Gene Characteristics

Gene Characteristics Gene Characteristics

Relations between genesRelations between genes

Relationships between Genes

I. Between Alleles

Dominance – recessiveness

Co-dominance

Lethal and semi-lethal genes

Poly-allelism

Gene families

II. Between Non-alleles

Epistasis

Genetic heterogeneity

Ask your questions in due time!

Dominance – Dominance – recessivenessrecessiveness

►Genes that influence the Genes that influence the

PHENOTYPE both in the PHENOTYPE both in the

homozygous and the homozygous and the

heterozygous state are heterozygous state are

dominantdominant. . Year introduced: 1968 Year introduced: 1968

►Genes that influence the Genes that influence the

PHENOTYPE only in the PHENOTYPE only in the

homozygous state are homozygous state are

recessive. recessive. ► ( 1968) ( 1968)

Dominance – Dominance – recessivenessrecessiveness► A dominant trait refers to a genetic feature that hides the

recessive trait in the phenotype of an individual.

► A dominant trait is a phenotype that is seen in both the

homozygous AA and heterozygous Aa genotypes.

► For example Huntington Disease is an abnormal dominant

trait in humans.

► A dominant trait when written in a genotype is always

written before the recessive gene in a heterozygous pair. A

heterozygous genotype is written Aa, not aA

Dominance – Dominance – recessivenessrecessiveness► Many traits are determined by pairs of

complementary genes, each inherited from a single parent.

► Often when these are paired and compared, one allele (the dominant) will be found to effectively shut out the instructions from the other, recessive allele.

► For example, if a person has one allele IIA A and one i, that person will always have blood type A.

► For a person to have blood type 0, both alleles must be i (recessive).


►When an individual has two dominant When an individual has two dominant alleles, the condition is referred to as alleles, the condition is referred to as homozygous dominant (e.g. homozygous dominant (e.g. IIAA I IAA); );

►An individual with two recessive An individual with two recessive alleles is called alleles is called homozygous homozygous recessive (e.g. ii)recessive (e.g. ii). .

►An individual carrying one dominant An individual carrying one dominant and one recessive allele is referred to and one recessive allele is referred to as as heterozygous (e.g. heterozygous (e.g. IIaai).i).

Words don’t come easy?Words don’t come easy?

►Repeat, exerciseRepeat, exercise

Parents Offspring Genotype Offspring Phenotype

1) AA x AA 100% AA (homozygotes) 100% A

2) AA x Aa 50% AA ; 50% Aa (homo-;heterozygotes) 100% A

3) AA x aa 100% Aa (heterozygotes) 100% A

4) Aa x aa 50% Aa; 50% aa (homo-; heterozygotes) 50% A; 50% a

5) Aa x Aa 25% AA; 50% Aa; 25% aa

(homo-; heterozygotes)

75% Aa; 25% aa

6) aa x aa 100% aa (homozygotes) 100% a

Dominant InheritanceDominant Inheritance

► If one of two parents (4. in the previous table) is affected by a

genetic condition with a dominant inheritance pattern, every

child has a one-in-two risk of being affected.

► So on average half their children will be affected and half

their children will not be affected and so will not pass on the

condition.

► However, as chance/probability determines inheritance, it is

also possible that all or none of their children will be affected.

► Examples of genetic conditions that show a dominant pattern

of inheritance are Huntington’s disease, achondroplasia and

neurofibromatosis.

AchondroplasiaAchondroplasia

People with this condition have an average People with this condition have an average body size, but body size, but shorter limbsshorter limbs. .

This is because the bones in their arms and This is because the bones in their arms and legs grow more slowly, both in the womb and legs grow more slowly, both in the womb and throughout childhood. throughout childhood.

Achondroplasia is one of the most common Achondroplasia is one of the most common causes of causes of short statureshort stature. .

Most people with achondroplasia do not Most people with achondroplasia do not consider themselves disabled, just different. consider themselves disabled, just different.

Young children with achondroplasia may have Young children with achondroplasia may have hearing, speech or breathing problems but all hearing, speech or breathing problems but all of these can be treated. of these can be treated.

Father and son, both with Father and son, both with achondroplasia.achondroplasia.

How is achondroplasia inherited?

People with achondroplasia may pass on the condition to their children.

If one parent is affected, each child has a one-in-two risk of having

achondroplasia, and a one-in-two probability of being of average height

(normal).

How is achondroplasia How is achondroplasia inherited?inherited?

If both parents have achondroplasia (An),

children have a one in four chance of

inheriting the gene from both parents,

being thus homozygotes (AA) for the

mutant gene.

Newborns who inherit both genes are

considered to have a severe form of

achondroplasia, where survival is usually

less than 12 months after birth..

How is achondroplasia How is achondroplasia inherited?inherited?

If both parents have achondroplasia (An),

children have a one in four chance of

inheriting the gene from both parents,

being thus homozygotes (AA) for the

mutant gene.

Newborns who inherit both genes are

considered to have a severe form of

achondroplasia, where survival is usually

less than 12 months after birth..

Average adult height of 131 cm (4 feet, 3.8 inches) for males and

123 cm (4 feet, 0.6 inches) for females

The FGFR3 gene is responsible for The FGFR3 gene is responsible for

causing achondroplasiacausing achondroplasia.. FGFR3 is the acronym for fibroblast growth factor receptor 3

Cytogenetic location of FGFR3 Gene : 4p16.3

Molecular location on chromosome 4: from base pair 1,762,853 to base pair 1,777,828

The protein plays a role in the development and maintenance of bone and brain tissue.

Researchers believe that this receptor regulates bone growth by limiting the formation of bone from cartilage, particularly in the long bones.

FGFR3 FunctionFGFR3 Function

► This protein is part of the family of fibroblast growth factor receptors. These proteins are very similar and play a role in several important cellular functions, which include:

► Regulation of cell growth and division Regulation of cell growth and division ► Determination of cell type Determination of cell type ► Formation of blood vessels Formation of blood vessels ► Wound healing Wound healing ► Embryo development. Embryo development.


Is a Is a bonebone growth disordergrowth disorder

Cartilage has difficulty converting to boneCartilage has difficulty converting to bone, ,

which results in which results in dwarfismdwarfism. .

Although the word literally means Although the word literally means "without "without

cartilage formation,"cartilage formation," the problem is not the the problem is not the

formation of cartilage. formation of cartilage. The problem occurs The problem occurs

when the cartilage has difficulty converting to when the cartilage has difficulty converting to

bone, especially in the bone, especially in the long bones of the arms long bones of the arms

and legsand legs..

► http://bones.emedtv.com/achondroplasia/achondroplasia.htmlhttp://bones.emedtv.com/achondroplasia/achondroplasia.html

From cartilage to boneFrom cartilage to bone

Achondroplasia and Achondroplasia and FGFR3 Gene FGFR3 Gene FunctionFunction

► The protein made by the FGFR3 gene is a receptor The protein made by the FGFR3 gene is a receptor that regulates bone growth bythat regulates bone growth by limiting limiting the formation the formation of bone from cartilage (a process called of bone from cartilage (a process called ossificationossification), ), particularly in the particularly in the long boneslong bones. .

► Researchers believe that Researchers believe that mutationsmutations in the FGFR3 in the FGFR3 gene cause the gene cause the receptor to be receptor to be overly overly activeactive, which , which interferes with ossification and leads to the interferes with ossification and leads to the disturbances in bone growth seen with this disorder.disturbances in bone growth seen with this disorder.

► This theory is supported by the This theory is supported by the knockout mouse knockout mouse modelmodel in which the in which the receptor is absentreceptor is absent, and so the , and so the negative regulation of bone formation is lost. The negative regulation of bone formation is lost. The result is a mouse with excessively long bones and result is a mouse with excessively long bones and elongated vertebrae, resulting in a long tail. elongated vertebrae, resulting in a long tail.


► Achondroplasia can be either Achondroplasia can be either inherited, or the result of a inherited, or the result of a new new mutationmutation in the FGFR3 gene ; in the FGFR3 gene ;

► In most cases (80 percent), the In most cases (80 percent), the condition is due to a condition is due to a randomrandom, new, , new, sporadicsporadic mutation of FGFR3. mutation of FGFR3.

► Scientists know this because people Scientists know this because people with this type of achondroplasia with this type of achondroplasia have parents of average size have parents of average size (normal), but scientists do not know (normal), but scientists do not know (yet) (yet) whywhy this mutation occurs. this mutation occurs.


► Achondroplasia can be detected before Achondroplasia can be detected before birth by the use of birth by the use of prenatal ultrasound. .

► The diagnosis can be made by fetal The diagnosis can be made by fetal ultrasound by by progressive discordanceprogressive discordance between the between the femur length and biparietal length and biparietal diameter by agediameter by age. The . The trident handtrident hand configuration can be seen if the fingers configuration can be seen if the fingers are fully extended.are fully extended.

► Additionally a DNA test can be Additionally a DNA test can be performed before birth to detect performed before birth to detect homozygosity, where two copies of the , where two copies of the mutant gene are inherited, a condition mutant gene are inherited, a condition which is which is lethallethal and leads to and leads to stillbirths. .

