MEDICAL GENETICS

医学遗传学

Dr. Zhao
Laboratory of Cell Biology, photo
Medical College,
photo photo
Hebei University of
Engineering
Mendelian inheritance

Gregor Johann Mendel

(1822–1884)
who is known as the
"father of modern genetics“.
Mendel deduced several important
genetic principles from his well-
designed experiments with garden
peas. 

• The principle (law) of segregation

• The principle (law) of independent assortment
St. Thomas' Abbey
BASIC DEFINITIONS

• Homologous chromosomes. The two chromosomes in

each diploid pair are said to be homologs, or homologous
chromosomes. They contain the same genes, but because
one is of paternal origin and one is of maternal origin, they
may have different alleles at some loci.
• X and Y chromosomes, or the sex chromosomes, have
some homologous regions but the majority of genes are
different.
• Nonhomologous chromosome
Genotype

The specific DNA sequence at a locus is termed a

genotype.
In diploid somatic cells a genotype may be:
• Homozygous(adj.) if the individual has the same allele
on both homologs (homologous chromosomes) at that
locus. (AA, aa) homozygote (n.)
• Heterozygous(adj.) if the individual has different
alleles on the two homologs (homologous
chromosomes) at that locus. (Aa) heterozygote (n.)
 Homologous

Heterozygote
Alleles
Homozygote
• Dominance in genetics is a relationship between alleles
of one gene, in which the effect on phenotype of one
allele masks the contribution of a second allele at the
same locus.
• The first allele is dominant and the second allele is
recessive.
• Often the dominant allele codes for a functional protein
whereas the recessive allele does not.
• Dominant requires only one copy of the mutation to
produce disease, recessive requires two copies of the
mutation to produce disease.
 dominant
Those diseases expressed in heterozygotes
were determined to be dominant.

recessive

Homozygous individuals with mutant

alleles, those diseases in which an
individual with two abnormal genes is
clinically symptomatic.

Dominant and recessive are used to describe

traits or phenotypes rather than genes.
Phenotype
• The phenotype is generally understood as the
expression of the genotype in terms of observable
characteristics.
• The phenotype is the physical, clinical, cellular, or
biochemical manifestation of the genotype.
 Inheritance of human traits
dominant dominant

free ear lobe attached ear lobe rolling tongue non-rolling tongue

double eyelids single eyelid dimple without a dimple

dominant dominant
• Homozygous dominant have two dominant
alleles.(AA)
• Homozygous recessive have two recessive alleles.
(aa)
• Test cross in genetics, a test cross involves the
breeding of an individual with a phenotypically
recessive individual, in order to determine the
zygosity of the former by analyzing proportions of
offspring phenotypes.
• Back cross a cross between an individual and an
individual of the original parent generation.
Mendel studied seven traits in the pea.
Common symbols of genetics

P —— parent
♀ —— female
♂ —— male
F1 —— first filial generation
F2 —— second filial generation
G —— generative cell, gamete
—— cross
—— self fertilization
Mendel's First Law Of Genetics:
• The Law of Segregation

Allele pairs separate during gamete production, a sperm

or egg carries only one allele for each inherited trait. When
sperm and egg unite at fertilization, each contributes its
allele, restoring the paired condition in the offspring. This
is called the Law of Segregation.
• Cytological basis of law of segregation
Separation of homologous chromosomes.
P: D × R F2 D: R The ratio
Round Wrinkled
RR rr
RR rr

R R r r

Rr R r

R r R r

5474 1850 RR Rr R r rr
3 : 1
 Test cross (Back cross)

F1 Rr rr P

R r r

Rr rr

1 : 1
Punnett square

• The Punnett square is a diagram that is used to predict

an outcome of a particular cross or breeding
experiment. It is named after Reginald C. Punnett, who
devised the approach.
• The diagram is used by biologists to determine the
probability of an offspring having a particular
genotype. The Punnett square is a tabular summary of
possible combinations of maternal alleles with paternal
alleles.
 R R RR rr r r

F1 Rr

R R
r Rr Rr

r Rr Rr
 R r
F1 R r Rr Rr R r

R RR Rr
F2 RR 2Rr rr
r Rr rr
1 : 2 : 1

Genotype 1 : 2:1
Phenotype 3 : 1
Test cross R r Rr rr r r

2Rr 2rr
1 : 1
R r
r Rr rr

r Rr rr
Classroom quiz
10 minutes
5 questions
10 points
Mendel's second law of genetics:
• The law of independent assortment

Mendel's law of independent assortment states that the

alleles of two (or more) different genes (located in the
nonhomologous chromosomes) get sorted into gametes
independently of one another.

