inheritance (i)

8/3/2019 Inheritance (I)

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Inheritance

Dr. Zeyad Akawi Jreisat, M.D., M.A., Ph.D.


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AUG TAAIntro

n

Exon

mRNA

Protein

Transcription

Translation


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Chromosomal Theory of Inheritance

Chromosomes contain the genetic material that istransmitted from cell to cell and from parent tooffspring

Chromosomes are replicated and passed along

generation after generation from parent to offspring. The nuclei of most eukaryotic cells contain

chromosomes that are found in homologous pairs.

During gamete formation, different types of

chromosomes segregate independently of eachother.

Each parent contributes one set of chromosomes toits offspring.


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- Mendelian

- Autosomal dominant

- Autosomal recessive

- X-linked recessive

- X-linked dominant

- Nontraditional

- Mitochondrial

- Imprinting

- Uniparental disomy

- Mosaicism

- Multi-factorial

Types of Inheritance


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Symbols for Pedigrees


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Symbols for Pedigrees


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Pedigree: Expression of segregation or transmission oftraits within families.

Proband or index case: 1st family member seekingmedical attention (P).

Generation: Roman numbers (I, II, etc.).

Individuals: Arabic numbers (1,2, etc.).

Age: Next or below the symbol.


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In order to understand Mendalian inheritance,several essential terms must first be defined


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Locus: A specific position on a chromosome.

Alleles: alternative forms of a gene, or of a DNA

sequence, at a given locus.

Homozygous: both alleles at a locus are identical.

Heterozygous: both alleles at a locus are different.

A compound heterozygote: two different mutant

alleles at a given locus.

Double heterozygote: One mutant allele at each of twodifferent loci.


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Genotype: the genetic constitution or composition of anindividual.

Phenotype: the observed results of the interaction of the

genotype with environmental factors.

Genotype & Phenotype: are a musical analogy.

Mendelian diseases: the result of a single mutant genethat has a large effect on phenotype, inherited in a simplepatterns.

Autosomal diseases: Encoded by genes on one of the22 pairs of autosomes (non-sex chromosomes).

X-linked: encoded by a mutant gene on the Xchromosome.


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A Comparison of Homologous Chromosomes


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Homozygous:

Both alleles at a

locus are thesame.

Heterozygous:

At the locus one

gene is the wildtype and the other

mutant.

Compound

heterozygote:

Both allele areabnormal but

different

variations.

or

N N Ab Ab N Ab Ab1 Ab2


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Mendelian genetics

Principle of segregation: Sexually reproducingorganisms possess genes that occur in pairs andthat only one member of this pair is transmitted tothe offspring

Principle of independent assortment: genes atdifferent loci are transmitted independently. In areproductive event, a parent transmits one allelefrom each locus to its offspring and the allele

transmitted at one locus has no effect on whichallele is transmitted at the other locus


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What is a trait?

WWor

Wwww

Widows peak


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How do we inherit a single trait?

We have to know the mode of inheritance

Dominant allele It is expressed when present

It is designated with a capital (uppercase) letter

An example is W for widows peak.

Recessive allele

It is only expressed in the absence of a dominantallele.

It is designated with a lowercase letter indicates

An example is w for continuous hairline.


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Proper use of the Punnett Square

A Punnett square can thenbe used to determine thephenotypic ratio among theoffspring

The punnett square can be

used when it is hard toimagine the phenotypicratio from any cross (i.e. YyX Yy).

Single gene: Yy X Yy = 3:1

Two genes: YyZz X YyZz =9:3:3:1


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Basic concepts of Probability

Laws of probability alone can be used to determineresults of a cross.

The laws are:

Multiplication rule: the probability that two ormore independent events will occur together isthe product of their chances occurring separately.

Addition rule: the chance that an event that canoccur in two or more independent ways is thesum of the individual chances.


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In the cross of Ww x Ww, what is the chance ofobtaining either a W or a w from a parent?

Chance of W = , or chance of w =

The probability of these genotypes is:

The chance of WW = x =

The chance of Ww = x =

The chance of wW = x =

The chance of ww = x =

The chance of widows peak (WW, Ww, wW) is + + = or 75%.


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Genotype versus Phenotype

Genotype refers to the genes of an individualwhich can be represented by two letters.

Homozygous means that both alleles are the

same; for example, WW stands for homozygous dominant

ww stands for homozygous recessive.

Heterozygous means that the members ofthe allelic pair are different for example,

Ww, a heterozygote


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Genotype versus Phenotype

Phenotype refers to the physical or observablecharacteristics of the individual.

