Transcript abnormalities of chromosome structure

EUGENE PARDI, DO
ESTRELLA MOUNTAIN COMMUNITY
COLLEGE
INTRODUCTION

 In the 19th century, microscopic studies of cells
led scientists to suspect that the nucleus of the
cell contained the important mechanisms of
inheritance.
 The chromatin in the nucleus condensed to form
CHROMOSOMES before cell division.
 With the rediscovery of Gregor Mendel’s
breeding experiments, it became apparent that
the chromosomes contained GENES, the basic
units of inheritance.
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INTRODUCTION

The primary constituent of the chromatin is
DEOXYRIBONUCLEIC ACID (DNA).
Genes are composed of sequences of DNA.
By serving as the blueprints of proteins in the
body, genes influence all aspects of body
structure and function.
An error in one of these genes can lead to a
recognizable genetic disease.
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INTRODUCTION

To date, more than 15,000 genetic conditions
have been identified and cataloged.
The proportion of beds in pediatric hospitals
occupied by children with genetic diseases
has risen to one third.
Many common diseases that affect primarily
adults are now known to have important
genetic components.
HTN, CAD, diabetes, cancer.
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DNA: COMPOSITION AND
STRUCTURE

 Genes are composed of DNA, which has three basic
components:
 The pentose sugar molecule DEOXYRIBOSE.
 A phosphate molecule.
 One of four types of nitrogenous bases:
 PYRIMIDINES
 CYTOSINE (C)
 THYMINE (T)
 PURINES
 ADENINE (A)
 GUANINE (G)
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DNA: COMPOSITION AND
STRUCTURE

These molecules are physically assembled
together in a DOUBLE – HELIX model.
DNA can be envisioned as a twisted
ladder, with chemical bonds as its rungs.
The two sides of the ladder are
composed of the sugar and phosphate
molecules, held together by strong
phosphodiester bonds.
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DNA: COMPOSITION AND
STRUCTURE

 Projecting from each side of the ladder are the
nitrogenous bases.
 The base projecting from one side is bound to the base
projecting from the other side by a hydrogen bond.
 The nitrogenous bases form the rungs of the ladder.
 Adenine pairs with thymine.
 Guanine pairs with cytosine.
 Each DNA subunit consists of one deoxyribose
molecule, one phosphate group, and one base.
 NUCLEOTIDE.
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DNA AS THE GENETIC CODE

 DNA can direct the synthesis of all the body’s proteins.
 Proteins are composed of one or more
POLYPEPTIDES, which are in turn composed of
sequences of AMINO ACIDS.
 The body contains 20 different types of amino acids,
and the amino acid sequences that make up
polypeptides must be specified by the DNA molecule.
 Each amino acid is specified in the DNA molecule
by a triplet of bases called a CODON.
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DNA AS THE GENETIC CODE

 Of the 64 possible codons, three signal the end of a
gene and are known as TERMINATION, or
NONSENSE, CODONS.
 The remaining 61 all specify amino acids.
 Most amino acids can be specified by more than
one codon.
 The genetic code is UNIVERSAL.
 All living organisms use the same DNA codes to
specify proteins.
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REPLICATION

DNA must be able to replicate itself
accurately during cell division.
Replication consists of the breaking
of the weak hydrogen bonds
between the bases, leaving a single
strand with each base unpaired.
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REPLICATION

COMPLEMENTARY BASE PAIRING is
the key to accurate replication.
It is the consistent pairing of adenine
with thymine and of guanine with
cytosine.
A portion of a single strand with a
sequence of bases will attract free
nucleotides with the complementary
bases.
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REPLICATION

When replication is complete, a
new double – stranded molecule
identical to the original is formed.
The single strand is said to be a
TEMPLATE on which a
complementary molecule is built.
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REPLICATION

 Several different proteins/enzymes are involved in
DNA replication:
 DNA POLYMERASE: travels along the single
DNA strand, adding the correct nucleotides to
the free end of the new strand.
 Also proofreads the new molecule in that
after the new nucleotide has been added to
the chain, it checks to make sure that its base
is actually complementary to the template
base.
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MUTATION

 A MUTATION is any inherited alteration of genetic
material.
 Some are subtle and are not seen as chromosomal
aberrations.
 BASE PAIR SUBSTITUTION: one base pair is replaced
by another.
 Also called MISSENCE MUTATION in that the codon
produced after transcription of the mutant gene is altered.
 Can result in a change in the amino acid (aa) sequence with
profound effects.
 It may have no consequence due to redundancy of the
genetic code.
 SILENT SUBSTITUTION
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MUTATION

