Genetics
 Genetics is the study of
genes
 Genes; sequences of
DNA.
 Genes are packaged
together as chromosomes
and are passed from
parent to offspring.
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 It is our genes that
determine who we are and
how we function at the
most basic cellular level.
Sometimes mistakes
(mutations) cause
significant disability or
death, or benefits.
Genes; 25,000 genes.
Chromosomes
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 Chromosomes are made
up of molecules of DNA,
complexed with proteins
called histones.
 Chromosomes together
carry the genetic
blueprint of an
individual.
 All human somatic (body)
cells contain 23 pairs of
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chromosomes, one pair from
each parent, for a total of 46
chromosomes. Each human
sex cell, an egg or a sperm,
contains 23 unpaired
chromosomes.
Gene Activation
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Although each somatic cell
contains the same 23 pairs
of chromosomes, only
certain genes are activated
in any given cell; therefore,
only certain proteins or
enzymes are produced by
that cell. Which genes are
activated in which cell is
determined during
embryologic development
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and throughout life by
circulating growth factors,
hormones, and chemical
produced by a given cell
and its neighboring cells.
Cellular Reproduction
All cells reproduce during
embryonic development,
which allows for growth of
the embryo and
differentiation
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(specialization) of the cells
making up tissues and
organs. After birth and
throughout adulthood,
many cells continue to
reproduce. Cells that
reproduce throughout a
lifetime include cells of the
bone marrow, skin, and
digestive tract. Liver and
kidney cells reproduce
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when replacement of lost
or destroyed cells is
required. Special cells,
called stem cells, are
capable of reproducing
indefinitely. Other cells,
including nerve, skeletal
muscle, and cardiac
muscle cells, do not
reproduce significantly
after the first few months
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following birth. Damage to
these tissues generally
cannot be repaired by
growth of new cells .
The Cell Cycle
The cell cycle refers to a
sequence of stages a cell
goes through during its
lifetime . During
embryogenesis, all cells go
through all stages, as do
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adult cells that continue to
reproduce. The rate at
which a cell goes through
its cell cycle depends on
the given cell and the
growth factors, hormones,
and chemicals to which it
is exposed. Cells that do
not continue to reproduce
after embryogenesis
remain in a resting stage
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and do not cycle through
the other stages. The cell
cycle is divided into two
parts: interphase and
mitosis.
Interphase
When not actively
dividing, a cell is said to be
in interphase.
Mitosis
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Mitosis is the stage of cell
division. Mitosis is a
shorter event than
interphase; it lasts
approximately 1 hour.
During mitosis, the cell
that has duplicated during
interphase splits into two
daughter cells that each
contain the 23 pairs of
chromosomes. Mitosis
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consists of the substages of
prophase, metaphase,
anaphase, and telophase.
Meiosis
Meiosis is the process
during which germ cells of
the ovary (primary
oocytes) or testicle
(primary spermatocytes)
give rise to mature eggs or
sperm . Meiosis involves
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DNA replication in the
germ cell, followed by two
cell divisions rather than
one, which results in four
daughter cells, each with
23 (unpaired)
chromosomes. In males, all
four daughter cells are
viable and continue to
differentiate into mature
sperm. In females, only
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one viable daughter cell
(egg) is formed; the other
three cells become
nonfunctional polar bodies.
During fertilization,
genetic information
contained in the 23
chromosomes of the egg
joins with genetic
information contained in
the 23 chromosomes of the
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sperm. This results in an
embryo with 46 total
chromosomes (two pairs of
23).
An interesting
phenomenon occurs during
DNA replication in the
first meiotic stage. At this
time, pieces of DNA may
shift between the matched
chromosome pairs, in a
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process called crossingover. Crossing-over
increases the genetic
variability of offspring,
and is one reason why
siblings within a family
may vary considerably in
genotype and phenotype.
Genotype and Phenotype
Precise genetic information
carried in the
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chromosomes of the
offspring is termed the
genotype. Physical
representation of genetic
information (tall or short,
dark or light) is called the
phenotype.
Genetic Testing
(cytogenetics)
Genetic testing, called
cytogenetics, involves
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looking at the overall
structure and number of
the chromosomes. Genetic
testing can be performed
on any cell of the body, but
in children and adults it is
usually done by
withdrawing white blood
cells in a venous blood
sample. For prenatal
testing, fetal cells may be
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gathered during the
processes of
amniocentesis, or during
chorionic villi sampling.
