Mendelian Inheritance

In order to understand Mendelian inheritance, several terms must be defined.

LOCUS:Is the site or location of a gene on a chromosome.

Alternative form of a gene, or a DNA sequence, at a given locus.

ALLELES:

HOMOLOGOUS CHROMOSOMES:Pair of chromosomes, one inherited from father, the other from the mother, that pair with each other during meiosis.

HOMOZYGOUS:

HOMOZYGOTE:

Both alleles at a particular locus on a pair of homologous chromosomes are identical

The individual who carry identical alleles at a locus on a pair of homologous chromosomes.

HETROZYGOUS:

HETEROZYGOTE

Both alleles at a particular locus on a pair of homologous chromosomes are different.

The individual who carry two different alleles at a locus on a pair of homologous chromosomes.

Indicate a normal gene or allele.

Indicate a gene that has been altered by mutation, e.g., a mutant gene leading to a disease.

WILD TYPE ALLELE

MUTANT ALLELE

Mendelian diseases are the result of a single mutant gene that has a large effect on phenotype and are inherited in simple pattern similar to those described by Mendel.

They are divided into two types:

1. Autosomal: if the trait or disease is determined by a gene is on one of the 22 pair chromosomes.

2. Sex-linked: if the trait or disease is determined by a gene on one of the sex chromosomes

They are divided into two types:

1. Autosomal:

2. Sex-linked:

They are divided into two types:

Each is also divided into:

1. DOMINANT ALLELE: Allele that exerts its phenotype effect in the heterozygous; it masks the expression of the recessive allele. It's usually assigned an upper case (capital).

2. RECESSIVE ALLELE: Allele that exerts its phenotype effect in the homozygous; it expression is masked by a dominant allele. It's usually given the same dominant letter but in lower case..

GENOTYPE AND PHENOTYPEGenotype is the genetic constitution of an individual or alleles present at one locus. It is usually indicated by letters

For example:Genotype TT is

Genotype tt is

Genotype Tt is

For example:Genotype TT is homozygous dominant

Genotype tt is homozygous recessive

Genotype Tt is heterozygous

Phenotype is the appearance (physical, biochemical and physiological) of an individual determined by the genotype and environmental factors.

Example: Individuals who carry a mutation of both alleles (homozygous recessive) (ss) in a β-gene (genotype), will develop a disease named Sickle cell disease (phenotype)

Probability of Inheritance

Risk assessment is an important part of medical genetics. For example, the physician or genetic counselor commonly informs couples about their risk of producing a child with a particular genetic disorder.

Your chance of having a second baby with Sickle cell Disease is 25 % , and you both should decide what choice you need to take in the future

A probability is defined as the proportion of times that specific outcome occurs in a series of events.

One of the easiest ways to calculate the mathematical probability of inheriting a specific trait was invented at early 20th century by an English geneticist named Reginald Punnett.

His technique employs what we now call a Punnett square. This is a simple graphical way of discovering all of the potential combinations of genotypes that can occur in children, given the genotypes of their parents

Genetic contribution of one parent

Genetic contribution of the other parent

Offspring genotype possibility

AAA

aaaa

a

FAMILY PEDIGREE

Drawing a family tree is one of the most commonly used tool in medical genetics to record

genetic information

MALE

FEMALE

P PREGNANCY

DEAD

Individual symbols

AFFECTED

CARRIER FOR AUTOSOMAL RECESSIVE

PROBAND, INDEX CASE,CONSULTAND

CARRIER FOR X-LINKED RECESSIVE

MATING (FATHER & MOTHER)

CONSANGUINEOUS MATING

DIVORCED OR SEPERATED

Mating symbols

SIBILNGS ARE DRAWN IN ONE LINE

3

Sometimes, to make the pedigree simpler, we may just mention the number of sons and daughters2

Siblings

DIZYGOTIC TWINS

MONOZYGOTIC TWINS

NO OFFSPRING

Drawing a Medical Family Tree

1- Draw a square for each male and a circle for each female.