FRAMESHIFT MUTATION:
alteration that involves the insertion or
deletion of one or more base pairs to
the DNA molecule.
Can change the entire “reading
frame” of the DNA sequence.
Can greatly alter the amino acid
sequence.
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MUTATION

 MUTAGENS: agents that are known to increase the
frequency of mutations.
 Radiation from x-rays or nuclear fallout forms
electrically charged ions that produce chemical
reactions which change DNA bases.
 A variety of chemicals can induce mutations because
they are chemically similar to the DNA bases.
 Some mimic the effects of ionizing radiation.
 Others interfere with base pairing.
 Some are much more potent mutagens than others.
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MUTATION

 Measurement of the mutation rate is difficult because
mutations are very rare events.
 SPONTANEOUS MUTATION: a mutation that
occurs in the absence of exposure to known
mutagens.
 MUTATIONAL HOT SPOTS: certain areas of some
chromosomes that have a particularly high mutation
rate.
 Sequences consisting of a cytosine base followed
by a guanine base
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FROM GENES TO PROTEINS

The transport of the DNA code from the
nucleus to cytoplasm and subsequent protein
formation involves two basic processes:
TRANSCRIPTION: formation of a mRNA
molecule based on the DNA code.
TRANSLATION: formation of a protein
from the mRNA using ribosomes and
tRNA.
Occurs in the cytoplasm.
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FROM GENES TO PROTEINS

 Both of these processes are mediated by RIBONUCLEIC
ACID (RNA).
 Chemically similar to DNA in that RNA is also
composed of a sugar molecule, phosphate group, and
nitrogenous base.
 Differs from DNA in that the sugar molecule is ribose,
not deoxyribose, and that uracil rather than thymine is
one of the four bases.
 Structurally similar to thymine so it pairs with
adenine.
 RNA usually occurs as a single strand instead of the
double strand as DNA has.
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TRANSCRIPTION

 TRANSCRIPTION is the process by which RNA is
synthesized from a DNA template.
 The result is the formation of MESSENGER RNA
(mRNA) from the base sequence specified by the
DNA molecule.
 An enzyme DNA – DEPENDENT RNA
POLYMERASE or RNA POLYMERASE binds to a
PROMOTER SITE on the DNA.
 A promoter site is a sequence of DNA that
specifies the beginning of a gene.
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TRANSCRIPTION

The RNA polymerase pulls a portion of
the DNA strands apart from one
another, allowing unattached DNA
bases to be exposed.
One of the DNA strands provides the
template for the sequence of mRNA
nucleotides.
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TRANSCRIPTION

Except for the presence of uracil, the mRNA
sequence is identical to that of the other DNA
strand.
Transcription continues until a DNA
sequence called a TERMINATION
SEQUENCE is reached.
RNA polymerase detaches and the
transcribed mRNA moves out of the
nucleus into the cytoplasm.
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GENE SPLICING

 The mRNA transcribed from the DNA template reflects
exactly the base sequence of the DNA.
 Called HETEROGENEOUS NUCLEAR RNA (hnRNA).
 Before migrating to the cytoplasm, many of the RNA
sequences are removed by nuclear enzymes.
 The remaining sequences are then spliced together to
form the functional mRNA.
 The excised sequences are called INTRONS.
 The sequences left to code for proteins are called
EXONS.
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TRANSLATION

TRANSLATION is the process by
which RNA directs the synthesis of a
polypeptide.
It interacts with TRANSFER RNA
(tRNA).
The molecule has a site for the
attachment of an amino acid at one
end.
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TRANSLATION

At the opposite side is a sequence of
three nucleotides called the
ANTICODON.
Undergoes complementary base
pairing with an appropriate codon in
the mRNA.
The mRNA specifies the sequence of
amino acids by acting through the tRNA.
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TRANSLATION

The site of actual protein synthesis is
the RIBOSOME.
Consists of roughly equal parts of
protein and RIBOSOMAL RNA
(rRNA).
During translation, the ribosome first
binds to an initiation site on the
mRNA sequence.
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TRANSLATION

It then binds tRNA to its surface
so that base pairing can occur
between tRNA and mRNA.
The ribosome then moves along
the mRNA sequence, codon by
codon.
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TRANSLATION

As each codon is processed, an
amino acid is translated by the
interaction of mRNA and tRNA.
The ribosome provides an enzyme
that catalyzes the formation of
peptide bonds between adjacent
amino acids., resulting in a
growing polypeptide.
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TRANSLATION

When the ribosome arrives at a
termination signal on the mRNA
sequence, translation and
polypeptide formation cease.
The polypeptide is released into the
cytoplasm to perform its function.
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CHROMOSOMES