• Cytological basis of independent assortment

Free combination of nonhomologous chromosomes
into a germ cell.
Mendel study one pair of relative traits, and deduced the
law of segregation, on this basis, he further study two or
more than two pairs of relative traits, deduced the law of
independent assortment.

• Two homozygous dominant traits：

Round (R), Yellow (Y)；
YYRR
• Two homozygous recessive traits：
Wrinkled (r), Green(y)。

yyrr
Genetic experiments on two relative traits
P

F1

F2

315 ： 101 ： 108 ： 32 total：556

ratio 9 ： 3 ： 3 ： 1
 Rr Y y

R r Y y

gamate R Y Ry rY ry

RY Ry rY ry
 P RRYY rryy

RY
RY
gamete RY ry
Ry
RRYY
rY Ry
RRYy
RRYy rY
ry
RrYY

F1
RRyy
Rr Y y Rr Y y RrYy RrYY ry
RrYy
RrYy RrYy
Rryy
r rYY
Rryy

r rYy r rYy

r ryy
F2
315 ： 101 ： 108 ： 32 totle：556
9 ： 3 ： 3 ： 1
 Test cross

F1 R r Y y r r y y

R Y R y r Y r y r y

R r Y y R r y y r r Y y r r y y

1 : 1 : 1 : 1
 RY RY RY RY
RRYY rryy RrYy
ry RrYy RrYy RrYy

ry RrYy RrYy RrYy RrYy

F1 RrYy ry RrYy RrYy RrYy RrYy

ry RrYy RrYy RrYy RrYy

 RY Ry rY ry
F1
RY RRYY RRYy RrYY RrYy
RrYy RrYy
Ry RRYy RRyy RyYy Rryy
F2
rY RrYY RrYy rrYY rrYy

ry RrYy Rryy rrYy rryy

9 : 3 : 3 : 1
Phenotype

phenotype
• Both dominant
9/16
• One dominant and one recessive
3/16+3/16=3/8
• Both recessive
1/16
Genotype

Genotype

• Both homozygous dominant

RRYY 1/16
• Both homozygous recessive
rryy 1/16
• Both heterozygous
RrYy 1/4
The Multiplication Rule:

P: probability RRYY: 1/4 × 1/4=1/16

A and B are independent events RrYy : 1/2 ×1/2=1/4
P(AB)=P(A) ×P(B) rryy: 1/4 ×1/4=1/16
RrYY: 1/2 ×1/4=1/8

RrYy RrYy

A: Rr Rr
B: Yy Yy
Review question

1. Homozygous red flower pea cross with white flower

red flower
pea, F1 are all red flower，so _________is
white flower
dominant traits，___________is recessive traits.
2. Free or attached earlobes controlled by a pair of
alleles, a male with attached earlobes
(Homozygous recessive ) married an free earlobe
women (whose mother with attached earlobes ),
the proportion of the free earlobe of their
1/2
children________________.
3. Colour of tomato fruit red to yellow is dominant,
the RR and rr crosses, then F1 self-cross,F2 get
2000
3000 red fruit, in these have ________Rr.
4. Rolling tongue (A) of non-rolling tongue (a) is
dominant. In a family, father can roll up tongue,
mother and daughter can not roll up the tongue ,
aa
the girl's mother's genotype_________and father's
Aa
genotype______________.
5. If the pea colour of gray and white are relative traits, the
experimental results are as follows. Fill the genotype of
parents (B represents the dominant, b represents
recessive).
gray white genotype of p

gray×white 82 78 Bb × bb
gray×gray 118 39 Bb × Bb
white×white 0 50 bb × bb

gray×white 74 0 BB × bb

gray×gray 90 0 BB×BB / BB×Bb

Quiz
Albinism and phenylketonuria are human autosomal
single gene disease. Normal husband and wife have one
daughter get albinism and phenylketonuria，so if the
couple have another child, the risk to get one
3/8
disease___________, probability of phenotype
9/16
normal____________, probability of phenotype normal
1/16
and can not has sick offspring_________.
Phenotype