The left image is a radiograph of the hand of a young patient with achondroplasia. The characteristic

"trident" deformity is present, consisting of separation of the first and second as well as the third and fourth

digits. Notice the shortened tubular bones of the hand, particularly the proximal phalanges.

The right image is of an

adult. To identify are the

short tubular bones with

a gracile distal ulna,

characteristic of

achondroplasia.

AchondroplasiaAchondroplasia► No No cure for achondroplasia currently exists. Therefore, currently exists. Therefore,

achondroplasia treatment involves achondroplasia treatment involves preventingpreventing or or treating the signs, symptoms, or health conditionstreating the signs, symptoms, or health conditions that occur as a result of the disorder.that occur as a result of the disorder.

► Health problems commonly associated with Health problems commonly associated with achondroplasia that may require treatment include:achondroplasia that may require treatment include: Reduced muscle strength Reduced muscle strength Recurring Recurring ear infections Breathing disorders (apnea) Breathing disorders (apnea) Obesity Obesity Crowded teeth. Crowded teeth.

► Social and family support, along with regular follow-Social and family support, along with regular follow-up visits with healthcare providers, are also an up visits with healthcare providers, are also an important part of achondroplasia treatment.important part of achondroplasia treatment.

AchondroplasiaAchondroplasia► Characteristic symptoms includeCharacteristic symptoms include::

o An average-size trunk. An average-size trunk. o Short arms and legs, with particularly Short arms and legs, with particularly

short upper arms and thighs. short upper arms and thighs. o An enlarged head with a prominent An enlarged head with a prominent

forehead. forehead. o Fingers that are typically short. The ring Fingers that are typically short. The ring

finger and middle finger may diverge, finger and middle finger may diverge, giving the hand a trident appearance. giving the hand a trident appearance.

Achondroplasia is one of the most common causes of dwarfism. Achondroplasia is one of the most common causes of dwarfism.

Characteristics of a person with the disease include: Characteristics of a person with the disease include:

A short stature with proportionately short arms and legs A short stature with proportionately short arms and legs

A large head A large head (macrocephaly),(macrocephaly),

A prominent forehead A prominent forehead (frontal bossing)(frontal bossing)

A flattened bridge of the nose. A flattened bridge of the nose.


► An example of an autosomal dominant human disorder is Huntington's disease (HD), which is a neurological disorder resulting in impaired motor function.

► The mutant allele results in an abnormal protein, containing large repeats of the amino acid glutamine. This defective protein is toxic to neural tissue, resulting in the characteristic symptoms of the disease.

► Hence, one copy of the deffective gene is sufficient to confer the disorder to the person carrying it..

1983

Scientists discover a gene marker

linked to HD on the short arm of

chromosome 4, which indicates that

the Huntington gene is also located

on chromosome 4. Predictive linkage

testing is introduced to assess the

likelihood of contracting HD.

Huntington disease (HD)Huntington disease (HD)► Huntington disease (HD) is a disorder Huntington disease (HD) is a disorder

affecting nerve cells in the brain.affecting nerve cells in the brain.

1993

The location of the Huntington

gene is discovered at the 4p16.3

gene site on chromosome 4. The

gene is found to contain codon C-

A-G in varying numbers.

An abnormal number of CAG repeats turns out to be a highly

reliable way to tell whether someone has the allele for HD.

Do not loose your enthusiasm, there is still more to find out

Huntington disease (HD)Huntington disease (HD)

►Huntington's disease is one of several trinucleotide repeat disorders, caused by the length of a repeated section of a gene exceeding the normal range. The huntingtin gene (HTT) normally provides the information to produce Huntingtin protein, but when affected, produces mutant Huntingtin (mHTT) instead.


►It is an inherited It is an inherited progressive progressive neurodegenerativeneurodegenerative disorder disorder characterized by:characterized by:

choreiform movements choreiform movements (uncoordinated, jerky body (uncoordinated, jerky body movements), movements),

psychiatric problems, and psychiatric problems, and dementia (dementia ( decline in some mental decline in some mental

abilities)abilities)


► This This genetic neurological disorder itself isn't fatal, but as itself isn't fatal, but as

symptoms progress, complications reducing symptoms progress, complications reducing

life expectancy increase. increase.

► Abnormal movements are initially exhibited as general lack Abnormal movements are initially exhibited as general lack

of coordination, an unsteady of coordination, an unsteady gait and slurring of speech, and slurring of speech,

but, as the disease progresses, any function that requires but, as the disease progresses, any function that requires

muscle control is affected, causing physical instability, muscle control is affected, causing physical instability,

abnormal abnormal facial expression, but the most characteristic , but the most characteristic

physical symptoms are jerky, random, and uncontrollable physical symptoms are jerky, random, and uncontrollable

movements called movements called chorea. .

Huntington diseaseHuntington disease► Mild symptoms, which include Mild symptoms, which include forgetfulness, clumsiness and forgetfulness, clumsiness and

personality changes first appear in middle agepersonality changes first appear in middle age. . ► Over the next 10-20 years, a person with HD Over the next 10-20 years, a person with HD gradually loses gradually loses

all control of their mental and physical abilities. all control of their mental and physical abilities.

►There is no

cure for HD at

the moment,

although some

of the

symptoms can

be treated with

drugs.

Huntington disease Huntington disease (Huntington chorea)(Huntington chorea)

► The advances in molecular The advances in molecular genetics make it possible to genetics make it possible to detect Huntington disease in a detect Huntington disease in a preclinical stage preclinical stage at or even before at or even before birthbirth. .

► The molecular approach does not The molecular approach does not replace prior approaches to replace prior approaches to Huntington disease but is Huntington disease but is synergistic and provides a model synergistic and provides a model of the new genetics.of the new genetics.


► The The HuntingtinHuntingtin gene ( (HTTHTT), also called ), also called HDHD ((Huntington diseaseHuntington disease) gene, or the ) gene, or the IT15IT15 ((""interesting transcript 15interesting transcript 15"") gene is ) gene is located on the located on the short arm of of chromosome 4 (4p16.3). (4p16.3).

► HTTHTT contains a sequence of three contains a sequence of three DNA bases——cytosine--adenine--guanine ( (CAG)—)—repeated multiple times repeated multiple times (i.e. ...CAGCAGCAG...) on its (i.e. ...CAGCAGCAG...) on its 5' end, known , known as a as a trinucleotide repeat/codon. /codon.

► CAG is coding for the CAG is coding for the amino acid glutamine, , so a series of them results in the production so a series of them results in the production of a chain of glutamine known as of a chain of glutamine known as polyglutamine or polyQ tract, and the , and the repeated part of the gene, the repeated part of the gene, the PolyQ regionPolyQ region

Where is the HTT gene located?

Cytogenetic Location: 4p16.3

Molecular Location on chromosome 4:

base pairs 3,046,205 to 3,215,484

Huntington disease (HD)Huntington disease (HD)► Huntington disease is caused by a Huntington disease is caused by a

abnormal abnormal trinucleotide (CAG) trinucleotide (CAG) expansionexpansion in the in the HD geneHD gene

► Normal persons have a CAG repeat Normal persons have a CAG repeat count of between count of between 7 and 357 and 35 repeats repeats

► HTTHTT gene encodes the protein gene encodes the protein huntingtinhuntingtin, and if , and if abnormalabnormal resulting in an resulting in an expanded expanded polyglutamine tractpolyglutamine tract. .

► HuntingtinHuntingtin is present in a large is present in a large number of tissues throughout the number of tissues throughout the body, with the highest levels of body, with the highest levels of expression seen in the brainexpression seen in the brain..

HuntingtinHuntingtin

► The exact function of this protein The exact function of this protein is yet not known, but it plays an is yet not known, but it plays an important role in important role in nerve cells. .

► Within cells, Within cells, huntingtinhuntingtin may be may be involved ininvolved in

o signaling, signaling,

o transporting materials, transporting materials,

o binding proteins and other structures, and binding proteins and other structures, and

o protecting against programmed cell death (protecting against programmed cell death (

apoptosis). ).

► Huntingtin proteinHuntingtin protein is required for normal is required for normal

development development beforebefore birth. .

HuntingtonHuntington disease (HD)disease (HD)

► The pathophysiology of HD is not fully The pathophysiology of HD is not fully understood, although it is thought to understood, although it is thought to be related tobe related to toxicity toxicity of the of the mutant mutant huntingtin proteinhuntingtin protein..

► However, pathology appears to be However, pathology appears to be limited to the central nervous system, limited to the central nervous system, with atrophy of the caudate and with atrophy of the caudate and putamen (the neostriatum) being putamen (the neostriatum) being most prominent. most prominent.

► At the cellular level, protein At the cellular level, protein aggregates are seen both in the aggregates are seen both in the cytoplasm and nucleus.cytoplasm and nucleus.


► Although most cases start clinically Although most cases start clinically in midadulthood, usually between in midadulthood, usually between 35 and 42 years of age, there is 35 and 42 years of age, there is great variability in age of onsetgreat variability in age of onset. .