Both WW and Ww result in widows peak,

the phenotype is a widow's peak

however, we have two genotypes resulting in thesame phenotype.

ww results in a straight hairline in this case, the phenotype can only result from

one genotype


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Genotype and gene frequency

The prevalence of many genetic diseases variesconsiderably from one population to another.

The variation is due to the difference in proportiongenotypes and alleles in a population.

Under simple conditions these frequencies can beestimated by direct counting.

(MM: 64, MN: 120 and NN: 16) Total 200 subjects

Genotype frequency = Genotype count/Total MM = 0.32; MN = 0.60; NN = 0.08 and the sum

equal 1.

G (All l ) f i il


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Gene (Allele) frequencies are easilyestimated from genotype frequencies

How were allele frequencies estimated ?

For Eskimo - Freq .of M = (0.835 + (0.5 x 0.156 )) = .913

Freq. of N = (0.009 + .(0.5 x 0.156 )) = .087


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Example

Imagine that we have typed 200 individuals in a population forMN blood group, of these we have 64 with MM genotype, 120with MN genotype and 16 with NN genotype.

What is the genotype frequency?It is obtained simply by dividing each genotype count by thetotal number of subjects, for MM genotype it is 64/200 = 0.32for MN genotype is 120/200 = 0.6 and for NN genotype is16/200 = 0.08 the sum of these frequencies must equal 1


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What is the gene frequency?

The gene frequency for each allele, M and N can be obtainedby the process of gene counting.

For M, each MM homozygous has two M alleles while eachMN heterozygous has one allele therefore, the number ofgenes is

(64 X 2) + 120 = 284 genes

For N, each NN homozygous has two N alleles while eachMN heterozygous has one allele therefore, the number ofgenes is

(16 X 2) + 120 = 152 genes

in total there are 400 genes at the MN locus

To obtained the frequency of M, we divide the number of M

allele by the total number of alleles at that locus248/400 = 0.62

The same for the N allele, 152/400 = 0.38

The sum of the two frequencies must equal 1


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Classification of genetic disorders

Single-gene disorders

Chromosome disorders

Multifactorial disorders


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Single-gene disorders

Caused by mutations in individual genes.

Mutations may be present in only one or both copiesof a gene.

Usually exhibit obvious and characteristic pedigreepatterns.

Affect 2% of population sometime over an entire lifespan.


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Many important and well-understood genetic diseases are theresult of a mutation in a single gene.

Single-gene or monogenic traits are also known as Mendeliantraits.

The variation in traits is caused by the presence of differentalleles at individual loci

Mendels key contributions to genetics were The principles of segregation

Independent assortment

The effects of one allele may mask those of another(dominance and recessiveness)


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Autosomal Dominant and Recessive

Inheritance


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Autosomal dominant disorders

Expressed when only one chromosome of apair carries the mutant allele.

Normal allele on the homologouschromosome.


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Simple dominant inheritance


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Certain important features about autosomaldominant conditions

Careful questioning may reveal multigenerational familyhistories of problems vertical transmission pattern.

Both sexes are involved equally.

50% risk to any child of an affected person.

Unaffected relatives do not transmit the phenotype totheir children.

Some individuals present with recognizable clinicalpictures that reflect new mutations.


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Certain important features about autosomaldominant conditions

Because dominant conditions are detectable in thepresence of the normal allele of the responsible gene,their physiologic bases often, but not always, are relatedto aberrant structural or developmental problems.

Dominant transmission includes the mechanism of so-called triplet repeat disorders.

Dominant disorders often show pleiotropy.

The severity or prominence of a particular aspect of adominant disorder may be unpredictable variableexpressivity.

So-called dominant tumor syndromes provide clinicalsupport for the Knudson hypothesis.


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Variations in Autosomal Dominant Conditions

New mutations in the gamate formation.

Decreased penetrance-obligate heterozygous for themutation.

Delayed onset of the disease.

Germline mosaicism.

The putative father is not the actual biological father.


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Autosomal Dominant disorders -examples

Achondroplasia

Marfan syndrome

Neurofibromatosis type 1

Dentinogenesis imperfecta Rieger syndrome (anodontia + iris dysplasia)

Oculodentodigital syndrome

Mandibulofacial dysostosis - Treacher Collins

syndrome


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Predicting inheritance pattern from pedigree

analysis A man who had purple ears came to the attention of a human

geneticist. The human geneticist did a pedigree analysis andmade the following observations:

In this family, purple ears proved to be an inherited trait due toa single genetic locus. The man's mother and one sister alsohad purple ears, but his father, his brother, and two other

sisters had normal ears. The man and his normal-eared wifehad seven children, including four boys and three girls. Twogirls and two boys had purple ears. The purple-ear trait is mostprobably:

A. autosomal, dominant

B. autosomal, recessive C. sex-linked, dominant

D. sex-linked, recessive

E. cannot be determined from this information
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A. autosomal dominant, A genetic trait that is passedfrom generation to generation to generation, from bothfathers to daughters and mothers to daughters, istypically autosomal dominant.