• One dominant and one recessive

3/16+3/16=3/8
• Both dominant
9/16
• Both dominant but no disease
1/16
single-gene disorder or
monogenic disorder

Some disorders result when a mutation causes the

product of a single gene to be altered or missing. These
disorders are inherited in simple patterns similar to or
identical with those described by Mendel for certain
discrete characteristics in garden peas. Therefore, it’s also
called Mendelian diseases.
Basic Pattern of Single Gene
Inheritance
Autosomal Dominant
Autosomal Recessive
X-linked Dominant
X-linked Recessive
Y-linked
1. Pedigree and Proband

① Humans are unique among organisms in many ways,

but one way which is near and dear to a geneticist's
heart is that humans are not susceptible to genetic
experimentation.
② The study of inherited Mendelian traits in humans must
rely on observations made while working with individual
families.
③ One of most powerful tools in human genetic studies is
pedigree analysis.
pedigree

① They are graphic representations of a family tree

which show the biological relationship of the index
case, or proband to the rest of the individuals.
② A family tree diagram that shows how a particular
genetic trait or disease has been inherited.
 When human geneticists first began to
publish family studies, they used a variety
of symbols and conventions. Now there
are agreed upon standards for the
construction of pedigrees.
Symbols
pedigree characteristics of different single gene
inheritance patterns
2. autosomal dominant inheritance

The pattern of autosomal dominant inheritance is

perhaps the easiest type of Mendelian inheritance
to recognize in a pedigree. One dose of the mutant
gene, one mutant allele, is all that is required for
the expression of the phenotype.
 There are three reasons why an
individual with an autosomal dominant
disease should always be considered as
being a heterozygote until proven
otherwise.
A. The disease is usually rare, with only about
1/10,000 individuals affected as an order of
magnitude. Affected individuals are most likely to
come from affected by normal matings. The
normal parent is homozygous recessive, thus
assuring that each product of the mating has at
least one normal gene.
B. 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. The exceptions are the autosomal dominant
diseases caused by the somatic expansion of
trinucleotide repeat sequences (e.g.,
Huntington's disease) that we will study later.
C. The mating of very closely related
individuals, the most likely way for two
affected individuals to know each other, is
forbidden in our society.
 With the understanding that almost all
affected individuals are heterozygotes,
and that in most matings involving a
person with an autosomal dominant trait
the other partner will be homozygous
normal, there are four hallmarks of
autosomal dominant inheritance.
There are four hallmarks of autosomal
dominant inheritance:

(1) Except for new mutations, which are rare in nature and
extremely rare on examination pedigrees, and the
complexities of incomplete penetrance to be discussed later,
every affected individual has an affected biological
parent. There is no skipping of generations.

(2) Males and females have an equally likely chance of

inheriting the mutant allele and being affected. The
recurrence risk of each child of an affected parent is 1/2.
There are four hallmarks of autosomal
dominant inheritance:

(3) Normal siblings of affected individuals do not

transmit the trait to their offspring.

(4)The defective product of the gene is usually a

structural protein, not an enzyme. Structural proteins are
usually defective when one of the allelic products is
nonfunctional; enzymes usually require both allelic products
to be nonfunctional to produce a mutant phenotype.
THE PUNNET SQUARE

In 1910, Punnett developed a simple

method of depicting the possible
genotypes one could get from various
matings. We call it the Punnett Square.
 Suppose a father is heterozygous for
an autosomal dominant gene, with allele
D, the mutant dominant allele, and allele
d, the recessive normal allele. He can
produce two types of gametes, D and d.
Suppose also his wife is homozygous
normal, having both d alleles. The Punnett
Square is constructed as follows:
 One gamete comes from each parent to produce
the genotype of the offspring. Two out of the four
possible combinations are affected; two out of four
are normal.
Familial Hypercholesterolemia, FH
Sample Pedigree