 Human cells can be categorized into two types:
 GAMETES: sperm and egg cells
 SOMATIC CELLS: all cells other than gametes.
 Each somatic cell has 46 chromosomes in its nucleus.
 DIPLOID CELLS: the chromosomes occur in
pairs.
 Each cell has 23 pairs of chromosomes.
 One member of each pair comes from an
individual’s mother, and one comes from the
father.
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CHROMOSOMES

 New somatic cells are formed through mitosis
and cytokinesis.
 The cell nucleus and cytoplasm are replicated.
 Gametes are HAPLOID CELLS.
 Have only one member of each chromosome
pair, or, 23 chromosomes.
 MEIOSIS is the process by which these cells
are formed from diploid cells.
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CHROMOSOMES

 In 22 of the 23 chromosome pairs, the two members
of each pair are virtually identical in appearance.
 Are HOMOLOGOUS to one another in both
males and females.
 Termed AUTOSOMES.
 The SEX CHROMOSOMES have two homologous
X chromosomes in females and a nonhomologous
par, X and Y in males.
 Males are HEMIZYGOUS for the X chromosome.
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CHROMOSOMES

 METAPHASE SPREAD: photograph of the
chromosomes as they appear in the nucleus of a somatic
cell during metaphase.
 KARYOTYPE: an ordered display of chromosomes.
 The chromosomes are arranged according to size, with
the HOMOLOGOUS CHROMOSOMES paired
together.
 The 22 autosomes are numbered according to length
and the position of the centromere.
 I  longest.
 22  shortest.
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CHROMOSOME ABERRATIONS
AND ASSOCIATED DISEASES

 Chromosome abnormalities are the leading known
cause of mental retardation and miscarriage.
 A major chromosome aberration occurs in at least 1
in 12 conceptions.
 50% of all recovered first trimester spontaneous
abortions have major chromosomal aberrations.
 1 in 150 live births has a diagnosable chromosome
abnormality.
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POLYPLOIDY

 EUPLOID CELLS: cells that have a multiple of
the normal number of chromosomes.
 A POLYPLOID CELL has more than the diploid
number of chromosomes.
 TRIPLOID – 3 copies of each chromosome.
 TETRAPLOID – 4 copies of each
chromosome.
 Both of these conditions are incompatible with
postnatal survival.
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ANEUPLOIDY

 An ANEUPLOID CELL is a somatic cell that does not
contain a multiple of 23 chromosomes.
 TRISOMY  3 copies of one particular chromosome.
 MONOSOMY  1 copy of a given chromosome in a
diploid cell.
 Among the autosomes, monosomy of any chromosome is
lethal.
 Newborns with trisomy of some chromosomes can
survive.
 Trisomy 21  Down’s syndrome.
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ANEUPLOIDY

 In general, loss of chromosome material has more serious
consequences than duplication of chromosome material.
 Aneuploidy of the sex chromosomes is less serious than
that of the autosomes.
 Y chromosome  very little genetic material is located
on this chromosome.
 X chromosome  inactivation of extra chromosomes
diminishes their effect.
 A zygote with no X chromosome will not survive.
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ANEUPLOIDY

 Aneuploidy is usually the result of
NONDISJUNCTION.
 Homologous chromosomes or sister chromatids fail
to separate normally during meiosis or mitosis.
 Nondisjunction during either stage of meiosis
produces some gametes that have two copies of a
given chromosome and others that have no copies
of the chromosome.
 Zygotes will either be trisomic or monosomic for
the given chromosome.
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AUTOSOMAL ANEUPLOIDY

 Trisomy can occur for any chromosome.
 Trisomies of the 13th, 18th, and 21st chromosomes are
seen with any appreciable frequency in live births.
 Fetuses with most other chromosomal trisomies
do not survive to term.
 PARTIAL TRISOMY: only an extra portion of a
chromosome is present in each cell.
 Consequences are not as severe as those of
complete trisomies.
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This baby with trisomy 13 has cyclopia
(single eye) with a proboscis (the
projecting tissue just above the eye).
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AUTOSOMAL ANEUPLOIDY

Trisomies also may occur in only some cells
of the body.
Individuals affected are
CHROMOSOMAL MOSAICS.
The body has two or more cell lines,
each of which has a different karyotype.
Usually formed by early mitotic
nondisjunction occurring in one embryo
cell but not in others.
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AUTOSOMAL ANEUPLOIDY

 DOWN SYNDROME: trisomy of the 21st
chromosome.
 Seen in 1 in 800 live births.
 Individuals have IQs ranging from 25 – 70.
 Facial appearance: low nasal bridge, epicanthal
folds (which produce an Asian appearance),
protruding tongue, and flat, low – set ears.
 Poor muscle tone (hypotonia) and short stature
are also characteristics.
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AUTOSOMAL ANEUPLOIDY