► About 3% of cases are diagnosed as About 3% of cases are diagnosed as juvenile Huntington disease before juvenile Huntington disease before the age of 15 years. Late onset is the age of 15 years. Late onset is well known after 50 years of age.well known after 50 years of age.


► Generally, the number of CAG Generally, the number of CAG repeats is related to how much the repeats is related to how much the person is affected, and correlates person is affected, and correlates with with age at onsetage at onset and the and the rate of rate of progressionprogression of symptoms. of symptoms.

► For example, 36–39 repeats result For example, 36–39 repeats result in much later onset and slower in much later onset and slower progression of symptoms than the progression of symptoms than the mean of ill persons, such that mean of ill persons, such that some individuals may die of other some individuals may die of other causes before they even manifest causes before they even manifest symptoms of Huntington disease, symptoms of Huntington disease, this is termed this is termed ""reduced/incompletereduced/incomplete penetrance””

Repeat Repeat countcount

ClassificatioClassificationn

Disease Disease statusstatus

<27<27 NormalNormal UnaffectedUnaffected

27–3527–35 IntermediateIntermediate UnaffectedUnaffected

36–3936–39 Reduced Reduced PenetrancePenetrance

+/- Affected+/- Affected

>39>39 Full Full PenetrancePenetrance

AffectedAffected

There is a variation in age of onset for any given CAG repeat

length, particularly within the intermediate range (40–50 CAGs).

For example, a repeat length of 40 CAGs leads to an onset

ranging from 40 to 70 years of age in one study. This variation

means that, although algorithms have been proposed for have been proposed for

predicting the age of onset, in practice, it can not be predicted predicting the age of onset, in practice, it can not be predicted

confidentlyconfidently

Understanding HDUnderstanding HD► The symptoms of Huntington The symptoms of Huntington

disease (HD) appear when an disease (HD) appear when an abnormal protein builds up in nerve abnormal protein builds up in nerve cells in certain areas of the brain, cells in certain areas of the brain, causing the cells to die. causing the cells to die.

► One of the brain areas affected is One of the brain areas affected is the the area that controls movement..

► Cells in the outer layer of the brain Cells in the outer layer of the brain also die, affecting mental abilities. also die, affecting mental abilities.

► Brain scan from a patient with Brain scan from a patient with Huntington disease (right) Huntington disease (right) showing a larger cavity where showing a larger cavity where brain cells have died, brain cells have died, compared with a normal brain compared with a normal brain (left). (arrows)(left). (arrows)

Testing for HDTesting for HD

As the symptoms of Huntington disease (HD) do not usually appear As the symptoms of Huntington disease (HD) do not usually appear until middle age, some people only discover they are at risk when until middle age, some people only discover they are at risk when one of their parents or grandparents is diagnosed.one of their parents or grandparents is diagnosed.

A genetic test is available to HD families that can tell people A genetic test is available to HD families that can tell people whether or not they have whether or not they have inherited the altered geneinherited the altered gene,, but not the but not the age at which they will start to develop symptomsage at which they will start to develop symptoms. .

Although there is no cure available at the moment, genetic tests can Although there is no cure available at the moment, genetic tests can help people at risk of HD make help people at risk of HD make decisions about their futuredecisions about their future. . However most decide not to take the test.However most decide not to take the test.

DNA analysis of

Huntington’s disease.

Each lane shows a

different person's DNA:

two bands in the normal

(N) range show someone

is unaffected.

One band in the H range

predicts the person will

get Huntington disease.

How is HD inherited?How is HD inherited?► Huntington disease (HD) is caused by a single altered gene, which Huntington disease (HD) is caused by a single altered gene, which

is passed on from one generation to the next in affected familiesis passed on from one generation to the next in affected families► With one affected parent, each child has a one-in-two chance of With one affected parent, each child has a one-in-two chance of

inheriting HD. inheriting HD.

► Children Children who do not

carry the altered gene

are free from the

condition and cannot not

pass it on to their own

children


► Genetic testing may infer information about relatives Genetic testing may infer information about relatives who do not want it. who do not want it.

► Testing a descendant of an undiagnosed parent has Testing a descendant of an undiagnosed parent has implications to other family members, since a positive implications to other family members, since a positive result automatically reveals the parent as carrying the result automatically reveals the parent as carrying the affected gene, and siblings (and especially affected gene, and siblings (and especially identical twins) as being 'at risk' of also inheriting it.) as being 'at risk' of also inheriting it.

► This emphasizes the importance of This emphasizes the importance of disclosuredisclosure, as , as individuals have to decide individuals have to decide whenwhen and and how how to reveal the to reveal the information to their children and other family information to their children and other family membersmembers. .

► For those at risk, or known to carry a mutant allele, For those at risk, or known to carry a mutant allele, there can be the consideration of there can be the consideration of prenatal genetic testing in order to ensure that the in order to ensure that the disorder is not passed on.disorder is not passed on.


► Embryonic screeningEmbryonic screening is another possibility for is another possibility for

affected or at-risk individuals to know if their affected or at-risk individuals to know if their

children will or will not inherit the disease. children will or will not inherit the disease.

► It is possible for women who would consider It is possible for women who would consider

abortionabortion of an affected fetus to test an of an affected fetus to test an

embryo in the womb (embryo in the womb (prenatal diagnosis). ).

► Other techniques, such as Other techniques, such as pp

reimplantation genetic diagnosis in the in the

setting of setting of in vitro fertilisation, can be used to , can be used to

ensure that the newborn is unaffected ensure that the newborn is unaffected

Co-dominanceCo-dominance

► In In genetics, , co-dominantco-dominant is denoting an is denoting an

equal degree of of dominance of two of two genes

, both , both being expressed in the expressed in the phenotype

of the of the individual; ;

► e.g., e.g., genes I IAA and I and IBB of the of the

ABO blood group are co-dominant; are co-dominant;

► individuals with both genes (genotype Iindividuals with both genes (genotype IA A

IIBB) are ) are type AB (phenotype). (phenotype).


►Co-dominant inheritance Co-dominant inheritance means means

that the two that the two alleles are individually are individually

expressed in the presence of each expressed in the presence of each

other, being thus other, being thus equipotentequipotent; ;

{there may be other {there may be other alleles

available at the available at the locus that may or that may or

may not may not exhibit co-dominance}. }. (Latin Dominari = to govern)(Latin Dominari = to govern)


► So, the heterozygous individual So, the heterozygous individual

expresses expresses bothboth phenotypes. phenotypes.

► A common example is the A common example is the

ABO blood group system. .

► The gene for blood types has three The gene for blood types has three

alleles: alleles: IIAA, I, IBB, and , and ii on on 9q34.1 - 9q34.1 -

q34.2q34.2 . .

► ii causes causes 00 blood blood type and is type and is recessiverecessive to to

both both IIAA andand IIBB

Co-dominanceCo-dominance► The A and B alleles are The A and B alleles are codominantcodominant with each with each

other. other.

► When a person has both an When a person has both an IIAA and a and a I IB B allele, allele,

the person has AB blood type.the person has AB blood type.

► When two persons with AB blood type have When two persons with AB blood type have

children, the children can be type A, type B, children, the children can be type A, type B,

or type AB. or type AB.

► There is a There is a 1A:2AB:1B phenotype ratio1A:2AB:1B phenotype ratio instead instead

of the 3:1 phenotype ratio found when one of the 3:1 phenotype ratio found when one

allele is dominant and the other is recessive. allele is dominant and the other is recessive.

Co-dominanceCo-dominance► In the ABO blood group both types of In the ABO blood group both types of

antigens are expressed on the surface antigens are expressed on the surface of the red blood cells, meaning that of the red blood cells, meaning that both alleles result in an effective both alleles result in an effective product.product.

The AB phenotype is less The AB phenotype is less frequent frequent

► If the Rhesus blood groups are added, If the Rhesus blood groups are added, the less frequent type is AB negative the less frequent type is AB negative (0.5%)(0.5%)

Co- dominanceCo- dominance

► Another normal trait which shows this type of Another normal trait which shows this type of

inheritance is represented by the inheritance is represented by the MN blood MN blood

groupgroup, where both alleles are fully expressed , where both alleles are fully expressed

in the phenotypein the phenotype

► This trait is inherited linked to another This trait is inherited linked to another

erythrocytic antigen S/s erythrocytic antigen S/s (dominant/ recessive) (dominant/ recessive)

► The proteins coded are :The proteins coded are :glycophoringlycophorin A in case A in case

of M and N and of M and N and glycophoringlycophorin B responsible for B responsible for

S and sS and s

Co- dominanceCo- dominance

► The MNS locus (= GYP) consists of The MNS locus (= GYP) consists of three closely linked genes on 4 q28-three closely linked genes on 4 q28-q31: q31:

5’-GYPA–GYPB-GYPE–3’5’-GYPA–GYPB-GYPE–3’► GYPA controls M and N antigensGYPA controls M and N antigens► GYPB controls S and sGYPB controls S and s► GYPE is not responsible for antigens GYPE is not responsible for antigens

on erythrocyteson erythrocytes► The three genes (each of about 30 The three genes (each of about 30

kb) show a high degree of sequence kb) show a high degree of sequence homology: almost 95 %homology: almost 95 %

Co- dominanceCo- dominance► The two different versions (alleles) of a gene are The two different versions (alleles) of a gene are

expressed, and each version makes a slightly expressed, and each version makes a slightly

different protein; as in the above different protein; as in the above illustration: GPA : GPA

as type M or Nas type M or N

► Both alleles influenceBoth alleles influence the genetic trait or determine the genetic trait or determine

the characteristics of the genetic condition the characteristics of the genetic condition

► Most molecular markers are considered to be Most molecular markers are considered to be

codominantcodominant


► Genes which result in the premature Genes which result in the premature

death of the organism = LETHAL death of the organism = LETHAL

GENESGENES

► DominantDominant lethal genes kill lethal genes kill

heterozygotes and homozygotesheterozygotes and homozygotes, ,

whereas whereas recessiverecessive lethal genes kill lethal genes kill

only homozygotesonly homozygotes. .