Amniocentesis
Amniocentesis is
performed by inserting a
needle through the
abdominal wall of a
pregnant woman into the
amniotic sac that surrounds
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the fetus. Amniotic fluid,
into which fetal cells have
been shed, is withdrawn.
Chromosomes present in
the fluid sample are then
cultured and fixed, and
their number and shape are
analyzed for genetic
integrity. This test is
usually done at
approximately 16 weeks'
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gestation and results are
available in approximately
2 weeks.
Chorionic Villi Sampling
Chorionic villi sampling
involves gathering cells of
the chorion , the outer
border of the fetal
membranes. The cells are
gathered by placing a
needle through the
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woman's lower abdomen
or cervix between 8 and 12
weeks of pregnancy. The
cells do not need to be
cultured, so the
chromosomal analysis is
available in approximately
1 to 2 days..
Pathophysiologic
Concepts
Mutation
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A mutation is an error in
the DNA sequence.
Mutations can occur
spontaneously, or after the
exposure of a cell to
radiation, certain
chemicals, or various viral
agents.
Most mutations will be
identified and repaired by
enzymes working in the
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cell. If a mutation is not
identified or repaired, or if
the cell does not undergo
programmed death, that
mutation will be passed on
in all subsequent cell
divisions. Mutations may
result in a cell becoming
cancerous. Mutations in
the gametes (the egg or
sperm) may lead to
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congenital defects in an
offspring.
congenital Defects
Congenital defects, also
called birth defects,
include genotypic and
phenotypic errors
occurring during
embryogenesis and fetal
development. Some
congenital defects, such as
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cleft palate and limb
abnormalities, may be
apparent at birth, whereas
other congenital defects,
such as an abnormal or
absent kidney and certain
types of heart disease, may
not be recognized
immediately. Congenital
defects may result from
genetic mistakes made
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during meiosis of the
sperm or egg, or from
environmental insults
experienced by the fetus
during gestation.
Chromosomal Breaks
During mitosis and
meiosis, pieces of
chromosomes may break
off, be added
inappropriately to other
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chromosomes, or be
deleted entirely. If
deletions or additions
occur during meiosis in the
egg or sperm, a congenital
defect or death of the
embryo may result.. If
deletions or additions of
chromosomes occur during
mitosis, the affected cell
line will usually die out.
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Errors in Chromosome
Number
Any change from the
normal human
chromosome number of 46
chromosomes is called
aneuploidy. An aneuploidy
in which there are only 45
chromosomes is called a
monosomy. An aneuploidy
in which there are 47
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chromosomes is called a
trisomy. Having more than
47 chromosomes is
possible but rare.
Monosomy
If any chromosome other
than the X or Y is lost, the
embryo will spontaneously
abort. However, the loss of
one of the sex
chromosomes may result in
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a viable offspring. Usually
the Y chromosome is lost,
resulting in 44 somatic
chromosomes and one sex
chromosome, for a total of
45 chromosomes (often
expressed 45, X/O, to
indicate no Y
chromosome). The
resulting disorder is called
Turner's syndrome.
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Monosomy of any
chromosome is a major
cause of spontaneous
abortion in the first
trimester.
Trisomy
A trisomy occurs when
somatic or sex
chromosomes do not
separate properly during
meiosis. This is called nons33
disjunction. Most trisomies
cause spontaneous
abortion of the embryo,
but rarely live births may
result. Trisomies that may
result in live births include
trisomies of the sex
chromosomes and
trisomies of chromosomes
8, 13, 18, and 21. Trisomy
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21 is called Down
syndrome.
Teratogenesis
Teratogenesis is an error
in fetal development that
results in a structural or
functional deficit (e.g., a
deficit in brain function).
Environmental stimuli that
cause congenital defects
are called teratogenic
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agents. Teratogenic agents
can lead to genetic
mutations or errors in
phenotype. Common
manifestations of
teratogenic exposure
include congenital heart
disease, abnormal limb
development, mental
retardation, blindness,
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hearing loss, and
abnormalities in growth.
Of the teratogenic agents
:
1 - Alcohol
The most common
teratogenic drug used in
the United States is
alcohol. Alcohol at any
dose is capable of causing
neurologic deficits and
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facial deformities ranging
from mild to severe.
Alcohol is the leading
cause of birth defects and
mental retardation; fetal
alcohol syndrome. Fetal
alcohol syndrome is 100%
preventable.
2 - The TORCH Group of
Teratogens
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 Several different
microorganisms are
known to be teratogenic
in humans. Many of
these are described under
the acronym TORCH, in
which each letter stands
for a particular
microorganism that may
infect the embryo or
fetus.
