Introduction to Human
Genetics
Dr Pupak Derakhshandeh, PhD
Ass Prof of Medical Science of Tehran
University
1
General Background
single gene disorders:
–diseases or traits : phenotypes are
largely determined : of mutations at
individual loci
2
chromosomal abnormalities:
–diseases where the phenotypes :
physical changes in chromosomal
structure - deletion, inversion,
translocation, insertion, rings, etc
–chromosome number - trisomy or
monosomy, or in chromosome
origin - uniparental disomy
3
multifactorial traits:
–diseases or variations: phenotypes
are strongly influenced : mutant
alleles at several loci
4
mitochondrial inheritance:
–Diseases: phenotypes are affected
by mutations of mitochondrial DNA
5
diseases of unknown etiology:
–"run in families"
6
Mendelian traits, or single gene
disorders
autosomal recessive inheritance :
–the locus: on an autosomal
chromosome
–both alleles : mutant alleles to
express the phenotype
7
By effect on function
Loss-of-function mutations
Gain-of-function mutations
Dominant negative mutations
Lethal mutations
8
Loss-of-function mutations
Wild type alleles typically encode a
product necessary for a specific
biological function
If a mutation occurs in that allele, the
function for which it encodes is also
lost
The degree to which the function is lost
can vary
9
Loss-of-function mutations
gene product having less or no
function:
– Phenotypes associated with such
mutations are most often recessive:
– to produce the wild type phenotype!
Exceptions are when the organism
is haploid
or when the reduced dosage of a
normal gene product is not enough
for a normal phenotype
(haploinsufficiency)
10
Mendelian traits, or single gene
disorders
autosomal dominant inheritance :
–the locus : on an autosomal
chromosome
–only one mutant allele : for
expression of the phenotype
11
Loss-of-function mutations
mutant allele will act as a dominant:
the wild type allele may not
compensate for the loss-of-function
allele
the phenotype of the heterozygote will
be equal to that of the loss-of-function
mutant (as homozygot)
– to produce the mutant phenotype !
12
Loss-of-function mutations
Null allele:
– When the allele has a complete loss of
function
it is often called an amorphic mutation
Leaky mutations:
– If some function may remain, but not at the
level of the wild type allele
The degree to which the function is lost can
vary
13
Gain-of-function mutations
change the gene product such that it gains a
new and abnormal function
These mutations usually have dominant
phenotypes
Often called a neomorphic mutation
A mutation in which dominance is caused by
changing the specificity or expression
pattern of a gene or gene product, rather
than simply by reducing or eliminating the
normal activity of that gene or gene product
14
Gain-of-function mutations
Although it would be expected that most
mutations would lead to a loss of function
it is possible that a new and important
function could result from the mutation:
– the mutation creates a new allele:
associated with a new function
Genetically this will define the mutation
as a dominant
15
Mendelian traits, or single gene
disorders
X-linked recessive inheritance:
–the locus :on the X chromosome
–both alleles : mutant alleles to
express the phenotype in females
16
Mendelian traits, or single gene
disorders
X-linked dominant inheritance:
–the locus: on the X chromosome
–only one mutant allele : for
expression of the phenotype in
females
17
Non Mendelian traits
gene disorders
mitochondrial inheritance:
–the locus : the mitochondrial
"chromosome"
18
Mitosis
cell division
responsible for the
development of the
individual from the zygote
somatic cells divide and
maintain the same
chromosomal
complement
each chromosome
duplicates forming two
chromatids
connected to a single
centromere
19
centromeres
the centromeres line up on the
metaphase plate
without the homologous pairing
recombination found in meiosis
exception for sister chromatid
exchange of identical DNA
information in mitosis
centromere divides each
chromatid : becomes a daughter
chromosome at anaphase of cell
division
two identical daughter cells with
identical DNA complements
20
Mitosis
Mutations: during DNA replication in
mitosis
these mutations: in somatic cell diseases,
such as cancer
most mitotic divisions/the fastest rate of
growth:
– before birth in the relatively protected
environment of the uterus
– Most of us only increase 15 to 30 times
our birth weight
21
Meiosis (I)
22
Meiosis (II)
23
PEDIGREE CONSTRUCTION
24
AUTOSOMAL
RECESSIVE
INHERITANCE
25
AUTOSOMAL RECESSIVE INHERITANCE
affected individuals: normal phenotypes
one in ten thousand live births
heterozygote frequency in the
population: one in fifty
26
The Punnett Square for autosomal
recessive diseases with an affected
child in the family
Within the normal siblings of affected
individual :
the probability of being a carrier is 2/3
27
hallmarks of autosomal
recessive inheritance
Males and females: equally likely to be affected
the recurrence risk to the unborn sibling of an
affected individual : 1/4
Parents of affected children: may be related
The rarer the trait in the general population, the more
likely a consanguineous mating is involved
28
1.