► Lethal genes cause the death of the Lethal genes cause the death of the

organisms that carry them. Sometimes, organisms that carry them. Sometimes,

death is not immediate; it may even take death is not immediate; it may even take

years, depending on the years, depending on the genegene. .

► In any case, if a In any case, if a mutationmutation results in results in

lethality, then this is indicative that the lethality, then this is indicative that the

affected affected genegene has a fundamental has a fundamental functionfunction

in the growth, in the growth, developmentdevelopment, and survival of , and survival of

an an organismorganism


► Another definition: A gene that in some Another definition: A gene that in some

(as homozygous) conditions may prevent (as homozygous) conditions may prevent

development or cause the death of an development or cause the death of an

organism or its germ cellsorganism or its germ cells -- called also -- called also

lethal factor, lethal mutant, lethal lethal factor, lethal mutant, lethal

mutationmutation

► Lethal genes can be Lethal genes can be recessiverecessive, , dominantdominant, ,

conditional, semi-lethal, or synthetic, conditional, semi-lethal, or synthetic,

depending on the depending on the genegene or genes involved or genes involved

Lethal Genes Lethal Genes ► At the beginning of the 20At the beginning of the 20thth century Cuénot and century Cuénot and

Baur discovered the first Baur discovered the first recessiverecessive lethal genes lethal genes because these altered Mendelian inheritance because these altered Mendelian inheritance ratios in their animal models.ratios in their animal models.

► Examples of human diseases caused by Examples of human diseases caused by recessiverecessive

lethal alleles include cystic fibrosis, lethal alleles include cystic fibrosis,

Tay-Sachs disease, , sickle-cell anemia. sickle-cell anemia.

► Achondroplasia is an autosomal Achondroplasia is an autosomal dominantdominant bone bone

disorder that causes dwarfism. While the disorder that causes dwarfism. While the

inheritance of one achondroplasia inheritance of one achondroplasia alleleallele can cause can cause

the the diseasedisease, the inheritance of , the inheritance of two alleles is fatal.two alleles is fatal.

Dominant Lethal Genes Dominant Lethal Genes ► DominantDominant lethal genes are expressed in both homozygotes and lethal genes are expressed in both homozygotes and

heterozygotes. heterozygotes.

► But how can alleles like this be passed from one But how can alleles like this be passed from one generation to the next if they cause death?generation to the next if they cause death?

► DominantDominant lethal genes are rarely detected due to their rapid lethal genes are rarely detected due to their rapid

elimination from populations. elimination from populations.

► One example of a One example of a diseasedisease caused by a caused by a dominantdominant lethal allelelethal allele is is

Huntington's Huntington's diseasedisease, which reduces life expectancy. Because , which reduces life expectancy. Because

the onset of the onset of Huntington's disease is slow, individuals carrying is slow, individuals carrying

the the alleleallele can pass it on to their can pass it on to their offspringoffspring. .

► This allows the This allows the alleleallele to be maintained in the to be maintained in the populationpopulation. .

► DominantDominant traits can also be maintained in the traits can also be maintained in the populationpopulation

through recurrent mutations beside the through recurrent mutations beside the low low of the of the genegene (less (less

than 100%), like in Huntington’s choreathan 100%), like in Huntington’s chorea..

Conditional Lethal Genes Conditional Lethal Genes

► FavismFavism is a sex-linked, inherited condition is a sex-linked, inherited condition that results from deficiency in an that results from deficiency in an enzymeenzyme called glucose-6-phosphate dehydrogenase. called glucose-6-phosphate dehydrogenase.

► It is most common among people of It is most common among people of Mediterranean, African, Southeast Asian, and Mediterranean, African, Southeast Asian, and Sephardic Jewish descent (Allison, 1960).Sephardic Jewish descent (Allison, 1960).

► The The diseasedisease was named because when was named because when affected individuals eat fava beans, they affected individuals eat fava beans, they develop develop hemolytic anemiahemolytic anemia, a condition in , a condition in which red blood cells break apart and block which red blood cells break apart and block blood vessels. Blockage can cause kidney blood vessels. Blockage can cause kidney failure and result in failure and result in deathdeath (Bowman & Walker, (Bowman & Walker, 1961).1961).

► Affected individuals may also develop anemia Affected individuals may also develop anemia when administered therapeutic doses of anti-when administered therapeutic doses of anti-malaria medications and other drugs. malaria medications and other drugs.

ConditionalConditional Lethal Genes Lethal Genes

► Note, however, that the defective glucose-6-phosphate Note, however, that the defective glucose-6-phosphate

dehydrogenase dehydrogenase alleleallele only causes death only causes death under certain under certain

conditions, which makes it a conditions, which makes it a conditional lethal conditional lethal

genegene. .

► But why would this But why would this alleleallele be so common? The be so common? The

interesting thing about individuals with the favism interesting thing about individuals with the favism alleleallele

is that they are is that they are resistant to malariaresistant to malaria, because it is more , because it is more

difficult for malaria parasites to multiply in cells with difficult for malaria parasites to multiply in cells with

deficient amounts of glucose-6-phosphate deficient amounts of glucose-6-phosphate

dehydrogenase. Therefore, carrying the dehydrogenase. Therefore, carrying the alleleallele for favism for favism

confers an intrinsic genetic or confers an intrinsic genetic or adaptive advantageadaptive advantage by by

protecting individuals from contracting malaria.protecting individuals from contracting malaria.

ConditionalConditional Lethal Genes Lethal Genes► Conditional lethal genes can also be expressed due Conditional lethal genes can also be expressed due

to specific circumstances, such as to specific circumstances, such as temperaturetemperature. . ► For example, a For example, a mutantmutant proteinprotein may be may be genetically genetically

engineeredengineered to be fully functional at 30°C and to be fully functional at 30°C and completely inactive at 37°C. Meanwhile, the completely inactive at 37°C. Meanwhile, the wild-wild-typetype proteinprotein is fully functional at both is fully functional at both temperatures.temperatures.

► The condition in which the The condition in which the mutantmutant phenotypephenotype is is expressed is termed expressed is termed non-permissivenon-permissive, while the , while the condition in which the condition in which the wild-typewild-type phenotypephenotype is is expressed is called expressed is called permissivepermissive. .

► In order to study a conditional lethal In order to study a conditional lethal mutantmutant, the , the organismorganism must be maintained under must be maintained under permissive conditions and then switched to the non-permissive condition during the permissive conditions and then switched to the non-permissive condition during the course of a specific experiment. By developing a conditional lethal version of a course of a specific experiment. By developing a conditional lethal version of a dominantdominant lethal lethal genegene, scientists can study and maintain organisms carrying , scientists can study and maintain organisms carrying dominantdominant lethal lethal alleles alleles

Synthetic LethalSynthetic Lethal► Two genes are synthetic lethal if Two genes are synthetic lethal if mutationmutation of either of either

alone is compatible with viability but mutation alone is compatible with viability but mutation of of both leads to deathboth leads to death. .

► So, targeting a gene that is synthetic lethal to a So, targeting a gene that is synthetic lethal to a cancer-relevant mutation should cancer-relevant mutation should kill only cancer kill only cancer cellscells and spare normal cells. and spare normal cells.

► Synthetic lethality therefore provides a conceptual Synthetic lethality therefore provides a conceptual framework for the development of cancer-specific framework for the development of cancer-specific cytotoxic agents. cytotoxic agents.

► This paradigm has not been exploited in the past This paradigm has not been exploited in the past because there were no robust methods for because there were no robust methods for systematically identifying synthetic lethal genes. systematically identifying synthetic lethal genes.

► This is changing as a result of the increased This is changing as a result of the increased availability of chemical and genetic tools for availability of chemical and genetic tools for perturbing gene function in somatic cells perturbing gene function in somatic cells

Semi-lethal or Sub-lethal GenesSemi-lethal or Sub-lethal Genes

►HemophiliaHemophilia is a hereditary is a hereditary diseasedisease

caused by caused by deficiencies in clotting factorsdeficiencies in clotting factors, ,

which results in impaired blood clotting which results in impaired blood clotting

and coagulation.and coagulation.

