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 Genetics
is the study of genes
 Genes; sequences of DNA.
 Genes are packaged together as
chromosomes and are passed from parent to
offspring.
 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.
Study of hereditary, the passing of traits from
parents to their children.
 Physical traits such as eye color are inherited as
well as biochemical and physiologic traits,
including the tendency to develop certain
diseases.
 Transmitting an inheritance
 Inherited traits are transmitted from parents to
offspring through genes in gametes (ova, and
sperms).
 A person’s genetic makeup is determined at
fertilization, when ovum and sperm are united.
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Chromosomes
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In the nucleus of each germ cell are structures called
chromosomes.
Chromosomes are made up of molecules of DNA,
complexed with proteins called histones.
Chromosomes together carry the genetic blueprint of
an individual.
DNA is a long molecule that’s made up of thousands
of segments called genes.
Each of the traits that a person inherits is coded in
their genes.
All human somatic (body) cells contain 23 pairs of
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.
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There are two genes for each trait that a person
inherits. One gene may be more influential
(dominant) than the other(recessive) in developing a
specific trait.
For example, a child may receive a gene for brown
eyes from one parent and a gene for blue eyes from
the other parent. The gene for brown eyes is
dominant. Therefore, the child is more likely to have
brown eyes.
A variation of a gene and the trait it controls is called
an allele. When two different alleles are inherited,
they’re said to be heterozygous. When the alleles are
identical, they’re termed homozygous. A dominant
allele may be expressed when it’s carried by only one
of the chromosomes in a pair. A recessive allele is not
expressed unless recessive alleles are carried by both
chromosomes in a pair.
 Of
the 23 pairs of chromosomes in each living
human cell, 22 pairs are somatic; they’re
called autosomes. The gender is determined
by the two sex chromosomes. Females have
two X chromosomes. Males have one X
chromosome and one is a smaller
chromosome Y.
 Each gamete produced by a male contains
either an X or a Y chromosome.
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X+X= female
X+X= male
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 and throughout life by
circulating growth factors, hormones, and
chemical produced by a given cell and its
neighboring cells.
All cells reproduce during embryonic
development, which allows for growth of the
embryo and differentiation (specialization) of
the cells making up tissues and organs.
 After birth and throughout adulthood, many cells
continue to reproduce.
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Cells that reproduce throughout a lifetime include cells
of the bone marrow, skin, and digestive tract.
Liver and kidney cells reproduce 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 following birth.
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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 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.
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In females, only 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
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 process called crossing-over.
Crossing-over increases the genetic
variability of offspring, and is one reason
why siblings within a family may vary
considerably in genotype and phenotype.
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Precise genetic information carried in the
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
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
gathered during the processes of amniocentesis,
or during chorionic villi sampling.
 Amniocentesis
is performed by inserting a
needle through the abdominal wall of a
pregnant woman into the amniotic sac that
surrounds the fetus.
 Chromosomes present in the fluid sample are
then cultured and tested for number and
shape are analyzed for genetic integrity.
 This test is usually done at approximately 16
weeks' gestation and results are available in
approximately 2 weeks.
 Involves
gathering cells of the chorion (the
outer border of the fetal membranes).
 The cells are gathered by placing a needle
through the 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.
Mutation:
A mutation is a permanent change in genetic
material
 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 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.
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Mutations in the gametes (the egg or sperm)
may lead to congenital defects in an offspring
Some mutations cause serious or deadly
disorders
that occur in three different forms:
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Single gene disorder
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Chromosomal disorder
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Multifactorial disorders
 Inherited
in clearly identifiable pattern
 Two important inheritance patterns are
called autosomal dominant and
autosomal recessive.
 Most hereditary disorders are caused by
autosomal defects:
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Autosomal dominant
Autosomal recessive
 Sex
linked disorders
 Male
& female equally affected
 One parent is usually affected
 If one parent is affected,
50% of offspring is being affected
 All
offspring affected, if both parents are
affected
 Ex:
Marfan syndrome
• Male and female are affected equally.
 • If both parents are unaffected but
heterozygous for the trait (carriers), each of
their offspring has a one in four chance of being
affected.
 • If both parents are affected, all of their
offspring will be affected.
 • If one parent is affected and the other is not a
carrier, all of the parents’ offspring will be
unaffected but will carry the altered gene.
 • If one parent is affected and the other is a
carrier, each of the offspring will have a chance
50% of being affected and 50%of being a carrier
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 If
the two parents are unaffected ,
each with an altered recessive gene (a)
on an autosome. Each offspring will have
25% chance of being affected and 50%
chance of being a carrier.
 Females:
homozygous for a disease allele,
 homozygous for a normal allele,
 or heterozygous.
Males:
a single X-linked recessive gene can cause disease
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 Males
are more commonly affected by Xlinked recessive diseases than females.
 During
mitosis and meiosis, pieces of
chromosomes may break off, be added
inappropriately to other 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.
 Nondisjunction
 During
cell division, chromosomes normally
separate in a process called disjunction.
Failure to do so—called nondisjunction—
causes an unequal distribution of
chromosomes between the two resulting
cells. Gain or loss of chromosomes is usually
due to nondisjunction of autosomes or sex
chromosomes during meiosis.