2- If a couple is married, draw a horizontal line between them and two lines if they are consanguineous

3- If a couple have children, draw a vertical line. On the row below, enter the symbols for each child, listing the children in chronological order with the oldest to the left. Be sure to list all siblings, including those miscarried or stillborn

4- Continue the process, entering extended family members. Remember to keep all members of the same generation on the same row.

Each individual within a single generation is indicated by Arabic numerals (1,2,3,4,5 )

Each generation is indicated by Roman numerals (I, II, II, IV, V, and VI.)

§Put a slash through the square or circle to indicate that the person is deceased. Make a note indicating the cause and age of death.

§Dark circle or square to indicate a disease, half dark to indicate carrier and indicate the disease name.

§Arrow to indicate the proband

5- Next, add markings to highlight pertinent health information: for example:

Heartdisease

Each generation is indicated by Roman numerals (I, II, II, IV, V, VI.)

Each individual within a single generation is indicated by Arabic numerals (1,2,3,4,5 )

CONSANGUINITY

It is defined as blood relationship because of common ancestry.

Mention a name for each of your following relatives (you may use different names other than their real names if you wish) and then draw your own family pedigree?

In the drawing mention:vThe generation numbervThe individual numbervConsanguinity if presentvAppropriate symbol for each individual

1. Your name2. Father name3. Mother name4. Relationship between father & mother5. Brothers name6. Sisters name7. Grand father (paternal)8. Grand mother (paternal)9. Grand father (maternal)10.Grand mother (maternal)11.Paternal uncles12.Patenal aunts13.Maternal uncles14.Maternal aunts

AUTOSOMAL DOMINANTDEFINITION: a dominant trait is the one that manifests in a heterozygous state. i.e., a person possessing both the abnormal (mutant) allele and the normal allele.

CHARACTER

1- Affected people are usually heterozygous for the abnormal allele.

CHARACTER

2- Males and females are both likely to be affected and both can transmit the disease to their offspring.

3. Can be traced through many generations of a family

4. Characterized by vertical transmission of the disease phenotype (disease pass from one generation to the next).

5. Father to son transmission can occur, but not required to establish autosomal dominant inheritance

ACHONDROPLASIA

MARFAN SYNDROME

MARFAN SYNDROME

GENETIC RISKThe Punnett square illustrates mating between affected and normal individual.

A aa Aa aaa Aa aa

Affected parent

Normalparent

A is the abnormal dominant allelea is the normal recessive allele

Aa is affected individual aa is normal individual

The abnormal allele is dominanta is the normal allele is recessive

vThe affected individual (Aa) can pass either the disease gene (affected dominant allele –A) or the normal gene (normal recessive allele – a) to his/her children.

vAny child born to such parents has a 1 in 2 (50%) chance of inheriting the mutant allele and being similarly affected.

Thus, even if the parents have already had a child with the disease, their recurrence risk remains 1/2. Even if they have had several children, all affected (or all unaffected) by the disease, the law of independence dictates that the probability that their next child will have the disease is still 1/2.

It is important to keep in mind that each birth is an independent event, as in the coin-tossing examples.

AUTOSOMAL RECESSIVE

DEFINITION

They are only manifest when mutant alleles are present in homozygous state.

CHARACTER 1.The characteristic pedigree is horizontal

rather than vertical. Autosomal Recessive diseases are usually observed

in one or more siblings but not in earlier generations.

Question: guess who are carriers in this pedigree?

2. Heterozygote are carriers and healthy.

3. Males and Female are both likely to be affected

4. Consanguinity increases the risk of recessive disorders because both parents are more likely to carry the same defective gene, which has been inherited from a common ancestor.

On the other hand, metabolic diseases are very rare diseases, so it is more likely to result from a consanguineous marriage.

For example, sickle cell disease in Bahrain is a common disease, so it is possible to have an affected patient from unrelated heterozygous parent.

8. The rarer the recessive disorder, the greater the frequency of consanguinity among the parent of affected individuals.

B- thalasemia Sickle Cell disease

Cystic Fibrosis

Carrier father

Carriermother

GENETIC RISK:The Punnett square illustrates mating between two carrier individuals.