► Because the Because the alleleallele responsible for responsible for

hemophilia is carried on the X hemophilia is carried on the X

chromosomechromosome, affected individuals are , affected individuals are

predominantly predominantly malesmales, and they , and they inheritinherit the the

alleleallele from their mothers from their mothers. .

HemophiliaHemophilia

► Normally, clotting factors help form a temporary Normally, clotting factors help form a temporary

scab after a blood vessel is injured to prevent scab after a blood vessel is injured to prevent

bleeding, but hemophiliacs cannot heal properly bleeding, but hemophiliacs cannot heal properly

after injuries because of their after injuries because of their low levels of blood low levels of blood

clotting factorsclotting factors. .

► Therefore, affected individuals Therefore, affected individuals bleedbleed for a longer for a longer

period of time until clotting occurs. period of time until clotting occurs.

► This means that normally This means that normally minor wounds can be minor wounds can be

fatalfatal in a person with hemophilia. in a person with hemophilia.

Semi-lethal or Sub-lethal Semi-lethal or Sub-lethal GenesGenes

►The alleles responsible for The alleles responsible for

hemophiliahemophilia are thus called are thus called semi-semi-

lethallethal or sub-lethal genes, or sub-lethal genes,

because they cause the death of because they cause the death of

only only somesome of the individuals or of the individuals or

organisms with the affected organisms with the affected

genotypegenotype..

LETHAL ALLELESLETHAL ALLELES

► They They differ in the developmental stage at differ in the developmental stage at

which they express their effects.which they express their effects.

► Human lethals illustrate this very well: Human lethals illustrate this very well: we we

are all estimated to be heterozygous for a are all estimated to be heterozygous for a

small number of recessive lethals in our small number of recessive lethals in our

genomes. genomes.

► The lethal effect is expressed in the The lethal effect is expressed in the

homozygoushomozygous progeny of a mating between progeny of a mating between

two people who by chance carry the same two people who by chance carry the same

recessive lethal in the heterozygous recessive lethal in the heterozygous

conditioncondition. .

LETHAL ALLELESLETHAL ALLELES► Some lethals are expressed as Some lethals are expressed as deaths deaths in in

uteroutero, where they either go , where they either go unnoticedunnoticed or are or are noticed as noticed as spontaneous abortionsspontaneous abortions. .

► Other lethals, such as those responsible for Other lethals, such as those responsible for Duchenne/Becker muscular dystrophy, cystic Duchenne/Becker muscular dystrophy, cystic fibrosis, or Tay-Sachs diseasefibrosis, or Tay-Sachs disease, exert their , exert their effects in effects in childhoodchildhood. .

► The time of death can even be in The time of death can even be in adulthoodadulthood, , as in as in Huntington diseaseHuntington disease. .

► The total of all the deleterious and lethal genes The total of all the deleterious and lethal genes that are present in individual members of a that are present in individual members of a population is called population is called genetic loadgenetic load,, a kind of a kind of genetic burden that the population has to carrygenetic burden that the population has to carry

Exactly what goes wrong in lethal Exactly what goes wrong in lethal mutations?mutations?

► In many cases, it is possible to trace the cascade of In many cases, it is possible to trace the cascade of

events that leads to death. events that leads to death.

► A common situation is that the allele causes A common situation is that the allele causes a a

deficiency in some essential chemical reactiondeficiency in some essential chemical reaction. The . The

human diseases human diseases PKUPKU (phenylketonuria) and (phenylketonuria) and cystic cystic

fibrosis fibrosis are good examples of this kind of are good examples of this kind of

deficiency. deficiency.

► In other cases, there is In other cases, there is a structural defecta structural defect. For . For

example, a lethal allele is expressed phenotypically example, a lethal allele is expressed phenotypically

in several different organs, resulting in lethal in several different organs, resulting in lethal

symptoms. Sickle-cell anemia, is an example.symptoms. Sickle-cell anemia, is an example.

►OVERALL... much is still being learned OVERALL... much is still being learned about genetics -- it is not as simple as we about genetics -- it is not as simple as we once thought -- but the principles above are once thought -- but the principles above are generally true.generally true.

Lethal…semi-lethal…..sub-

lethal….conditional……is there a

difference?

Electrophoresis of hemoglobin from a person with sickle-cell anemia, a heterozygote (called sickle-cell trait), and a normal person. The smudges show the positions to which the hemoglobins migrate on the starch gel

Despite the 3 phenotypes, which can be proven in the lab, usually the sickle cell trait is considered recessive in pathology!

Thus explaining the inheritance of the disease!

Still biologists use the term “intermediate inheritance”, that describes the presence of 3 distinct phenotypes in the laboratory findings.

►Often, evolution is not totally Often, evolution is not totally straightforward in practice.... straightforward in practice....

►One example in humans: One example in humans: Malaria and Malaria and sickle-cell anemia. sickle-cell anemia.

►This is actually a This is actually a balanced balanced polymorphismpolymorphism, where natural selection , where natural selection is working in two opposite directions is working in two opposite directions at once, which holds the different at once, which holds the different allele frequencies in balance... instead allele frequencies in balance... instead of gradually eliminating one!of gradually eliminating one!

Normal red blood cells and a sickle Normal red blood cells and a sickle cell.cell.

(diagnosis: sickle cell anemia)(diagnosis: sickle cell anemia)Under special conditions (low oxygen pressure) the normal cells might prove the carrier state!

HbA/HbS

Plasmodium falciparum does not ‘enjoy’ either cells: of the homozygous, ill person (SS) or the (AS) heterozygous/carrier one.

► Hemoglobin molecules in the red blood cells carry oxygen to Hemoglobin molecules in the red blood cells carry oxygen to

the body's tissues.the body's tissues.

► Alleles for hemoglobin:Alleles for hemoglobin:

► A for normal Hb --> normal cellsA for normal Hb --> normal cells

► S for hemoglobin that doesn't carry as much oxygen, and S for hemoglobin that doesn't carry as much oxygen, and

which crystallizes inside the red blood cell, causing it to which crystallizes inside the red blood cell, causing it to

become sickle-shaped. become sickle-shaped.

► These sickled cells are fragile, can't carry much oxygen, and These sickled cells are fragile, can't carry much oxygen, and

can't get down the tiny capillary blood vessels to the body's can't get down the tiny capillary blood vessels to the body's

tissues.... resulting in pain, anemia, general disability, andtissues.... resulting in pain, anemia, general disability, and if if

left untreated, early death.left untreated, early death.

► If a person has If a person has one copy one copy of Hb (S), they can be quite fine, of Hb (S), they can be quite fine,

being a being a carriercarrier, showing occasional sickle-like cells, but not , showing occasional sickle-like cells, but not

suffering from sickle crisis and most of them have only very suffering from sickle crisis and most of them have only very

mildmild signs and symptoms. signs and symptoms.

► If they have If they have two copies two copies of Hb(S), they are usually very ill.of Hb(S), they are usually very ill.

Die

Selected

Die

So why hasn't the gene for sickle cell simply So why hasn't the gene for sickle cell simply vanished over time due to natural selection vanished over time due to natural selection

working against it?working against it?

► Because in one circumstance, it's actually an ADVANTAGE to have one Because in one circumstance, it's actually an ADVANTAGE to have one

copy of Hb(S): in areas with a high prevalence of copy of Hb(S): in areas with a high prevalence of malariamalaria..

► The malaria parasite (a protozooan, genus The malaria parasite (a protozooan, genus PlasmodiumPlasmodium) is transmitted by ) is transmitted by

mosquitoes, and lives in the red blood cells, where it obtains the oxygen mosquitoes, and lives in the red blood cells, where it obtains the oxygen

that it needs to live. that it needs to live.

► Malaria can be Malaria can be fatal, and often hits children (i.e. before reproductive age).fatal, and often hits children (i.e. before reproductive age).

► The Plasmodium can't live in sickle cells! So... if you have The Plasmodium can't live in sickle cells! So... if you have somesome sickled sickled

cells... your malaria infection isn't as bad as if you have all normal red cells... your malaria infection isn't as bad as if you have all normal red

blood cells!blood cells!

► So the effects of sickle cell anemia push the population's Hb alleles in one So the effects of sickle cell anemia push the population's Hb alleles in one

direction, while the effects of malaria push the population's Hb alleles in direction, while the effects of malaria push the population's Hb alleles in

the other direction.the other direction.

Whether an allele is lethal or not often Whether an allele is lethal or not often depends on the environment depends on the environment in which in which

the organism developsthe organism develops► Whereas certain alleles are lethal in virtually Whereas certain alleles are lethal in virtually

any environment, others are viable in one any environment, others are viable in one environment but lethal in another. environment but lethal in another.

► For example, the human hereditary diseases For example, the human hereditary diseases cystic fibrosiscystic fibrosis and and PKUPKU are diseases that are diseases that would be lethal without would be lethal without treatmenttreatment. .

► Furthermore, many of the alleles favored and selected Furthermore, many of the alleles favored and selected by animal and plant breeders would almost certainly by animal and plant breeders would almost certainly be eliminated in nature as a result of competition with be eliminated in nature as a result of competition with the members of the natural population. Modern grain the members of the natural population. Modern grain varieties provide good examples; only careful nurturing varieties provide good examples; only careful nurturing by farmers has maintained such alleles for our benefit.by farmers has maintained such alleles for our benefit.