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 T stands for
toxoplasmosis,
 R for rubella,
 C for cytomegalovirus,
and
 H for the herpes
simplex virus.
 The letter O stands for
all other infections,
especially syphilis,
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hepatitis B, mumps,
gonorrhea, and
chickenpox.
A newborn infected
during gestation with any
of the TORCH group of
microorganisms may show
microcephaly,
hydrocephaly, mental
retardation, or loss of
hearing or sight.
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Congenital heart defects
are common, especially
with rubella.
3 - Radiation exposure
may increase the risk that
the child will later develop
cancer.
*Whether an embryo or
fetus will be affected by
any teratogenic agent
depends on several factors,
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which include the timing
and dose of exposure, and
maternal and paternal
health and nutritional
status.
Timing of Exposure to a
Teratogen
- Because most organs and
tissues are formed during
the first trimester,
teratogenic agents are most
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likely to cause structural
defects at this time.
- However, the nervous
system is always
susceptible to a teratogen
because it continues to
develop even after birth.
- Infants exposed to an
infectious agent in the third
trimester or during the
birth process are at
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increased risk of
developing the disease.
This is true for neonatal
infection by hepatitis B
virus or HIV.
Dose of a Teratogen
- The dose of exposure is
important in determining
the likelihood that a
teratogenic agent will
cause a congenital defect.
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- Levels of radiation used
in most diagnostic
techniques or low
concentrations of a drug
may not produce any effect
on the fetus.
- Higher doses of radiation
or a drug may adversely
affect the fetus.
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Maternal Health and
Nutritional Status
This play a role in
determining teratogen
effect. Infants born to
women with diabetes or
seizure disorders are at
higher risk of fetal
anomalies, the latter
perhaps due to the effects
of both the seizures
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themselves and the
medications used to treat
the disorder.
Maternal diets low in folic
acid have been associated
with development of neural
tube defects(NTD) such as
spina bifida.
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Down Syndrome
Down syndrome is a
genetic disorder caused by
a trisomy of chromosome
21. Down syndrome is
seen in 1 in 800 live births,
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making it the most
common chromosomal
disorder seen in live births.
In 95% of cases, Down
syndrome is caused by
non-disjunction of
maternal chromosome
number 21 during meiosis.
The incidence of Down
syndrome related to nons50
disjunction increases with
maternal age.
Clinical Manifestations
- Variable levels of mental
retardation.
- Upward slanting of the
eyes.
- Short hands that have
only one crease on the
palm (a simian crease)
- low-set ears.
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- Short stature.
- Protruding tongue.
Complications
- Congenital heart or other
organ defects are frequent .
- Risk of childhood
leukemia is increased in
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children with Down
syndrome.
- Spontaneously abortion
of about 20% between 10
and 16 weeks' gestation.
Turner syndrome
Is a monosomy of the sex
chromosomes. Infants born
with Turner syndrome
have 45 chromosomes: 22
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pairs of somatic
chromosomes and 1 sex
chromosome, usually the X
(45, X/O). This disorder is
common in spontaneously
aborted fetuses, and is
present in approximately 1
in 2,500 live births.
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Females with Turner
syndrome lack ovaries.
Clinical Manifestations
- Clinical manifestations
may be nonexistent, mild,
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or moderate and include:
- Short stature and
Webbing of the neck.
- Lack of secondary sex
characteristics and
amenorrhea .
Complications
- Congenital heart defects
may accompany the sex
chromosome monosomy.
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- Increased risk of
childhood bone fractures
and adult osteoporosis due
to lack of estrogen.
- Some individuals may
demonstrate signs of
learning disability.
Klinefelter Syndrome
Klinefelter syndrome is a
polysomic disorder
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characterized by one or
more extra X
chromosomes in a
genotypic male (47,
X/X/Y; 47, X/X/X/Y).
This syndrome occurs in
approximately 1 in 600
live births. Klinefelter
syndrome may result from
non-disjunction of the
male or female X
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chromosome during the
first meiotic division, at
approximately equal rates
in males and females.
Clinical Manifestations
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Although the infant may
appear normal at birth, he
may show a decrease in
male secondary sex
characteristics during
puberty.
Gynecomastia (breast
enlargement) and other
female patterns of fat
deposit.
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Infertility and sexual
dysfunction.
Tall stature in adult life
because decreased levels of
testosterone do not
contribute to epiphyseal
bone plate closure.
Individuals may
demonstrate reduced
mental functioning,
especially with increasing



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number of X
chromosomes.
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