A a

A AA Aaa Aa aa

a is the abnormal recessive alleleA is the normal dominant allele.

AA is normal individualAa is carrier individualaa is affected individual

Marriage of carrier father and carrier mother:

vThe carrier individual (Aa) can pass either the disease gene (affected recessive allele – a) or the normal gene (normal dominant allele – A) to his/her children.

Any child born to such parents has:

1 in 4 (25%) chance of inheriting two mutant alleles and being affected.1 in 2 (50%) chance of inheriting one mutant allele from either parent and one normal allele from the other and being carrier like his / her parent.1 in 4 (25%) chance of inheriting two normal alleles and being normal.

It is important to keep in mind that each birth is an independent event.

Thus, even if the parents have already had a child with the disease, their recurrence risk remains 1/4. Even if they have had several children, all affected or all unaffected or all carriers for the disease, the law of independence dictates that the probability that their next child will have the disease is still 1/4.

Affected father

Carriermother

Marriage of affected father and carrier mother:

a a

a aa aaA Aa Aa

a is the abnormal recessive alleleA is the normal dominant allele.

Any child born to such parents has:1 in 2 (50%) chance of inheriting two mutant alleles and being affected.1 in 2 (50%) chance of inheriting one mutant allele from either parent and one normal allele from the other and being carrier like his / her parent.

AA is normal individualAa is carrier individual aa is affected individual

Affected father

normalmother

Marriage of affected father and normal mother :

a a

A Aa AaA Aa Aa

a is the abnormal recessive alleleA is the normal dominant allele.

AA is normal individualAa is carrier individual aa is affected individual

There is 100 % chance i.e., all children will be a carrier for the disease

Because this pattern of inheritance mimics that of an autosomal dominant trait, it is sometimes referred to as pseudo-dominance

DEFINITION:

X-linked recessive trait is one determined by a gene carried on the X-chromosome.

X –LINKED RECESSIVE

CHARACTER:

It is usually manifest only in males, because they have only a single copy of gene carried by the X chromosome.

Males are (XY) (hemizygote), X is fully expressed in male.

While in female, they are (XX). However, only one X – chromosome is genetically active while the other is inactive (Lyonization theory).

Disease is transmitted by either healthy heterozygous female to her sons or by an affected male to all his daughters.

Mother transmits X-chromosome to both sons and daughters.

Father transmits X-chromosome to daughters and Y- chromosome to sons. Thus, he does not transmit the disease to his sons. i.e., no male-to-male transmission.

Selected members of the pedigree •I-1 = King George III •III-1 and III-2 = Prince Albert and Queen Victoria •IV-5 and IV-6 = Alice of Hesse and Ludwig IV of Hesse •V-13 and V-14 = Alix and Nicholas II (Tsar of Russia) •VI-16 = Alexei•VIII-1 = Prince Charles

A Pedigree of Hemophilia in the Royal Families of Europe

normal father

Carriermother

GENETIC RISKThe Punnett square illustrates mating between carrier mother and normal father.

The abnormal allele is Recessive while the normal allele is Dominant

X Y

X* X*X X*Y

X XX XY

X* is the abnormal recessive alleleX is the normal dominant allele.

XY is normal maleXX is normal femaleX*X is carrier female X*Y is affected male

Marriage of normal male with carrier female:

vThe carrier female (X*X) can pass either the disease x-chromosome (affected recessive allele – X*) or the normal x-chromosome (normal dominant allele – X) to her sons or daughters.

vThe normal father passes only X chromosome to his daughters and Y chromosome to his sons.

vEach son born to such parents has a 1 in 2 (50%)chance of being affected and each daughter has a 1 in 2 (50%) chance of being a carrier.

vEach offspring represent an independent event with a 50 % probability for males being affected

Affected father

normalmother

Marriage of affected male with normal female:

X* Y

X XX* XYX XX* XY

All daughters are carriers and all the sons are normal.