Lethal and semi-lethal genes► Geneticists commonly encounter situations in which Geneticists commonly encounter situations in which

expected phenotypic ratios are consistently skewed in expected phenotypic ratios are consistently skewed in one direction by reduced viability caused by one allele.one direction by reduced viability caused by one allele.

► For example, in the cross For example, in the cross AA//aa × × aa//aa, we predict a , we predict a progeny ratio of:progeny ratio of: 50% 50% AA//aa and and 50 % 50 % aa//aa, ,

► but we might consistently observe a ratio such asbut we might consistently observe a ratio such as 55 %: 45 % or 55 %: 45 % or 60 %: 40%. 60 %: 40%.

► In such a case, the In such a case, the recessive phenotype is said to be recessive phenotype is said to be sub-vital, or semi-lethal, because the lethality is sub-vital, or semi-lethal, because the lethality is expressed in only some individuals. expressed in only some individuals.

► Thus, lethality may range from 0 to 100 Thus, lethality may range from 0 to 100 percent, depending on the gene itself, the rest percent, depending on the gene itself, the rest of the genome, and the environment.of the genome, and the environment.

Cystic fibrosis►Is an autosomal recessive disorder

►It is due to mutations in the CFTR gene(= cystic fibrosis transmembrane

regulatory gene)The gene is large (over 250kb)

consisting of 27 exons encoding a 6.5 kb transcript with several alternatively spliced forms of mRNA.

Cystic fibrosis – clinical aspects

► The disease primarly affects:► the bronchial system► the gastrointestinal tract

► It is severe, progressive with formation of viscous mucus, leading to frequent, recurrent bronchopulmonic infections

► Average life expectancy in typical CF is about 30 years

► The high frequency of heterozygotes (1:25) is thought to result from a selective advantage: they have reduced liability to epidemic diarrhea as for example in cholera

Cystic fibrosis

Multiple allelism Multiple allelism ► A gene can have several different states or A gene can have several different states or

forms—called multiple allelesforms—called multiple alleles. .

► The alleles are said to constitute an The alleles are said to constitute an allelic seriesallelic series, ,

and the members of a series can show various and the members of a series can show various

degrees of dominance to one another.degrees of dominance to one another.

► As examples (the normal genetic systems studied) the As examples (the normal genetic systems studied) the

two erythrocytic enzymes: acid phosphatase and two erythrocytic enzymes: acid phosphatase and

glucose-6-phosphate dehydrogenaseglucose-6-phosphate dehydrogenase..

► Official Symbols:Official Symbols:

ACP1 for acid phosphatase 1, the ACP1 for acid phosphatase 1, the gene being located on gene being located on 2p252p25

G6PD glucose-6-phosphate G6PD glucose-6-phosphate dehydrogenase; Gene map locus: dehydrogenase; Gene map locus: Xq28

ACID PHOSPHATASE 1 ACID PHOSPHATASE 1 ► Hopkinson et al. described in 1963 a new human Hopkinson et al. described in 1963 a new human

polymorphism involving polymorphism involving erythrocyte acid phosphatase erythrocyte acid phosphatase as as

demonstrated in starch-gel demonstrated in starch-gel electrophoresiselectrophoresis. .

► Three alleles: Three alleles: P(a), P(b) and P(c), P(a), P(b) and P(c), are thought to be involved, are thought to be involved,

their frequency being estimated to be 0.35, 0.60 and 0.05, their frequency being estimated to be 0.35, 0.60 and 0.05,

respectively. Another rare allele, respectively. Another rare allele, P(r)P(r), was described by Giblett , was described by Giblett

and Scott (1965). and Scott (1965).

► Dissing and Johnsen (1992) provided evidence for the molecular Dissing and Johnsen (1992) provided evidence for the molecular

basis of the 3 common alleles in Caucasians: basis of the 3 common alleles in Caucasians:

ACP1*A, ACP1*A,

ACP1*B, and ACP1*B, and

ACP1*C, ACP1*C,

which give rise to 6 possible genotypes and which give rise to 6 possible genotypes and

these to 6 phenotypes (A, B, C, AB, AC, and BC). these to 6 phenotypes (A, B, C, AB, AC, and BC). ( so the 3 ( so the 3

alleles are codominant)alleles are codominant)

GLUCOSE-6-PHOSPHATE DEHYDROGENASEGLUCOSE-6-PHOSPHATE DEHYDROGENASE

► G6PD DEFICIENCY causes chronic ANEMIAG6PD DEFICIENCY causes chronic ANEMIA

► Since identification of deficiency of G6PD (Carson et al., Since identification of deficiency of G6PD (Carson et al.,

1956) and of its X-chromosomal determination (Childs et 1956) and of its X-chromosomal determination (Childs et

al., 1958) in the 1950s and demonstration of al., 1958) in the 1950s and demonstration of

electrophoretic variants of this enzyme in the early 1960s electrophoretic variants of this enzyme in the early 1960s

(Boyer et al., 1962), the genetic, clinical and biochemical (Boyer et al., 1962), the genetic, clinical and biochemical

significance of this polymorphism has been found to be significance of this polymorphism has been found to be

great. great. ► G6PD is in the hexose monophosphate pathway, the only NADPH-generation G6PD is in the hexose monophosphate pathway, the only NADPH-generation

process in mature red cells, which lack the citric acid cycle. For this reason G6PD process in mature red cells, which lack the citric acid cycle. For this reason G6PD

deficiency has adverse physiologic effects. deficiency has adverse physiologic effects.


► Deficiency of the red cell enzyme, in various Deficiency of the red cell enzyme, in various

forms, is the basis of forms, is the basis of favismfavism, , primaquine sensitivity primaquine sensitivity

and some other drug-sensitive hemolytic anemias, anemia and and some other drug-sensitive hemolytic anemias, anemia and

jaundice in the newborn, and chronic nonspherocytic hemolytic jaundice in the newborn, and chronic nonspherocytic hemolytic

anemiaanemia

► Different variants of the enzyme are found in Different variants of the enzyme are found in

high frequency in African, Mediterranean and high frequency in African, Mediterranean and

Asiatic populations and heterozygote Asiatic populations and heterozygote

advantage vis-a-vis malaria has been invoked advantage vis-a-vis malaria has been invoked

to account for the high frequency of the to account for the high frequency of the

particular alleles in these populations. particular alleles in these populations.


► The variety of forms of the enzyme is great, as The variety of forms of the enzyme is great, as

illustrated by the published tables (Yoshida and illustrated by the published tables (Yoshida and

Beutler) Beutler)

► The demonstrated The demonstrated polymorphism polymorphism at this X-linked at this X-linked

locus rivals that of the autosomal loci for the locus rivals that of the autosomal loci for the

polypeptide chains of hemoglobin.polypeptide chains of hemoglobin.

► Single amino acid substitution Single amino acid substitution has been demonstrated has been demonstrated

as the basis of the change in the G6PD molecule as the basis of the change in the G6PD molecule

resulting resulting from mutation from mutation (Yoshida et al., 1967).(Yoshida et al., 1967).

Designation of variant Gene’s

short name Mutation type Subtype Structure change Function change

G6PD-A(+) Gd-A(+) Polymorphism nucleotide

A→G Asparagine→

Aspartic acid

No enzyme defect (variant)

G6PD-A(-) Gd-A(-) Substitution nucleotide

G→A Valine→Methionine Asparagine→Aspartic acid

Lower function

G6PD-Mediterran Gd-Med Substitution nucleotide

C→T Serine→Phenylalanine Favism

G6PD-Canton Gd-Canton Substitution nucleotide

G→T Arginine→Leucine

G6PD-Chatham Gd-Chatham Substitution nucleotide

G→A Alanine→Threonine

G6PD-Cosenza Gd-Cosenza Substitution nucleotide

G→A Arginine→Proline

G6PD-Mahidol Gd-Mahidol Substitution nucleotide

G→A Glycine→Serine

G6PD-Orissa Gd-Orissa Substitution nucleotide

Alanine→Glycine

G6PD-Asahi Gd-Asahi Substitution A→G Asparagine→Aspartic acid

Multiple allelism Multiple allelism ► Is the state of having more than two Is the state of having more than two

alternative contrasting characters controlled alternative contrasting characters controlled by multiple alleles at a single genetic locus. by multiple alleles at a single genetic locus.

► E.g. All mutations that cause G6PD E.g. All mutations that cause G6PD deficiency are found on the long arm of the deficiency are found on the long arm of the X chromosome, on band Xq26. , on band Xq26.

► The normal G6PD gene spans some 18.5 The normal G6PD gene spans some 18.5 kilobases being symbolized being symbolized GGddBB. The 9 . The 9 variants and mutations in the table above variants and mutations in the table above are well-known and described. are well-known and described.

What are gene families?What are gene families?

► A gene family is a group of genes that share A gene family is a group of genes that share

important characteristics. important characteristics.

► 1. In many cases, genes in a family share a 1. In many cases, genes in a family share a similar similar

sequence of DNAsequence of DNA building blocks (nucleotides). building blocks (nucleotides).