Autosomal recessive inheritance
29
rare autosomal recessive
diseases
individuals in the direct line of descent within
the family : carriers
those individuals from outside the family are
30
considered homozygous normal
AUTOSOMAL
DOMINANT
INHERITANCE
31
Autosomal dominant diseases
usually rare
To produce a affected homozygote: two
affected heterozygotes would have to mate
they would have only a 1/4 chance of having a
normal offspring
In the extremely rare instances:
– where two affected individuals have mated:
the homozygous affected individuals :
usually are so severely affected they are
not compatible with life
32
Autosomal dominant diseases
The mating of very closely related
individuals:
–two affected individuals to know each
other, isn’t forbidden in our society
in most matings: affected individuals :
heterozygotes
–the other partner will be homozygous
normal
33
Autosomal dominant diseases
new mutations:
– rare in nature
every affected individual: an affected
biological parent
Males and females :
– an equally likely chance of inheriting the
mutant allele
The recurrence risk of each child of an
affected parent :
– 1/2
Normal siblings of affected individuals:
– do not transmit the trait to their offspring
34
The defective product of
the gene
usually a structural protein, not an
enzyme
Structural proteins : usually defective:
–one of the allelic products is
nonfunctional
enzymes usually :
–require both allelic products to be
nonfunctional to produce a mutant
phenotype
35
The Punnett Square for autosomal recessive
One gamete comes from each parent
Two out of the four possible
combinations: affected
two out of four: normal
36
AUTOSOMAL DOMINANT
INHERITANCE
37
AUTOSOMAL DOMINANT
INHERITANCE
Variable Expressivity
Late Onset
High Recurrent Mutation Rate
Incomplete Penetrance
38
VARIABLE EXPRESSIVITY (AD)
One example : Marfan syndrome
autosomal dominant disease
caused by:a mutation in collagen
formation
It affects about 1/60,000 live births
Symptoms of Marfan syndrome
– skeletal
– Optical
– cardiovascular abnormalities
Skeletal abnormalities:
– arachnodactyly (long fingers and toes)
– extreme lengthening of the long bones
39
dislocation of the lens of the eye
40
VARIABLE EXPRESSIVITY (AD)
Marfan syndrome
Optical abnormalities:
– a dislocation of the lens of the eye
Cardiovascular abnormalities
– responsible for the shorter life span of
Marfan syndrome patients
Each patient may express all of the
symptoms, or only a few!
That is variable expressivity
Each patient with the mutant allele for Marfan
syndrome:
– expresses at least one of the symptoms
41
VARIABLE EXPRESSIVITY (AD)
Marfan syndrome
Almost all are taller than average
Almost all have long fingers
Some may be very mildly affected
and lead normal lives
while others, more severely affected:
have a shorter life expectancy
The disease :
–recurrent mutations
42
LATE ONSET (AD)
Some autosomal dominant diseases :
do not express themselves until later in
life
the disease: passed the mutant allele
along to their offspring before they
themselves know they are affected
In some cases even grandchildren are
born before the affected grandparent
shows the first signs of the disease
43
LATE ONSET (AD)
Huntington disease (Huntington's
Chorea):
choreic movements expressed
Progressive
a good example of a late onset
disease
Age of onset varies from the teens to
the late sixties
with a mean age of onset between
ages 35 and 45
44
Huntington disease
Nearly 100% of the individuals born
with the defective allele will develop
the disease by the time they are 70
The disease : progressive with death
usually occurring between four and
twenty-five years after the first
symptoms develop
45
Huntington disease (AD)
At the gene level:
the expansion of an unstable
trinucleotide repeat sequence
CAG
“POLYGLUTAMINE DISEASES”
Somatic mutations: expansion of
trinucleotide repeat sequences
in the coding region of the gene to
produce a mutant allele
46
Other diseases (AD):
myotonic dystrophy:
an autosomal dominant disease
expression is delayed
expansion of unstable trinucleotide
sequences
CTG
47
myotonic dystrophy
unstable sequence lies in a nontranslated region of the gene
the size of the inherited expansion
correlates to the age of onset
or the severity of disease
48
Repeats in non-coding sequences
49
HIGH RECURRENT MUTATION
RATE
Achondroplasia:
the major causes of dwarfism
Motor skills may not develop as
quickly as their normal siblings
but intelligence is not reduced
about 1/10,000 live births
50
Achondroplasia
Almost 85% of the cases : new mutations
both parents have a normal phenotype
The mutation rate for achondroplasia may
be as much as 10 times the "normal"
mutation rate in humans
This high recurrent mutation is largely
responsible for keeping the mutant gene in
the population at its present rate
51
INCOMPLETE PENETRANCE
It should never be confused with variable
expressivity
variable expressivity:
–the patient always expresses some of
the symptoms of the disease
–and varies from very mildly affected to
very severely affected
incomplete penetrance:
–the person either expresses the disease
phenotype or he/she doesn't
52
Incomplete
penetrance
and
variable
expressivity
are
phenomena associated only
with
dominant
inheritance,
never with recessive inheritance
53
INCOMPLETE PENETRANCE
in a known autosomal dominant disease
54
X-LINKED DOMINANT
INHERITANCE
55
X-LINKED DOMINANT INHERITANCE
A single dose of the mutant allele will
affect the phenotype of the female!