Affected father

carriermother

Marriage of affected male with carrier female:

X* Y

X * X * X* X * Y

X XX* XY

vThe carrier female (X*X) can pass either the disease x-chromosome (affected recessive allele – X*) or the normal x-chromosome (normal dominant allele – X) to her sons or daughters.

vThe affected father passes only X chromosome to his daughters and Y chromosome to his sons.

vEach son born to such parents has a 1 in 2 (50%)chance of being affected and each daughter has a 1 in 2 (50%) chance of being a carrier and 1 in 2 (50%) chance of being affected.

vEach offspring represent an independent event with a 50 % probability for males and females being affected

Other situations where female can be affected with X-Linked recessive diseases include:

1- The female has only one X-chromosome(hemizygous) i.e., patients with Turner syndromethey have one X - chromosome (XO) instead of (XX)

2- Skewed X-inactivation, where in heterozygous female, the active X chromosome in most of her cells could be the one with the mutant allele.

Everyone should see a 12 .

DEFINITION: The trait manifests in heterozygote female as well as male.

The pattern and the risk are same as X-linked recessive except that the carrier female is affected in X-linked dominant.

X-LINKED DOMINANT

1. The condition is usually lethal or more sever in male because they have only one X-chromosome

CHARACTER:

2. There is excessive affected females

3. The pattern of inheritance resemble autosomal dominant. However, affected male transmit the trait to all his daughters and none of his sons. i.e., no male-to-male transmission.

What happens when males are so severely affected that they cannot reproduce?

There are no affected males to test for X-linked dominant inheritance to see if they produce affected daughters and no affected sons

Some of the rare genetic defects expressed almost exclusively in females appear to be X-Linked dominant conditions that are lethal in males before birth. Typical pedigrees of such conditions show transmission by affected females, who produce affected daughters, normal daughters or normal sons

IncontinentiaPigmenti

HypophoshatemicRickets

normal father

Affectedmother

GENETIC RISK:The Punnett square illustrates mating between affected mother and normal father. The abnormal allele is dominant while the normal allele is recessive.

X Y

X* X*X X*YX XX XY

X* is the abnormal dominant alleleX is the normal recessive allele.

XY is normal maleXX is normal female X*X is affected female X*Y is affected male (more sever)

The affected female (X*X) can pass either the disease x-chromosome (affected dominant allele – X*) or the normal x-chromosome (normal recessive allele – X) to her sons or daughters.

The normal father passes only X chromosome to his daughters and Y chromosome to his sons.

Affected females are usually heterozygote and thus have a 50 % chance of passing the disease allele to their daughters and sons.

Each pregnancy represents an independent event with a 50 % probability for males and females being affected.

Affected father

normalmother

Marriage of affected male with normal female:

X* Y

X XX* XY

X XX* XY

All daughters are affected and all the sons are normal.

Y-LINKED DISORDERS

It affects only males (females have no Y-chromosomes)

Transmission is only from father to sonAll sons of affected father are affected.

Summary of Mendelial Inheritance:

These are single gene defects which can be either on:

One of the 22 autosomes or on sex chromosomes.

defective gene can be either

Dominant (capital letter) or

Recessive (small letter).

22 pairs of autosomes (2 alleles)

(1)Abnormalalleleisdominant(A)andnormalalleleisrecessive(a)=

(Autosomal Dominant)

•Bothallelesareabnormal(dominant)(AA)=•Affected(moreseverandveryrare)

•Onealleleisabnormal(dominant)andonenormal(recessive)(Aa)=Affected

•Bothallelesarenormal(aa)=Normalphenotype

22 pairs of autosomes (2 alleles)

(1)Abnormalalleleisrecessive(a)andnormalalleleisdominant(A)=

(Autosomal Recessive)

•Bothallelesareabnormal(recessive)(aa)=Affected

•Onealleleisabnormal(recessive)andonenormal(dominant)(aA)=Carrier

•Bothallelesarenormal(aa)=Normalphenotype

Sex Chromosome

Female (XX)(1)AbnormalX- alleleisdominant(X*)andnormalX- alleleisrecessive(X)=

(X-Linked Dominant)