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Any change from the normal human
chromosome number of 46 chromosomes is
called aneuploidy.
aneuploidy in which there are only 45
chromosomes is called a monosomy.
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An aneuploidy in which there are 47
chromosomes is called a trisomy. Having
more than 47 chromosomes is possible but
rare.
 An
 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 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. Monosomy of any chromosome is
a major cause of spontaneous abortion in
the first trimester
A
trisomy occurs when somatic or sex
chromosomes do not separate properly
during meiosis. This is called nondisjunction.
 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 21 is called Down syndrome
Nondisjunction may occur during very early cell
divisions after fertilization and may or may not
involve all the resulting cells.
 A mixture of cells, some with a specific
chromosome abnormality and some with normal
cells, results in mosaicism. The effect on the
offspring depends on the percentage of normal
cells.
 The incidence of nondisjunction increases with
parental age, especially maternal age.
Miscarriages can also result from chromosomal
abnormality. Fertilization of an ovum with a
chromosome aberration by a sperm with a
chromosome aberration usually doesn’t occur.
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 Chromosome
break and rejoin in an abnormal
arrangement
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Balanced, reserve genetic material
Imbalanced, visible abnormalities (partial
monosomies / trisomies)
Translocation
Robertsonian
translocation
Reciprocal translocation
 Genetic
& environmental factors
(cleftlip/palate, spina bifida)
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maternal age
• use of chemicals
• maternal infections during pregnancy or
existing diseases in the mother
• maternal or paternal exposure to radiation
• maternal nutritional factors
• general maternal or paternal health
• other factors, including high altitude,
maternal-fetal blood incompatibility,
maternal smoking, and poor-quality prenatal
care.
•
multifactorial disorders (cleft lip and cleft
palate)
 • six single-gene disorders (cystic fibrosis,
hemophilia, Marfan syndrome,
phenylketonuria [PKU], sickle cell anemia)
 • a chromosomal disorder (Down syndrome).
Also called birth defects, include genotypic and
phenotypic errors occurring during
embryogenesis and fetal development.
 Some congenital defects, such as 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 during meiosis of the sperm or
egg, or from environmental insults experienced
by the fetus during gestation.
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 hereditary
= derived from parents
 familial = transmitted in the gametes
through generations
 congenital = present at birth (not always
genetically determined - e.g. congenital
syphilis, toxoplasmosis)
 ! not all genetical diseases are congenital
- e.g. Huntington disease - 3rd to 4th
decade of life
 Teratogens
 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 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, hearing loss, and
abnormalities in growth.
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Alcohol.
TORCH Group of Teratogens
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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,
hepatitis B, mumps, gonorrhea, and chickenpox.
A newborn infected during gestation with any of the
TORCH group of MOs may show microcephaly,
hydrocephaly, mental retardation, or loss of hearing or
sight.
Congenital heart defects are common, especially with
rubella.
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, which include the timing and dose of exposure,
and maternal and paternal health and nutritional status.
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- Teratogenic agents are most likely to cause structural
defects at the first trimester, 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 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.
- 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
 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 themselves and
the medications used to treat the disorder.
 Maternal diets low in folic acid have been
associated with development of neural tube
defects such as spina bifida..
 Down
syndrome produces mental
retardation, characteristic facial features,
and distinctive physical abnormalities. It’s
also associated with heart defects and other
congenital disorders. Life expectancy and
quality of life for patients with Down
syndrome
 have increased significantly because of
improved treatment
 of related complications and better
developmental education programs.
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Variable levels of mental retardation.
- Upward slanting of the eyes.
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- Short hands that have only one crease
on the palm (a simian crease)
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- low-set ears.
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- Short stature.
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- Protruding tongue.
Clinical Features of Down Syndrome
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 July 2005 09:03 PM)
© 2005 Elsevier
 Spontaneously
abortion of about 20%
between 10 and 16 weeks' gestation.
 Congenital heart or other organ defects are
frequent .
 Risk of childhood leukemia is increased in
children with Down syndrome.
 Premature senile dementia, similar to
Alzheimer’s disease
 Acute and chronic infections, diabetes
mellitus, and thyroid disorders.
 Is
a monosomy of the sex chromosomes.
Infants born with Turner syndrome have 45
chromosomes: 22 pairs of somatic
chromosomes and 1 sex chromosome, usually
the X (45, X/O). This disorder is common in
spontaneously aborted fetuses. Females with
Turner syndrome lack ovaries.
Clinical Manifestations
Clinical manifestations may be nonexistent,
mild, 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.
Increased risk of childhood bone fractures and
adult osteoporosis due to lack of estrogen.
-Some individuals may demonstrate signs of
learning disability.
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 Klinefelter
Syndrome
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 Klinefelter
syndrome is a polysomic disorder
characterized by one or more extra X
chromosomes in a genotypic male (47,
X/X/Y; 47, X/X/X/Y).. Klinefelter syndrome
may result from non-disjunction of the male
or female X chromosome during the first
meiotic division, at approximately equal
rates in males and females.
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Clinical Manifestations 
 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.
 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 number of
X chromosomes.
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