① Both males and

females are affected in
approximately equal
numbers.
② Persons are affected in
each generation and
males can transmit the
condition to males or
females and vice versa.
③ Unaffected persons do
not transmit the condition.
l It is equally likely that a
child will receive the
mutant or the normal
allele from the affected
parent, and so on
average there is a 1 in 2
or 50% chance that
each child of a
heterozygous parent will
be affected.
3. autosomal recessive inheritance

The first and most important thing to

remember about autosomal recessive
inheritance is that most, if not all, affected
individuals have parents with normal
phenotypes.
 The Punnett Square for autosomal
recessive diseases with an affected child in the
family almost always looks like the following:
 When the father and mother are both
Dd (dd is the recessive affected individual,
Dd the heterozygous carrier individual,
and DD the homozygous normal
individual), The Punnet Square shows the
origin of the famous Mendelian ration of
3/4 normal to 1/4 affected.
 For most autosomal recessive diseases, but
not all, the heterozygote cannot be distinguished
from the normal homozygote. In the normal
phenotype categories of offspring in the above
Punnett Square (Dd and DD produce the same
normal phenotype), please note that two of the
three are heterozygotes (carriers); one of the
three is homozygous normal.

Within the normal siblings of an affected

individual the probability of being a carrier
is 2/3.
AR patients are often the result of a marriage between two carriers.

Aa × Aa
A quarter of the children
born to two carriers after
marriage are affected,
and about two-thirds of
the children with normal
phenotypes are carriers.
AA Aa Aa aa
carriers affected

Phenotypic normal 1/4

There are five hallmarks of autosomal
recessive inheritance:

(1) Males and females are equally likely to be affected.

(2) On average, the recurrence risk to the unborn sibling of an

affected individual is 1/4.

(3) The trait is characteristically found in siblings, not parents of

affected or the offspring of affected.

(4) Parents of affected children may be related. The rarer the trait in
the general population, the more likely a consanguineous mating
is involved.

(5) The trait may appear as an isolated (sporadic) event in small

sibships.
Sickle - shaped red cells
in a sickle haemoglobin (HbS)
homozygote.
• Sample pedigree
On average, one-quarter of
their children will be
homozygous normal, one-half
heterozygous and one-quarter
homozygous affected.
Two points must be borne in mind.
Firstly, it is unlikely that any
single family will have produced
sufficient children to give the ratio
exactly.
Secondly, there is an automatic
bias, as families only come to
medical attention by virtue
of an affected child, and those
carrier parents who, by chance,
produce only unaffected children
will be missed.
 Homework
Below is an albino pedigree, assuming albino gene carrier
frequency is 1/100 in groups, try to calculate what is the
risk for the affected children after Ⅱ3 and Ⅱ 4 marriage?

Ⅰ
1 2

Ⅱ
1 2 3 4
？
4. X-linked dominant inheritance

When an X-linked gene is said to express

dominant inheritance, it means that 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.
Affected father x normal mother. Affected mother x normal father.
The following are the hallmarks of X-linked
dominant inheritance:

(1)The trait is never passed from father to son.

(2)All daughters of an affected male and a normal female are

affected. All sons of an affected male and a normal female are
normal.

(3)Matings of affected females and normal males produce 1/2 the

sons affected and 1/2 the daughters affected.

(4)Males are usually more severely affected than females. The trait
may be lethal in males.

(5)In the general population, females are more likely to be affected

than males, even if the disease is not lethal in males.
Sample pedigree
vitamin D-resistant Rickets
5. X-linked recessive disease

Everyone has heard of some X-linked

recessive disease even though they are, in
general, rare. Hemophilia, Duchenne muscular
dystrophy, Becker muscular dystrophy, and
Lesch-Nyhan syndrome are relatively rare in
most populations, but because of advances in
molecular genetics they receive attention in the
media.
the hallmarks of X-linked recessive inheritance

(1) As with any X-linked trait, the disease is never passed

from father to son.

(2) Males are much more likely to be affected than females.

If affected males cannot reproduce, only males will be
affected.

(3) All affected males in a family are related through their

mothers.