•Bothallelesareabnormal(dominant)(X*X*)=•Affected(moreseverandalmostnotexisting)

•Onealleleisabnormal(dominant)andonenormal(recessive)(XX*)=Affected

•Bothallelesarenormal(XX)=Normalphenotype

Sex Chromosome

Female (XX)(1)AbnormalX- alleleisrecessive(X*)andnormalX- alleleisdominant(X)=

(X-Linked Recessive)

•Bothallelesareabnormal(recessive)(X*X*)=•Affected(incommonandmilddiseasessuchasG6PDdefeciency)

•Onealleleisabnormal(recessive)andonenormal(dominant)(XX*)=Carrier

•Bothallelesarenormal(XX)=Normalphenotype

Sex Chromosome

Male (XY)(1)AbnormalX- alleleisdominant(X*)

(X-Linked Dominant)

•Xalleleisabnormal(dominant)(X*Y)=Affected(severorlethal)

•Xallelesisnormal(XY)=Normalphenotype

Sex Chromosome

Male (XY)(1)AbnormalX- alleleisrecessive(X*)

(X-Linked Recessive)

•Xalleleisabnormal(Recessive)(X*Y)=•Affected(severorlethal)

•Xallelesisnormal(XY)=Normalphenotype

DOMINANT

HORIZANTAL

NO MALE TO MALE TRANSMISSION

AUTOSOMAL

RECESSIVE

X- LINKED

AFFECTS MALE AND FEMALE

VERTICAL

FAMILY PEDIGREE

VERTICAL = DOMINANT HORIZANTAL = RECESSIVE

AutosomalDominant

affect male and female

Male to male transmission

X-LinkedDominant

affect male and female (males more sever or lethal)

No male to maleAll daughter of affected male are affected

AutosomalRecessive

affect male and female

X-LinkedRecessive

Usually affect male only

No male to maletransmission

There are a number of non classical mendelian mode of inheritance, these usually manifest in autosomal dominant and include:

vVariable ExpressionvReduced PenetrancevLate onset diseasevNew MutationvHomozygous affected individual

1- VARIABLE EXPRESSION

DEFINITION: The variation in the severity of phenotypic features seen in persons with autosomal dominant disorders. Even within the same family members, a disorder may vary in the severity of any one manifestation.

Example: Father with a disease known as “Neurofibromatosis” is only mildly affected with skin manifestations, while others are more severely affected

Mild Sever

2- REDUCED PENETRANCE:

DEFINITION: An individual who has the genotype for a disease may not exhibit the disease phenotype at all, even though he or she can transmit the disease gene to the next generation.

Failure of penetrance in a pedigree can lead to apparent skipping of generations, and this complicates pedigree interpretation. This is because normal person with abnormal gene can transmit the disease to his or her children

3- LATE ONSET DISORDERS

While most genetic diseases expressed during early life, some do not appear until adulthood. An example is a disease called Huntington disease, where symptoms do not usually appear until age 30 years or later. Thus those who develop the disease often have children before they are aware that they carry the gene.

Huntington disease

A person whose parent has Huntington disease has a 50% chance of inheriting the disease gene. Until recently, this individual would be confronted with a torturous question: Should I have children, knowing that there is a 50% chance that I might have this disease gene and pass it to half of my children? With the identification of the mutation responsible for Huntington disease, it is now possible for at-risk individuals to know with a high degree of certainty whether they carry a disease-causing allele.

4- NEW MUTATION:

DEFINITION: If the child has been born with a genetic disease and there is no history of the disease in the family, it is possible that the disease is the product of a new mutation. This is more likely if the disease is an autosomal dominant.

Example: in case of Achondroplasia child, affected parent has 50% chance to have children with same condition

But, it is not uncommon for such children being born to a normal height parents secondary to a new mutation

5- HOMOZYGOUS AFFECTED INDIVIDUALS

This result in children from parent where both of them are heterozygous affected for the same dominant allele.

They are much more severely affected or even lethal.AA is homozygous affected (25 %) (Sever) Aa is heterozygous affected (50 %) aa is homozygous normal.(25 %)