 Congenital heart defects affect about one third to one
half .
 A reduced ability to fight respiratory infections and an
increased susceptibility to leukemia contribute to a
reduced survival rate.
 By 40 years of age, individuals virtually always
develop symptoms identical to Alzheimer’s disease.
 ¾ of fetuses known to have Down syndrome are
spontaneously aborted.
 Average life expectancy is now about 60 years.
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AUTOSOMAL ANEUPLOIDY

The overwhelming majority of cases of
Down syndrome are caused by
nondisjunction during formation of the
mother’s egg cell.
About 1% of individuals with Down
syndrome are mosaics.
The effects of the trisomic cells are
attenuated by the normal cells and
symptoms are often less severe.
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AUTOSOMAL ANEUPLOIDY

Risk of having a child with Down
syndrome increases with maternal
age.
Begins to rise after 35 years of age
and reaches 3% to 5% for women
older than 45 years of age.
Due to age of maternal egg cells.
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SEX CHROMOSOME
ANEUPLOIDY

Among live births, about 1 in 400 males and 1
in 650 females has a form of sex chromosome
aneuploidy.
Conditions are less severe than autosomal
aneuploidies.
All forms except complete absence of an X
chromosome allow at least some
individuals to survive.
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SEX CHROMOSOME
ANEUPLOIDY

 TRISOMY X: affecting 1 in 1000 newborn females.
 3 X chromosomes in each cell.
 No overt physical abnormalities.
 Sterility, menstrual irregularity, or mental
retardation is sometimes seen.
 4 X chromosomes  more often mentally
retarded.
 5 or more X chromosomes  more severe
retardation and various physical defects.
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SEX CHROMOSOME
ANEUPLOIDY

TURNER SYNDROME: has a single X
chromosome, karyotype designated as 45,X.
Since no Y chromosome, are female.
Usually sterile, have gonadal streaks
rather than ovaries.
These streaks of CT are susceptible to
cancer in mosaics who have some cells
containing a Y chromosome.
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SEX CHROMOSOME
ANEUPLOIDY

 Other features include: short stature, webbing of
the neck, widely spaced nipples, coarctation of the
aorta, edema of the feet in newborns, reduced
carrying angle at the elbow, and sparse body hair.
 Not considered retarded, but, there is some
impairment of spatial and mathematical
reasoning ability.
 ¾ inherit their X chromosome from the mother.
 Thus, most cases are caused by a loss of the
paternal X chromosome.
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A patient with Turner syndrome is
shown. This posterior view shows a low
hairline and a shield-shaped chest. Note
the narrow hip development.
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SEX CHROMOSOME
ANEUPLOIDY

Teenagers with Turner syndrome are
treated with estrogen to promote the
development of secondary sexual
characteristics.
Dose is continued at a reduced level to
maintain these characteristics and to
help avoid osteoporosis.
Human growth hormone is sometimes
administered to increase stature.
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SEX CHROMOSOME
ANEUPLOIDY

KLINEFELTER SYNDROME: have two X
chromosomes and a Y chromosome in each
cell.
47,XXY karyotype.
Due to the presence of a Y chromosome,
these individuals have a male appearance.
Are usually sterile, and about half develop
female – like breasts.
GYNECOMASTIA
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G-banded 47,XXY karyotype.
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Adolescent male with gynecomastia and
Klinefelter syndrome.
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SEX CHROMOSOME
ANEUPLOIDY

Other characteristics: testes are small, body
hair is sparse, voice is high pitched, stature
is elevated, and a moderate degree of
mental impairment may be present.
Frequency is about 1 in 1000 male births.
2/3 of the cases are caused by
nondisjunction of the X chromosomes in
the mother.
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Adolescent male with Klinefelter
syndrome who has female-type
distribution of pubic hair and testicular
dysgenesis.
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Child with Klinefelter syndrome. Other
than a thin build and disproportionately
long arms and legs, the phenotype is
normal.
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SEX CHROMOSOME
ANEUPLOIDY

Frequency rises with maternal age.
XXXY and XXXXY karyotypes also have
Klinefelter Syndrome.
Degree of physical and mental
impairment increases with each
additional X chromosome.
All have a male appearance, no matter
how many X chromosomes are present.
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SEX CHROMOSOME
ANEUPLOIDY

47,XYY syndrome: individuals tend to be taller
than average, and they have a 10 to 15 point
reduction in average IQ.
Causes few physical problems.
Incidence in prison populations was about 1
in 30 vs. 1 in 1000 in the general population.
No increase in violent crimes, but there is
an increase in incidence of behavioral
disorders.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