► These genes provide instructions for making These genes provide instructions for making products products

(such as proteins) that have a (such as proteins) that have a similar structure or similar structure or

functionfunction. .

► 2. In other cases, dissimilar genes are grouped 2. In other cases, dissimilar genes are grouped

together in a family because together in a family because proteins produced from proteins produced from

these genes work togetherthese genes work together as a unit or participate in as a unit or participate in

the same process.the same process.

GENE FAMILIES

►Classifying individual genes into families Classifying individual genes into families

helps researchers describe how genes are helps researchers describe how genes are

related to each other.related to each other.

► Researchers can use gene families Researchers can use gene families to to

predict the predict the functionfunction of newly identified of newly identified

genesgenes based on their similarity to known based on their similarity to known

genes. genes.

► Similarities among genes in a family can also Similarities among genes in a family can also

be used to predict be used to predict where and whenwhere and when a a

specific gene is activespecific gene is active (expressed). (expressed).

►Additionally, gene families may provide Additionally, gene families may provide

clues for clues for identifying genes that are identifying genes that are

involved in particular diseases.involved in particular diseases.

►Sometimes not enough is known about a Sometimes not enough is known about a

gene to assign it to an established family. gene to assign it to an established family.

► In other cases, genes may fit into more In other cases, genes may fit into more

than one family. than one family.

►No formal guidelines define the criteria No formal guidelines define the criteria

for grouping genes together. for grouping genes together.

Classification systems for genes continue Classification systems for genes continue

to evolveto evolve as scientists learn more about as scientists learn more about

the structure and function of genes and the structure and function of genes and

the relationships between them.the relationships between them.

For more information about gene For more information about gene familiesfamilies

► Genetics Home Reference provides Genetics Home Reference provides information about gene families including a brief description of each gene family and a list of the including a brief description of each gene family and a list of the genes included in the family.genes included in the family.

► The The HUGO Gene Nomenclature Committee (HGNC) has classified (HGNC) has classified many human genes into families. Each grouping is given a name many human genes into families. Each grouping is given a name and symbol, and contains a table of the genes in that family.and symbol, and contains a table of the genes in that family.

► The textbook Human Molecular Genetics (second edition, 1999) The textbook Human Molecular Genetics (second edition, 1999) provides background information on provides background information on human gene families ..

► The The Gene Ontology database lists the protein products of genes by database lists the protein products of genes by their location within the cell (cellular component), biological their location within the cell (cellular component), biological process, and molecular function.process, and molecular function.

► The The Reactome database classifies the protein products of genes database classifies the protein products of genes based on their participation in specific biological pathways. For based on their participation in specific biological pathways. For example, this resource provides tables of genes involved in example, this resource provides tables of genes involved in controlled cell death (apoptosis), cell division, and DNA repair.controlled cell death (apoptosis), cell division, and DNA repair.

► http://ghr.nlm.nih.gov/geneFamily

Blood group gene family► Blood is classified into different groups according to the

presence or absence of molecules called antigens on the surface of every red blood cell in a person's body.

► The genes that provide instructions for making the antigens are known as blood group determining genes.

► Antigens determine blood type and can either be proteins or complexes of sugar molecules (polysaccharides).

► Blood group proteins, which carry antigens, serve a variety of functions within the cell membrane of red blood cells. These protein functions include: transporting other proteins and molecules into and out of the cell, maintaining cell structure, attaching to other cells and molecules and participating in chemical reactions.

Blood group gene family► Blood group antigens play a role in recognizing foreign

cells in the bloodstream. ► For example, if a person with blood type A receives a

blood transfusion with blood type B, the recipient's immune system will recognize the type B cells as foreign and mount an immune response. Antibodies against type B blood cells (anti-B antibodies) are made, which attack and destroy the type B blood cells.

► This sort of blood type mismatch can lead to illness. ► Some blood types are associated with more severe

immune reactions than others (Rh)► The blood type of donated cells, or tissues in the case

of organ donation, is checked before being given to a recipient in order to prevent this immune response.

Blood group gene family

► There are 29 recognized blood groups, most involving

only one gene (pair), like Xg.

► Variations (polymorphisms) within the genes that determine blood

group give rise to the different antigens for a particular blood

group protein. For example, changes in a few DNA building blocks

(nucleotides) in genes give rise to the A, B, and 0 blood types.

► The changes that occur in the genes that determine blood groups

typically affect only the blood type and are not associated with

adverse health conditions, although exceptions do occur (Rh-

mothers having a second Rh+ conception product).

► Erythrocytic non-enzymatic genetic systems which belong here

are beside ABO, Rh and Xg, the glycophorins A and B.

► Another gene family is that of the globins.

C. Relations between GenesI. Between Alleles

Dominance – recessiveness Co-dominanceLethal and semi-lethal genesPoly-allelismGene families

II. Between Non-allelesEpistasisGenetic heterogeneity

D. Correlation Genotype–Phenotype-Environment D. Correlation Genotype–Phenotype-Environment

InfluencesInfluences

PleiotropyPleiotropy

Polygenic – Multifactorial InheritancePolygenic – Multifactorial Inheritance

GenomicGenomic imprinting

EpistasisEpistasis

► EpistasisEpistasis occurs when the alleles of one occurs when the alleles of one gene (e.g. H) cover up or alter the gene (e.g. H) cover up or alter the expression of alleles of another gene (I). expression of alleles of another gene (I).

► Some genes mask the expression of other Some genes mask the expression of other genes (e.g. h/h) genes (e.g. h/h) just asjust as a fully dominant a fully dominant allele masks the expression of its recessive allele masks the expression of its recessive counterpart. counterpart.

► A gene that masks the phenotypic effect of A gene that masks the phenotypic effect of another gene is called an epistatic gene; another gene is called an epistatic gene; the gene it subordinates is the the gene it subordinates is the hypostatic hypostatic genegene..

► In the following example H/h are epistatic, while IA/IB/i are hypostatic.

Fucosyltransferase 1 Fucosyltransferase 1 also known as also known as FUT1FUT1

couples L-fucose to the precursor in the couples L-fucose to the precursor in the

erythrocytic membrane, when there is at erythrocytic membrane, when there is at

least one allele H on chromosome 19q, the least one allele H on chromosome 19q, the

H antigen being thus formed.H antigen being thus formed.

H/H or

H/hThis is the H antigen on the membrane of the red blood cells of H/H and H/h

h is the FUT1 gene with a point mutation (T725); H is dominant and h is recessive;

in case of the h/h, recessive homozygote the transferase is not synthesized, so that L-fucose is not going to be coupled to the precursor and thus no H

antigen is built up!

Precursor on the membrane

If on 9q there is at least one gene IB, D – galactose-transferase is synthesized and in the presence of at least one H, D – Galactose couples to the H antigen building up the B antigen of the B blood group.

Gene on chromosome

19q 9q

The FUT1 (H) gene is expressed predominantly in erythroid tissues whereas the FUT2 (Se) gene is expressed predominantly in secretory

tissues. When alleles of both genes are recessive (h and se, respectively), individuals bearing them, in homozygous state, lack the substrates for the A or B transferases and do not express the A and B

antigens.

If on 9q there is at least one IA then N- acetyl-galactosamine-transferase is synthesized

N- acetylgalactosamine transforms the H antigen into A

No A or B antigen can be built up!

If h/h or se/se on 19q, even if on the chromosome 9q there is an IA /IB the blood group is still O, the so called “apparent” O or Bombay phenotype

‘true”O true”O

blood blood

groupgroup

i = I o

The alleles on 19q control the activity of the alleles on 9q: h/h

individuals do not express on their erythrocytes the A or B antigen,

maybe because they lack the L- fucose (no antigen

H)

If a person is H/H or H/h and has an i/i combination on chromosome 9, the blood group If a person is H/H or H/h and has an i/i combination on chromosome 9, the blood group

is O, also called “true” O, having on the erythrocytes the H antigen.is O, also called “true” O, having on the erythrocytes the H antigen.

Notes ► Chromosomal location: 19 q13.3 for FUT1 and FUT2, which are 35kb apart, in

the same orientation, namely, Cent-FUT2-FUT1-Ter;

► Primary gene products of functional alleles are closely homologous alpha 1,2 fucosyltransferases that use nearly identical substrates but are expressed in different tissues. Their products serve as substrates for the glycosyltransferases that result in epitopes for the A and B blood group antigens; in addition, the product of FUT2 is a precursor of epitopes resulting in antigens of the Lewis blood group system. Although their precise function is still not known,the fucosylated glycans that are the products of FUT1 and FUT2 may serve as ligands in cell adhesion or as receptors for certain microorganisms.

► FUT1 product is expressed predominantly in erythoid tissues, vascular endothelium and primary sensory neurons of peripheral nervous system; the product of FUT2 is expressed in saliva and other exocrine secretions, and in epithelia.

► Expression of the antigens is known to undergo changes during development, differentiation and maturation.

► Aberrant expression is often observed in human pre-malignant and malignant cells.