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Recurrence risks for an autosomal dominantdisorder

Parents at risk for producing children with a genetic diseaseare often concerned with the question: what is the chance thatour future children will have this disease?

When one or more children have already been born with agenetic disease, the parents are given a recurrence risk

When the parents have not yet had children but are known tobe at risk for having children with a genetic disease, anoccurrence risk can be given

Each birth is an independent event

The occurrence and recurrence risks for each child are 1/2


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Autosomal recessive disorders

Expressed only when both chromosomes ofa pair carry a mutant allele.


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Simple recessive inheritance


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Several important aspects of recessive

inheritance should be considered Heterozygotes are generally unaffected clinically.

An individual manifesting recessive disorder usually hasheterozygous parents.

Once a homozygote is identified, the recurrence risk forother mating of the same parents is 25%.

Two-thirds of the unaffected siblings of an individual withan autosomal recessive disorder are likely to be

heterozygotes.

The likelihood that any two individuals selected randomlywill be heterozygous for the same mutant allele is low.


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Several important aspects of recessiveinheritance should be considered

Consanguinity can lead to an increased likelihood of matingbetween heterozygotes.

A homozygote must contribute one abnormal gene copy to anyoffspring because he or she has no normal copies of the geneat the responsible locus.

If a homozygote mates within a community where thefrequency of heterozygotes is high (e.g., a geographicallyisolated community), a pattern resembling dominantinheritance may occur.

Metabolic abnormalities are common in recessive disorders.

Quasidominant inheritance: recessive pattern that mimics thatof an autosomal dominant trait


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Autosomal recessive disorders -examples

Cystic fibrosis

Alpha 1-antitrypsin deficiency

Congenital adrenal hyperplasia

Phenylketonuria

Tay-Sachs disease

Sickle cell anaemia

Albinism


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Inheritance pattern for Tay Sachs Disease

A couple has a female child with Tay Sachs disease,and three unaffected children. Neither parent nor anyof the four biological grandparents of the affectedchild has had this disease. The most likely geneticexplanation is that Tay Sachs disease is inherited asa(n) ______________ disease.

A. autosomal dominant

B. autosomal recessive

C. sex-linked recessive

D. sex-linked dominant

E. cannot make a reasonable guess from thisinformation
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B. autosomal recessive; the disease is recessive because bothparents are unaffected, and autosomal because a female childis affected but her father is not.


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Recurrence risks for an autosomalrecessive disorder

Many autosomal recessive diseases are severe enough thataffected individuals are less likely to become parents

The recurrence risk for the offspring of carrier parents is

The recurrence risk for a carrier with a homozygous for thedisease gene is (Quasidominant inheritance)


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Dominant versus recessive: some cautions

A dominant disease allele will produce disease in aheterozygote, whereas a recessive disease allele will not

A disease may be inherited in autosomal dominant fashion insome cases and in autosomal recessive fashion in others(familial isolated growth hormone deficiency, IGHD)

Beta-thalassemia cases occurs as a result of autosomalrecessive mutations, a small proportion inherited in autosomal

dominant fashion


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Factors that may complicate inheritancepatterns

New mutations: It is estimatedthat 7/8 of all cases ofachondroplasia are caused bynew mutations, while only 1/8are transmitted byachondroplastic parents.

Germline mosaicism:Osteogenesis imperfecta type II,caused by mutations in the typeI procollagen genes,

achondroplasia,neurofibromatosis type I,Duchenne muscular dystrophyand hemophilia A.


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Mosaicism

The presence of two or more cell lines with differentgenotypes within a single individual.

May be chromosomal or single gene

May or may not have an impact on the phenotypeof the individual

Types

Somatic

Gonadal


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Mosaicism

Somatic mutation

Mutation which occurs after fertilization

Neither parent has the altered genetic make-up

Not every cell in the individual is defective Generally limited to dominant traits or

chromosomal syndromes since only onedefective unit is needed for expression

If germ cells affected next generation at risk Clinical phenotype is depend on ratio of normal:

abnormal.


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Egg

Normal Sperm

Normal

Zygote

Normal

Mitosis


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N

N N

N N N Abn

Abn AbnN N N N N N

Mitosis


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Mosaic

Abnormal Cells

Normal Cells


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Mosaicism

Germinal (Germ-line) or gonadal mutations

An individual who shows no clinical expression ofa disease but a proportion of gametes contain amutation for a genetic trait.