Parts of chromosomes can be lost or
duplicated as gametes are formed.
Also, the arrangement of genes on
chromosomes can be altered.
These changes sometimes do not have
serious consequences for an
individual’s health.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

 During meiosis and mitosis, CHROMOSOME
BREAKAGE occasionally occurs.
 Mechanisms exist to repair these breaks perfectly
with no damage to the daughter cell.
 Sometimes, the breaks remain, or, they heal in a
fashion that alters the structure of the chromosome.
 The extent of chromosome breakage is increased in
the presence of certain harmful agents called
CLASTOGENS.
 Ionizing radiation, some viral infections, certain
chemicals.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

 DELETIONS are caused by broken chromosomes
and loss of DNA.
 Usually a gamete with a deletion unites with a
normal gamete to form a zygote.
 The zygote has one chromosome with the
normal complement of genes and one with
some missing genes.
 A fairly large number of genes can be lost in a
deletion, serious consequences can result, even
though one copy of the chromosome is normal.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

CRI DU CHAT SYNDROME: “cry of the
cat” describes the characteristic cry of the
affected child.
Other Sx: low birth weight, severe
mental retardation, microcephaly, heart
defects, and the typical facial
appearance.
Caused by a deletion of part of the short
arm of chromosome 5.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

DUPLICATIONS of chromosome
material are a form of chromosome
aberration.
Deficiency of genetic material is
more harmful than an excess, so,
duplications usually have less
serious consequences than deletions.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

An INVERSION is the occurrence of two
breaks on a chromosome, followed by the
reinsertion of the missing fragment at its
original site but in an inverted order.
Chromosome ABCDEFG becomes
chromosome ABEDCFG.
There is no loss or gain of genetic material
– a “balanced” alteration of chromosome
structure.
Often have no apparent physical effect.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

 Genes are sometimes influenced by neighboring DNA
sequences – POSITION EFFECT.
 Thus a change in a gene’s expression caused by a
change in position can result in physical defects in
persons with inversions.
 The serious problems caused by inversions usually occur
in the offspring of individuals carrying the inversion.
 Prevents lining up of homologous chromosomes
during prophase I of meiosis.
 Can result in chromosome deletions or duplications.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

 TRANSLOCATIONS: the interchanging of genetic material
between nonhomologous chromosomes.
 A ROBERTSONIAN TRANSLOCATION is clinically the
most important type of translocation.
 The long arms of two nonhomologous chromosomes
fuse at the centromere, forming a single chromosome.
 Confined to chromosomes 13, 14, 15, 21, and 23.
 Short arms are small and contain no genetic material.
 The carriers lose no genetic material and are normal,
though they only have 45 chromosomes.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

 Offspring may have serious deletions or
duplications.
 Eg: fusion of the long arms of chromosomes 21 and
14.
 Offspring who receive the fused chromosome
receive an extra copy of the long arm of
chromosome 21 and develop Down syndrome.
 Parents who are carriers of this chromosome
have an increased risk of having multiple
offspring with Down syndrome.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

A RECIPROCAL TRANSLOCATION
occurs when breaks take place in two
different chromosomes and the material is
exchanged.
The carrier of the translocation is usually
normal.
Gamete’s can be normal, carry the
translocation, or can have duplications
and deletions.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

 A number of areas on chromosomes develop distinctive
breaks and gaps when the cells are cultured in a folate –
deficient medium.
 Most of these FRAGILE SITES have no apparent
relationship to disease.
 FRAGILE X SYNDROME: one fragile site located on
the long arm of the X chromosome associated with
mental retardation.
 Is the second most common genetic cause of mental
retardation after Down syndrome.
 Affects 1 in 4000 males and 1 in 8000 females.
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ABNORMALITIES OF
CHROMOSOME STRUCTURE

 Males who inherit the mutation do not necessarily express
the disease condition but they can pass it on to descendants
who express it.
 About 1/3 of carrier females are affected, less severely than
males.
 Unaffected transmitting males have an elevated number of
repeated DNA sequences in the first exon of the fragile X
gene.
 Affected males have a much larger number of these repeats.
 An increase in the number of these repeated sequences in
successive generations can lead to expression of the fragile
X syndrome.
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ELEMENTS OF FORMAL
GENETICS

The mechanisms by which an
individual’s set of paired
chromosomes produces traits are the
principles of genetic inheritance.
Many traits are caused by single
genes and are called MEDELIAN
TRAITS.
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ELEMENTS OF FORMAL
GENETICS