ReminderReminder

► Human blood type is determined by three Human blood type is determined by three different alleles, known as Idifferent alleles, known as IAA, I, IBB, and i. The I, and i. The IAA and I and IB B

alleles are codominant, and the i allele is alleles are codominant, and the i allele is recessive. recessive.

► The possible human phenotypes for blood group The possible human phenotypes for blood group are type A, type B, type AB, and type O. Type A are type A, type B, type AB, and type O. Type A and B individuals can be either homozygous (Iand B individuals can be either homozygous (IAAIIAA or Ior IB B IIBB, respectively), or heterozygous (I, respectively), or heterozygous (IAAi or Ii or IBBi, i, respectively). respectively).

► A woman with type A blood and a man with type B A woman with type A blood and a man with type B blood could potentially have offspring with which blood could potentially have offspring with which of the following blood types? A, B, AB and/or O.of the following blood types? A, B, AB and/or O.

QUIZ

Which are the possibilities of alleles on chromosome 19 in each case?

EpistasisEpistasis: absence of expected phenotype as a result : absence of expected phenotype as a result of masking expression of one gene pair by the of masking expression of one gene pair by the expression of another gene pair. expression of another gene pair. The homozygous recessive condition masks the effect The homozygous recessive condition masks the effect of a dominant allele at another locus. of a dominant allele at another locus.

Genetic heterogeneityGenetic heterogeneity

► The phenomenon that a single disorder may be The phenomenon that a single disorder may be caused by different allelic or non-allelic caused by different allelic or non-allelic mutationsmutations. .

► For example, there are mutant genes that in the For example, there are mutant genes that in the homozygous state produce profound deafness in homozygous state produce profound deafness in humans. One would expect that the children of two humans. One would expect that the children of two persons with such hereditary deafness would be deaf. persons with such hereditary deafness would be deaf. This is frequently not the case, because the This is frequently not the case, because the parents’ parents’ deafness is often caused by different genesdeafness is often caused by different genes. Since the . Since the mutant genes are not alleles, mutant genes are not alleles, the child becomes the child becomes heterozygous for the two non-allelic genes and hears heterozygous for the two non-allelic genes and hears normallynormally. In other words, the two mutant genes . In other words, the two mutant genes complementcomplement each other in the child. each other in the child.

► So, this is another form of interaction between So, this is another form of interaction between nonallelic genes. nonallelic genes.

Genetic HeterogeneityGenetic Heterogeneity- - definition from Online Medical Dictionarydefinition from Online Medical Dictionary

► The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees/ the same family tree (next).

► In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including Alzheimer's Disease, Cystic Fibrosis, and Polycystic Kidney Disease.

The affected persons are deaf and muteThe affected persons are deaf and mute

aa/ BB AA/ bb

Children in generation IV are normal, being in the genotype double heterozygotes: Aa/Bb

Correlation Genotype–Phenotype-

Environment Influences

Pleiotropy

► a single gene exerts an effect on many aspects of a single gene exerts an effect on many aspects of

an individual's phenotype. an individual's phenotype.

► The phenomenon whereby a single The phenomenon whereby a single

mutation affects several apparently mutation affects several apparently

unrelated aspects of the phenotypeunrelated aspects of the phenotype

► The control by a single gene of several distinct

and seemingly unrelated phenotypic effects.

Pleiotropism

► For example in MARFAN’s SYNDROME, a For example in MARFAN’s SYNDROME, a mutant gene is unable to code for mutant gene is unable to code for production of a normal protein, production of a normal protein, fibrillinfibrillin. .

► This results in the This results in the inability to produce inability to produce normal connective tissuenormal connective tissue..

► Individuals with Marfan syndrome tend to Individuals with Marfan syndrome tend to be tall and thin with long legs, arms, and be tall and thin with long legs, arms, and fingers; are nearsighted; and the wall of fingers; are nearsighted; and the wall of their aorta is weak. their aorta is weak.

► From this view Abraham Lincoln may have From this view Abraham Lincoln may have had Marfan syndromehad Marfan syndrome

What is Marfan syndrome?What is Marfan syndrome?

Marfan syndrome is a disorder of the connective tissue. Marfan syndrome is a disorder of the connective tissue.

► Connective tissue provides strength and flexibility to Connective tissue provides strength and flexibility to

structures throughout the body such as bones, ligaments, structures throughout the body such as bones, ligaments,

muscles, the walls of blood vessels, and heart valves.muscles, the walls of blood vessels, and heart valves.

► Marfan syndrome affects most organs and tissues, Marfan syndrome affects most organs and tissues,

especially the skeleton, lungs, eyes, heart, and the large especially the skeleton, lungs, eyes, heart, and the large

blood vessel that distributes blood from the heart to the blood vessel that distributes blood from the heart to the

rest of the body (the aorta). rest of the body (the aorta).

► The signs and symptoms of Marfan syndrome The signs and symptoms of Marfan syndrome vary widely vary widely

in severity, timing of onset, and rate of progressionin severity, timing of onset, and rate of progression. .

► Affected individuals often are tall and slender, have Affected individuals often are tall and slender, have

elongated fingers and toes (arachnodactyly), and have an elongated fingers and toes (arachnodactyly), and have an

arm span that exceeds their body height.arm span that exceeds their body height.

Arachnodactyly

Marfan syndromeMarfan syndrome► Most people with Marfan syndrome have Most people with Marfan syndrome have

abnormalities of the heart and the aorta.abnormalities of the heart and the aorta.► Leaks in valves that control blood flow through the Leaks in valves that control blood flow through the

heart can cause shortness of breath, fatigue, and heart can cause shortness of breath, fatigue, and an irregular heartbeat felt as skipped or extra beats an irregular heartbeat felt as skipped or extra beats (palpitations).(palpitations).

► If leakage occurs, it usually affects the mitral valve, If leakage occurs, it usually affects the mitral valve, which connects two chambers of the heart, or the which connects two chambers of the heart, or the aortic valve, which regulates blood flow from the aortic valve, which regulates blood flow from the heart into the aorta. heart into the aorta.

► The aorta can weaken and stretch, which may lead The aorta can weaken and stretch, which may lead to a bulge in the blood vessel wall to a bulge in the blood vessel wall (an aneurysm).(an aneurysm).

► Stretching of the aorta may cause the aortic valve Stretching of the aorta may cause the aortic valve to leak, which can lead to a sudden tearing of the to leak, which can lead to a sudden tearing of the layers in the layers in the aorta wall aorta wall (aortic dissection). (aortic dissection).

► Aortic aneurysm and dissection can be life Aortic aneurysm and dissection can be life threatening.threatening.

What gene is related to Marfan What gene is related to Marfan syndrome?syndrome?

► Mutations in the FBN1 gene cause Marfan syndrome. Mutations in the FBN1 gene cause Marfan syndrome.

► The FBN1 gene provides instructions for making a The FBN1 gene provides instructions for making a

protein called fibrillin-1. protein called fibrillin-1. ► Fibrillin-1 binds to itself and other proteins and molecules to Fibrillin-1 binds to itself and other proteins and molecules to

form threadlike filaments called form threadlike filaments called microfibrils.microfibrils. ► Microfibrils become part of the fibers that provide strength Microfibrils become part of the fibers that provide strength

and flexibility to connective tissue.and flexibility to connective tissue.► Additionally, microfibrils hold molecules called growth Additionally, microfibrils hold molecules called growth

factors and release them at the appropriate time to control factors and release them at the appropriate time to control the growth and repair of tissues and organs throughout the the growth and repair of tissues and organs throughout the body. body.

► A mutation in the FBN1 gene can reduce the amount and/or A mutation in the FBN1 gene can reduce the amount and/or

quality of fibrillin-1 that is available to form microfibrils.quality of fibrillin-1 that is available to form microfibrils.

► As a result, growth factors are released inappropriately, As a result, growth factors are released inappropriately,

causing the characteristic features of Marfan syndrome.causing the characteristic features of Marfan syndrome.

Because FBN 1 is active in many cells of the

body, the syndrome associates abnormalities in

different organs.

Bone anomalies dislocated lensdislocated lens

Heart valve anomaly Aortic dissectionAortic dissection

deathdeath

Marfan syndromeMarfan syndrome► This condition is inherited in an This condition is inherited in an

autosomal dominant pattern, autosomal dominant pattern, which means one copy of the which means one copy of the altered gene in each cell is altered gene in each cell is sufficient to cause the disorder.sufficient to cause the disorder.

► At least 25 percent of classic At least 25 percent of classic Marfan syndrome cases result Marfan syndrome cases result from a from a new mutationnew mutation in the FBN1 in the FBN1 gene. These cases occur in people gene. These cases occur in people with no history of the disorder in with no history of the disorder in their family.their family.

► Beside pleiotropy the syndrome Beside pleiotropy the syndrome also shows variable expressivity in also shows variable expressivity in families.families.

What ever you want to do……stop it!

Learn or at least remember that

Gene Characteristics

Documents

homozygous aa

aa homozygotes100

aa heterozygotes100

heterozygous aa genotypes

aa homoheterozygotes100

aa homo heterozygotes75

aa homo heterozygotes50

homozygous dominant