Risk to offspring may be as high as 50%

Has made geneticist cautious when counseling

for recurrence risk for what seems to be a newmutation in a family.


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P

Osteogenesis

Imperfecta

Autosomal dominant disease

What is the risk for indicated pregnancy?


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Gonadal mosaicism

The affected child appears to be a de novo (new)mutation, because both parents are clinically normaland the condition is 100% penetrant. Without therisk of gonadal mosaicism, the risk for the newpregnancy would be the possibility of a newmutation about 1 in 10,000 to 100,000. But from datacollected from multiple families the true risk is about6% because of gonadal mosaicism.


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Penetrance

Penetrance refers to the probability of any

expression of a diseased phenotype during anindividuals lifetime.

Conditions where an abnormal genotype always

show clinical symptoms are considered 100%penetrant.

If a condition shows reduced penetrance, there is achance the individual will have no clinical symptoms

of the disease despite an abnormal genotype.(nonpenetrance)

Offspring of the nonpenetrant individual would be at

risk for clinical disease.


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Penetrance Example

Hereditary breast cancer. Mutations in the BRCA1

gene are found in about 40% of familial or hereditary

breast cancer. At least 20% of women who

inherit a gene associatedwith breast cancer will not

develop cancer in theirlifetime.

These women would beconsidered nonpenetrant.

F t th t li t i h it


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Reduced penetrance: an individual who has the genotype for adisease may not exhibit the disease phenotype at all, eventhough he or she can transmit the disease gene to the nextgeneration (retinoblastoma). About 10% of the obligatorycarriers of the retinoblastoma susceptibility gene do not have

the disease. The penetrance of the gene is then said to be 90%

Age dependent penetrance: a delay in the age of onset of agenetic disease. Examples, Huntington disease, familialAlzheimer disease, breast cancer.

F t th t li t i h it


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Variable expression: the penetrance may be complete, but theseverity of the disease can vary greatly, neurofibromatosis typeI.Causes:- Environmental effects- Interaction of other genes (modifier genes) with the diseasegene- Allelic heterogeneity (different types of mutations at the samedisease locus), Example is beta-globin mutations that cancause either sickle cell disease or various beta-thalassemias

Pleiotropy and heterogeneity: Pleiotropic, are genes that havemore than one discernible effect on the body (Marfansyndrome). Locus heterogeneity, the causation of the samedisease phenotype by mutations at distinct loci (Adultpolycystic kidney disease, APKD can be caused by PKD1mutation and by PKD2 mutation)


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Neurofibromatosis type 1

Variable Expressivity in


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Variable Expressivity inHoloprosencephaly

Marfan Syndrome


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y


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Genomic imprinting

- The term imprinting implies a type of marking process that has

a memory

- The term genomic imprinting refers to a situation where asegment of DNA is marked, and that mark is retained andrecognized throughout the life of the organism inheriting themarked DNA

- Imprinted genes follow a Non-Mendelian pattern of inheritance

- The marking process causes the offspring to distinguishbetween maternally and paternally inherited alleles


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Genomic imprinting

- Depending on how the genes are marked, the offspring willexpress one of the two alleles, but not both

- Imprinting may involve a single gene, a part of a chromosome,an entire chromosome or even all the chromosomes from oneparent

- Imprinting can be divided into three stages:- Establishment of the imprint during gametogenesis- Maintenance of the imprint during embryogenesis and in

adult somatic cells- Erasure and reestablishment of the imprint in the germ cells


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Genomic imprinting

- Examples:- Prader-Willi syndrome, gene defected encode for small nuclear

riboprotein that is expressed in the brain (SNRPN) that inherited fromthe father

- Angelman syndrome, gene defected encodes for a protein involved inubiquitin-mediated protein degradation during brain development thatinherited from the mother

- Seventy percent of the cases caused by chromosome deletion- These two diseases might be caused by uni-parental disomy

(individual inherits two copies of a chromosome from oneparent and none from the other), point mutation and by smalldeletion in imprinting center

- Beckwith-Wiedmann syndrome: minority of this disease is caused by

the inheritance of two copies of a chromosome from the father andnone from the mother (uni-parental disomy)- Insulin-like growth factor 2 (IGF2): this gene is imprinted (inactive) on

the maternally derived chromosome and active only on the paternalchromosome

Th l f i i i i h d l f l


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The role of imprinting in the development of angelmanand prader-willi syndromes


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DNA methylation in the imprinting process

inheritance (i)

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