Each gene occupies a position along a
chromosome known as a LOCUS.
Genes at a particular locus can take different
forms (have different nucleotide sequences).
Called ALLELES.
A locus that has two or more alleles that
occur with an appreciable frequency is
said to be POLYMORPHIC or
POLYMORPHISM.
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ELEMENTS OF FORMAL
GENETICS

At a given locus an individual has one gene
whose origin is paternal and one whose
origin is maternal.
When the two genes are identical, the
individual is HOMOZYGOUS at that
locus.
When the genes are not identical, the
individual is HETEROZYGOUS at the
locus.
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PHENOTYPE AND GENOTYPE

The composition of genes at a given locus
is known as the GENOTYPE.
The outward appearance of an individual
is the PHENOTYPE.
The phenotype reflects the interaction
of the genotype with the environment.
E.g. phenylketonuria
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DOMINANCE AND
RECESSIVENESS

 At a locus that is heterozygous for a trait, the effects of
one allele can mask the effects of the other allele when the
two are found together.
 The allele whose effects are observable is said to be
DOMINANT
 The allele whose effects are hidden is said to be
RECESSIVE.
 For loci having two alleles, the dominant allele is
denoted by an uppercase letter and the recessive allele
is denoted by a lowercase letter (e.g. A  dominant; a
 recessive).
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DOMINANCE AND
RECESSIVENESS

 When one allele is dominant over another, the
heterozygote genotype (Aa) has the same
phenotype as the dominant homozygote (AA).
 For the recessive allele to be expressed, it
must exist in the homozygote form (aa).
 When the heterozygote is distinguishable from
both homozygotes, the locus is said to exhibit
CODOMINANCE.
 E.g. ABO blood group.
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DOMINANCE AND
RECESSIVENESS

A CARRIER is an individual who has a
disease gene but is phenotypically
normal.
Most genes for recessive diseases
occur in heterozygotes who carry one
copy of the gene but do not express
the disease.
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DOMINANCE AND
RECESSIVENESS

Many recessive genes are lethal in the
homozygous state, so they are eliminated
from the population when they occur in
homozygotes.
By hiding in carriers, most recessive genes
for diseases survive to be passed on to the
next generation.
i.e. sickle cell anemia, cystic fibrosis.
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TRANSMISSION OF GENETIC
DISEASES

 MODE OF INHERITANCE: the pattern in
which a disease is inherited through the
generations of a family.
 Mendel, in his studies of garden peas, proposed
two basic laws of inheritance:
 PRINCIPLE OF SEGREGATION:
homologous genes separate from one another
during reproduction and that each
reproductive cell carries only one of the
homologous genes.
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TRANSMISSION OF GENETIC
DISEASES

PRINCIPLE OF INDEPENDENT
ASSORTMENT: the hereditary
transmission of one gene has no effect on
the transmission of another.
Mendel had no knowledge of chromosomes.
Geneticists have found that the behavior of
chromosomes corresponds to Mendel’s laws.
CHROMOSOME THEORY OF
INHERITANCE.
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TRANSMISSION OF GENETIC
DISEASES

 Single – gene diseases can be classified into four
major modes of inheritance:
 Autosomal dominant
 Autosomal recessive
 X-linked dominant
 X-linked recessive.
 The first two categories involve genes known to
occur on the 22 pairs of autosomes.
 The last two types occur on the X chromosome.
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TRANSMISSION OF GENETIC
DISEASES

 The PEDIGREE chart summarizes family
relationships and shows which members of a
family are affected by a genetic disease.
 The pedigree begins with one individual in
the family, the PROBAND, or PROPOSITUS
(MALE) or PROPOSITA (FEMALE).
 Usually the first person in the family
diagnosed with the disease or seen in a
clinic.
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FRAGILE X INHERITANCE
123
AUTOSOMAL DOMINANT
INHERITANCE

 Diseases caused by autosomal dominant genes are rare.
 Uncommon that two individuals both affected by
the same autosomal dominant disease to produce
offspring together.
 More often, affected offspring are produced by the
union of an affected heterozygous parent with a
normal unaffected parent.
 On average, half the children will be normal and
half will be heterozygous and will express the
disease.
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AUTOSOMAL DOMINANT
INHERITANCE

 Characteristics of autosomal dominant traits:
 The two sexes exhibit the trait in approximately equal
proportions and both are likely to transmit the trait to
their offspring.
 There is no skipping of generations.
 Affected heterozygous individuals transmit the trait to
approximately half of their children.
 Due to independent assortment and chance
fluctuations, it is possible that all or none of the
offspring of an affected parent may have the trait.
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Pedigree for achondroplasia
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AUTOSOMAL DOMINANT:
RECURRENCE RISKS

