memory loss, incapacitation, and eventually death (usually from pneumonia or heart
failure).
The onset of Huntington’s disease is typically 35 to 45 years.
It is caused by a repeated DNA sequence (AGC). The normal allele has 11-34 copies;
affected people have 42 - 120 copies.
The severity and time of onset depends on the number of repeats.
People who are most at risk inherit the gene from their father. This is an example of
genomic imprinting.
The gene is on chromosome 4. A diagnostic test is available.
X-Linked Recessive
More males than females have x-linked recessive traits.
A son with the trait can have parents that do not have the trait.
There is no father to son transmission of the gene.
The trait can skip generations; grandfather to grandson transmission can occur.
If a female has the trait, her father has it, her mother is a carrier (or has it), and all her
sons will have it.
Color Blindness
3 different kinds
2 X-linked forms: 1 for green insensitivity (6% of all males), one for red insensitivity
(2% of all males); 1 in 12 males have some form of colorblindness.
Hemophilia
People with hemophilia lack a clotting factor in their blood and as a result, their blood
does not form clots normally. This results in excessive bleeding from even minor cuts.
Internal hemorrhaging from bruises is common and leads to painful complications.
The incidence is in 1,500 newborn males. Most (75%) have hemophilia A, a lack of
clotting factor VIII. Hemophilia B- "Christmas Disease" is a defect in clotting factor IX.
Transfusions of fresh whole blood or plasma or factor concentrates control bleeding but
have previously caused AIDS infections.
The human gene has been isolated and cloned using recombinant DNA techniques. This
is leading to improved treatment.
Royal Families of Europe
Victoria (granddaughter of George III) was a carrier and spread the gene to the royal
families of Europe. Her granddaughter Alix- married Czar Nicholas II of Russia. The
Czar’s son Alexis, heir to the throne, had hemophilia.
The Czar's preoccupation with Alexis' health contributed to the revolution that overthrew
the throne and eventually led to the communist government.
Duchenne Muscular Dystrophy
There are four different kinds of X-linked muscular dystrophy. They are multiple alleles
at a single locus.
Duchenne’s is the most common and most severe form of muscular dystrophy.
1 in 5,000 live male births (Duchenne’s)
One in 4000 newborn males have some form of muscular dystrophy. One third of these
are new mutations.
Muscular deterioration begins between ages 3 to 5. Affected individuals are confined to a
wheelchair by age12 and rarely survive past age 20. Death is usually due to breathing or
heart problems.
It is transmitted primarily by female carriers (males rarely reproduce)
Sex-Influenced Inheritance
Sex-influenced traits are those that are dominant in one sex but recessive in the other
This difference is due to the different hormonal environments between the sexes.
Sex-influenced genes are not necessarily located on the X chromosomes. Don’t confuse
this with X-linked inheritance.
Examples
Pattern baldness is male dominant.
A gene that causes the index finger to be longer than the third finger is female dominant.