(4) Trait or disease is typically passed from an affected

grandfather, through his carrier daughters, to half of his
grandsons.
Sample pedigree
① On average, one-half of the
daughters will be carriers and one-
half of the sons will be affected.
② The carrier female is usually
clinically normal. A woman with an
affected child and an affected
brother, or a woman with more
than one affected child, is an
obligate carrier, as the alternative
explanation of multiple new
mutations is so unlikely.
③ For each daughter of an obligate
carrier there is, on average, a 1 in
2 risk that she too is a carrier.
hemophilia
6. Y-linked

A gene on the Y chromosome. A Y-linked gene

is by necessity passed from father to son, since
the Y chromosome can only be transmitted by a
man to his male progeny.
a number of genes were known to be Y-linked
including:

ASMTY (acetylserotonin methyltransferase), TSPY (testis-

specific protein), IL3RAY (interleukin-3 receptor), SRY (sex-
determining region), TDF (testis determining factor), ZFY (zinc finger
protein), PRKY (protein kinase, Y-linked), AMGL (amelogenin),
CSF2RY (granulocyte-macrophage colony-stimulating factor
receptor, alpha subunit on the Y chromosome), ANT3Y (adenine
nucleotide translocator-3 on the Y), AZF2 (azoospermia factor 2),
BPY2 (basic protein on the Y chromosome), AZF1 (azoospermia
factor 1), DAZ (deleted in azoospermia), RBM1 (RNA binding motif
protein, Y chromosome, family 1, member A1), RBM2 (RNA binding
motif protein 2) and UTY (ubiquitously transcribed TPR gene on Y
chromosome).
Sample pedigree
 7. SPECIAL FEATURES
Penetrance
The likelihood a given gene will result
in disease. For example, if half (50%) of
the people with the neurofibromatosis (NF)
gene have the disease NF, the penetrance
of the NF gene is 0.5.
Expressivity
The consistency of a genetic disease.
For example, Marfan disease shows
variable expressivity. Some persons with
Marfan's merely have long fingers and
toes while others have the full-blown
disease with dislocation of the lens and
dissecting aneurysm of the aorta.
Phenocopy

(1) An environmental condition that imitates

(copies) one produced by a gene.
(2) The person who has an environmentally-
produced condition that mimics one
produced by a gene.
Genetic heterogeneity
Here a similar clinical picture may be
produced by different mutations at the
same locus or at different loci. Retinitis
pigmentosa may be caused by both
autosomal dominant or recessive
inheritance.
Anticipation
A remarkable phenomenon in which a genetic
disease appears earlier appearance and with increased
from with each succeeding generation. Anticipation was
once thought not to exist in genetics. It was chalked off
as a meaningless statistical artifact. However,
anticipation has now been proven to occur in a large
number of important genetic disorders, including
Huntington disease and myotonic dystrophy. In
molecular terms, anticipation is due to the expansion of a
trinucleotide repeat sequence in the DNA. This
phenomenon also occurs in the fragile X syndrome, the
most common inherited form of mental retardation.
Genomic imprinting
The phenomenon of parent-of-origin gene
expression. The expression of a gene
depends upon the parent who passed on
the gene.
 For instance, two different disorders - Prader-Willi
syndrome and Angelman syndrome -- are due to
deletion of the same part of chromosome 15. When the
deletion involves the chromosome 15 that came from the
father, the child has Prader-Willi syndrome, but when the
deletion involves the chromosome 15 that came from the
mother, the child has Angelman syndrome.
Genomic imprinting plays a critical role in fetal growth
and development. Imprinting is regulated by DNA
methylation and chromatin structure.
New mutations

Seen as isolated cases.

Increased paternal age may be
associated with new mutations.
Majority of Achondroplasics are
new mutations.
 In guinea pigs, the colour of fur, black and white is a pair
of relative traitssurface rough and smooth are a relative
traits according to the following produce offspring, filling
the parental genotypes(B,b/R,r) :

Black Black White White

P-Genotype
rough smooth rough smooth
Black Smooth ×
White smooth 0 18 0 14 Bbrr ×bbrr
Black rough
White smooth × 10 8 7 9 BbRr×bbrr
Black rough
White rough × 15 6 16 3 BbRr×bbRr
Back smooth
White rough
× 25 0 0 0 BBrr×bbRR

Black and Rough are dominent