 RECURRENCE RISK: when one child of a family
has a disease, it is the probability that subsequent
children also will have the disease.
 In an autosomal dominant disease, when one
parent is heterozygous and exhibits the disease
and the other parent is normal, the recurrence risk
for each child is ½ or 50%.
 Each birth is an independent event, so, the
recurrence risk is for each pregnancy and is not
dependent on the number of children in the
family.
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AUTOSOMAL DOMINANT:
RECURRENCE RISKS

 If a child has been born with an autosomal dominant
disease and there is no history of the disease in the family,
the child is probably the product of a new mutation.
 The genes at this locus in most of the parent’s other
germ cells would still be normal.
 In this case, the recurrence risk for the parent’s
subsequent offspring is not greater than that of the
general population.
 The offspring of the affected child, however will have
an occurrence risk of ½.
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AUTOSOMAL DOMINANT:
RECURRENCE RISKS

 Many autosomal dominant diseases reduce the
potential for reproduction.
 A large proportion of the observed cases are the
result of new mutations.
 Occasionally, two or more offspring will present
symptoms of an autosomal dominant disease when
there is no family history of the disease.
 Unlikely due to multiple mutations in the same
family.
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AUTOSOMAL DOMINANT:
RECURRENCE RISKS

 GERMLINE MOSAICISM: a mutation that
occurred during embryonic development of one
of the parents that affected all or part of the
germline but few or none of the somatic cells of
the embryo.
The parent carries the mutation in his or her
germline but does not actually express the
disease.
Can transmit the mutation to multiple
offspring.
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AUTOSOMAL DOMINANT:
PENETRANCE AND EXPRESSIVITY

 The PENETRANCE of a trait is the percentage of
individuals with a specific genotype who also exhibit
the expected phenotype.
 INCOMPLETE PENETRANCE means that
individuals who have the gene for a disease may not
exhibit the disease phenotype at all, even though the
gene and the associated disease may be transmitted
to the next generation.
 OBLIGATE CARRIERS: those who have an
affected parent and children and therefore must
carry the gene.
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AUTOSOMAL DOMINANT:
PENETRANCE AND EXPRESSIVITY

RETINOBLASTOMA: the most common
malignant eye tumor affecting children.
Exhibits incomplete penetrance in that
10% are obligate carriers and do not
exhibit any symptoms of the disease.
The penetrance of the gene is thus
90%.
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AUTOSOMAL DOMINANT:
PENETRANCE AND EXPRESSIVITY

The gene responsible has been mapped to
the long arm of chromosome 13.
The gene is known as a TUMOR
SUPPRESSOR GENE.
It is a protein that regulates the cell cycle
so that cells do not grow uncontrollably.
A mutation alters the protein so its
tumor suppressing capacity is lost and a
tumor can form.
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AUTOSOMAL DOMINANT:
PENETRANCE AND EXPRESSIVITY

 HUNTINGTON DISEASE: another autosomal dominant
disease.
 A neurologic disorder whose main features are
progressive dementia and increasingly uncontrollable
movements of the limbs.
 Known as CHOREA.
 Symptoms of the disease are not usually seen until age
40 years or later.
 AGE – DEPENDENT PENETRANCE.
 People who develop the disease often have had
children before they are aware that they have the gene.
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AUTOSOMAL DOMINANT:
PENETRANCE AND EXPRESSIVITY

EXPRESSIVITY: the extent of variation
in phenotype associated with a
particular genotype.
If expressivity of a disease is
variable, the penetrance may be
complete, but the severity of the
disease can vary greatly.
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AUTOSOMAL DOMINANT:
PENETRANCE AND EXPRESSIVITY

 Several factors cause variable expressivity:
 Genes at other loci sometimes modify the expression of a
disease gene.
 Environmental factors can influence expression of a
disease gene.
 Different mutations at a locus can cause variation in
severity.
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AUTOSOMAL DOMINANT:
PENETRANCE AND EXPRESSIVITY

 TYPE I NEUROFIBROMATOSIS or VON
RECKLINGHAUSEN DISEASE: autosomal
dominant disease with variable expressivity.
 The gene has been mapped to the long arm of
chromosome 17.
 It is also a tumor suppressor gene.
 The expression of the gene varies from a few
harmless café – au – lait spots on the skin to
numerous neurofibromas, scoliosis, seizures,
gliomas, neuromas, HTN, and mental retardation.
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AUTOSOMAL DOMINANT:
PENETRANCE AND EXPRESSIVITY