A recessive X-linked gene:
–requires two doses of the mutant
allele to affect the female
phenotype
–The trait is never passed from
father to son
56
X-LINKED DOMINANT
INHERITANCE
All daughters of an affected male and a normal
female are affected (100%)
All sons of an affected male and a normal
female are normal (100%)
Mating of affected females and normal males
produce 1/2 the sons affected and 1/2 the
daughters affected (50% :50%)
Males are usually more severely affected than
females
57
X-LINKED DOMINANT INHERITANCE
Males: usually more severely affected than
females
in each affected female: there is one
normal allele producing a normal gene
product
and one mutant allele producing the nonfunctioning product
while in each affected male there is only
the mutant allele with its non-functioning
product and the Y chromosome, no normal
gene product at all
58
X-LINKED DOMINANT INHERITANCE
All daughters are affected (100%) / All sons are normal (100%)
59
One example of an X-linked
dominant: incontinentia pigmenti (IP)
extremely rare
The main features occur in the skin where a blistering
rash occurs in the newborn period
brown swirls
a "marble cake-like" appearance on the skin
the eyes
central nervous system
Teeth
nails, and hair
The severity varies from person to person
60
incontinentia pigmenti
61
key for determining: X-L D/AD
to look at the offspring of the mating of an
affected male and a normal female
If the affected male has an affected son:
– then the disease is not X-linked
62
What happens when males are so severely
affected that they can't reproduce?
This is not uncommon in X-linked
dominant diseases
There are no affected males:
– to test for X-linked dominant
inheritance to see if the produce all
affected daughters and no affected
sons !!!
63
What happens when males are so
severely affected that they can't
reproduce?
Next pedigree shows the effects of
such a disease in a family
There are no affected males
only affected females, in the
population!
64
X-linked dominant
inheritance (severe)
65
X-LINKED
RECESSIVE
INHERITANCE
66
X-LINKED RECESSIVE
INHERITANCE
They are, in general, rare
Hemophilia (A/B)
Duchenne muscular dystrophy
Becker muscular dystrophy
Lesch-Nyhan syndrome
67
X-LINKED RECESSIVE
INHERITANCE
More common traits:
glucose-6-phosphate dehydrogenase
deficience
color blindness
68
A rare X-linked recessive disease
69
The hallmarks of X-linked
recessive inheritance
the disease is never passed from father to son
Males are much more likely to be affected than
females
If affected males cannot reproduce, only males will
be affected
All affected males in a family are related through
their mothers
Trait or disease is typically passed from an affected:
– grandfather, through his carrier daughters, to half
of his grandsons
70
X-linked recessive inheritance
71
SEX LIMITED
INHERITANCE
72
SEX LIMITED INHERITANCE
In some X-linked recessive: diseases, such as
Duchenne muscular dystrophy
– expression of the disease phenotype is
limited exclusively to males
In some X-linked dominant traits, such as
incontinentia pigmenti :
– expression is limited to females
DMD
incontinentia pigmenti
– males do not survive to term
There are autosomal diseases that are limited to
expression in only one sex:
– Precocious puberty / beard growth are
factors expressed only in males
– The hereditary form of prolapsed uterus is
expressed only in females
73
MITOCHONDRIAL
INHERITANCE
74
MITOCHONDRIAL INHERITANCE
• A few human diseases:
• to be associated with mitochondrial inheritance
• Leber optic atrophy : a disease of mitochondrial
DNA
• The ovum, originating in the female
• 100,000 copies of mitochondrial DNA
• the sperm, originating in the male
• has fewer than 100 copies, and these are
probably lost at fertilization
• Virtually all of ones mitochondria come from his, or
her, mother
• Affected fathers produce no affected offspring
• while the offspring of affected mothers are affected
75
Mitochondrial inheritance pattern
76
IMPRINTING
77
IMPRINTING
1/10,000 and 1/30,000 live births
for some genes: the origin of the gene
may be important
For some loci:
– the gene inherited from the father
–acts differently from the gene
inherited from the mother
–even though they may have the
same DNA
78
Prader-Willi syndrome
About 75% of patients with Prader-Willi
syndrome :
– a small deletion of the long arm of
chromosome 15
this deletion is on the paternal
chromosome (the father's genes are
missing)
79
Prader-Willi syndrome
80
Angelman syndrome
When this deletion is on the maternal
chromosome (the mother's genes are
missing) Angelman syndrome results
81
Angelman syndrome
82
uniparental disomy
The two diseases have very different
clinical symptoms
a rare chromosomal event in which both
chromosomes come from a single parent
(mother or father)
both chromosomes 15 are derived from
the mother: Prader-Willi syndrome
When both chromosomes 15 are derived
from the father: Angelman syndrome
83
normal development an
individual
inherit one copy of this chromosomal region
from his or her father and one from his or her
mother
Several other regions : show uniparental
disomy without this effect on the phenotype!
Small deletions usually affect the phenotype but
they produce the same phenotype whether of
maternal or paternal origin
Imprinting represents an exception to Mendel's
laws and remains an important area of research
84
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