A parent with mild expression of the
disease can transmit the gene to a child,
who may exhibit severe expression of the
disease.
Variable expressivity provides a
mechanism by which autosomal dominant
genes can be maintained at higher
prevalence rates in populations.
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AUTOSOMAL RECESSIVE
INHERITANCE

Autosomal recessive disorder
Abnormal allele is recessive and a person
must be homozygous for the abnormal
trait to express the disease
The trait usually appears in the children,
not the parents, and it affects the genders
equally because it is present on a pair of
autosomes
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AUTOSOMAL RECESSIVE
INHERITANCE

Autosomal recessive disorder
recurrence risk
Recurrence risk of an autosomal
dominant trait
When two parents are carriers of
an autosomal recessive disease, the
occurrence and recurrence risks for
each child are 25%
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AUTOSOMAL RECESSIVE
INHERITANCE


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Characteristics
 Condition expressed equally in males and females
 Affected individuals most often the offspring of
asymptomatic heterozygous carrier parents
 Approximately 1/4 of offspring will be affected;
1/2 will be asymptomatic carriers; and 1/4 will
be unaffected
 Individuals must be homozygous for the
condition to be expressed
 Generational skipping may be present
 Consanguinity may be present
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AUTOSOMAL RECESSIVE
INHERITANCE

CONSANGUINITY: refers to the mating of
two related individuals.
The offspring of such matings are said to
be INBRED.
Mating of two related individuals
Dramatically increases the recurrence risk
of recessive disorders
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SEX LINKED DISORDERS

 Disorders involve X and Y chromosomes
 X-linked disorders usually expressed by males
because females have another X chromosome to
mask the abnormal allele
 Males, having only one X chromosome, are
HEMIZYGOUS for genes on this chromosome.
 Most are recessive
 Y-linked disorders uncommon because Y
chromosome contains relatively few genes
 Father-son transmission present
 No father-daughter transmission
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X INACTIVATION

 X INACTIVATION: one X chromosome in the somatic
cells of females is permanently inactivated.
 Explains why most gene products coded by the X
chromosome are present in equal amounts in males and
females.
 Called DOSAGE COMPENSATION.
 Observable in many interphase cells as highly condensed
intranuclear chromatin bodies.
 BARR BODIES.
 Normal females have one Barr body in each somatic
cell, whereas males have no Barr bodies.
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X INACTIVATION

Inactivation occurs 7 – 14 days after
fertilization in embryonic development.
Random selection of whether the paternal or
maternal X chromosome is inactivated.
Once the X chromosome is inactivated, all the
descendants of that cell have the same
chromosome inactivated.
Inactivation is RANDOM but FIXED.
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X LINKED RECESSIVE
DISORDERS

 Characteristics
 Males most commonly affected
 Affected males cannot transmit the genes to
sons, but they can to all daughters
 Unaffected carrier females
 Sons of female carriers have a 50% risk of being
affected
 Pedigree analysis
 Generational skipping often present
 No father-to-son transmission
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X LINKED RECESSIVE
DISORDERS

A. Outcomes for offspring of
an unaffected father and a
heterozygous unaffected
carrier mother (most
common scenario)
B. Outcomes for offspring of
an affected father and a
homozygous unaffected
mother
C. Outcomes for offspring of
an affected father and a
heterozygous unaffected
carrier mother
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X LINKED RECESSIVE
DISORDERS

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
Hemophilia
 Bleeding disorders resulting from a congenital
deficiency of coagulation factors
 Hemophilia A: factor VIII deficiency
 20.6/100,000 male births in U.S.
 Hemophilia B: factor IX deficiency
 5.3/100,000 male births in U.S.
 Mutations associated with factor VIII deficiency:
 Large deletions or insertions, frameshift and
splice junction changes, and nonsense and
missense mutations
 Mutations vary across families but tend to be
similar within families
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MULTIFACTORIAL
INHERITANCE

 Characteristics of multifactorial disorders
 Result from hereditary and environmental factors
 Hereditary component is polygenic
 Individual involved genes follow mendelian
principles
 Many genes act together to influence the expressed
trait
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MULTIFACTORIAL
INHERITANCE

 Concordance and discordance
 Concordance
 Expression of the disease in two related family
members
 Discordance
 Expression of the disease in one family member but
not a second
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MULTIFACTORIAL
INHERITANCE

 Twin studies and concordance
 Genetic conditions
 Monozygotic (MZ) twins: 100% concordance
 Dizygotic (DZ) twins: less than 100% and similar to
that among other siblings
 Environmental conditions
 Equal concordance rates among MZ and DZ twins
 Multifactorial conditions
 MZ twins with greater concordance than DZ twins,
but rates are not 100%
 Adoption studies
 Gene-environment-lifestyle interaction
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