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Introduction to Human Introduction to Human GeneticsGenetics

Dr PupakDr Pupak Derakhshandeh, PhDDerakhshandeh, PhD

Ass Prof of Medical Science of Tehran Ass Prof of Medical Science of Tehran UniversityUniversity

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General BackgroundGeneral Background

single gene disorders:single gene disorders:

–diseases or traits : phenotypes are diseases or traits : phenotypes are largely determined : of mutations at largely determined : of mutations at individual locusindividual locus

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chromosomal abnormalities:chromosomal abnormalities:–diseases where the phenotypes : diseases where the phenotypes :

physical changes in chromosomal physical changes in chromosomal structure - deletion, inversion, structure - deletion, inversion, translocation, insertion, rings, etctranslocation, insertion, rings, etc

–chromosome number - trisomy or chromosome number - trisomy or monosomy, or in chromosome origin monosomy, or in chromosome origin - uniparental disomy- uniparental disomy

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multifactorial traits:multifactorial traits:

–diseases or variations: phenotypes diseases or variations: phenotypes are strongly influenced : mutant are strongly influenced : mutant alleles at several loci alleles at several loci

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mitochondrial inheritance:mitochondrial inheritance:–Diseases: phenotypes are affected Diseases: phenotypes are affected

by mutations of mitochondrialby mutations of mitochondrial DNA DNA

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diseases of unknown etiology:diseases of unknown etiology:

–"run in families" "run in families"

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Mendelian traits, or single gene Mendelian traits, or single gene disordersdisorders

autosomal recessive inheritanceautosomal recessive inheritance ::– the locus: on an autosomal the locus: on an autosomal

chromosomechromosome –both alleles : mutant alleles to both alleles : mutant alleles to

express the phenotypeexpress the phenotype

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Loss-of-function mutationsLoss-of-function mutations

Wild type alleles typically encode a Wild type alleles typically encode a product necessary for a specific product necessary for a specific biological functionbiological function

If a mutation occurs in that allele, the If a mutation occurs in that allele, the function for which it encodes is also function for which it encodes is also lostlost

The degree to which the function is lost The degree to which the function is lost can varycan vary

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Loss-of-function mutationsLoss-of-function mutationsgene product having less or no function:gene product having less or no function:– Phenotypes associated with such Phenotypes associated with such

mutations are most oftenmutations are most often recessive recessive::– to produce the to produce the wild typewild type phenotype! phenotype!

Exceptions are when the organism is Exceptions are when the organism is haploidhaploid

or when the reduced dosage of a normal or when the reduced dosage of a normal gene product is not enough for a normal gene product is not enough for a normal phenotype phenotype (haploinsufficiency)(haploinsufficiency)

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Mendelian traits, or single gene Mendelian traits, or single gene disordersdisorders

autosomal dominant inheritance :autosomal dominant inheritance :– the locus : on an autosomal the locus : on an autosomal

chromosomechromosome

–only one mutant allele : for only one mutant allele : for expression of the phenotypeexpression of the phenotype

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Loss-of-function mutationsLoss-of-function mutations

mutant allele will act as a mutant allele will act as a dominantdominant::

the wild type allele may not the wild type allele may not compensate for the loss-of-function compensate for the loss-of-function alleleallele

the phenotype of the heterozygote will the phenotype of the heterozygote will be equal to that of the loss-of-function be equal to that of the loss-of-function mutant (as mutant (as homozygothomozygot))

– to produce the to produce the mutantmutant phenotype ! phenotype !

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By effect on functionBy effect on function

Loss-of-function mutationsLoss-of-function mutations

Gain-of-function mutationsGain-of-function mutations

Dominant negative mutationsDominant negative mutations

Lethal mutationsLethal mutations

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Loss-of-function mutationsLoss-of-function mutations

Null allele:Null allele:– When the allele has a complete loss of When the allele has a complete loss of

function function it is often called an it is often called an amorphicamorphic mutation mutation

Leaky mutationsLeaky mutations::– If some function may remain, but not at the If some function may remain, but not at the

level of the wild type allelelevel of the wild type allele

The degree to which the function is lost can The degree to which the function is lost can varyvary

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Gain-of-function mutationsGain-of-function mutations

change the gene product such that change the gene product such that it gains a new and abnormal it gains a new and abnormal functionfunction

These mutations usually have These mutations usually have dominant dominant phenotypesphenotypes

Often called a Often called a neomorphic neomorphic mutationmutation

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Gain-of-function mutationsGain-of-function mutationsAlthough it would be expected that most Although it would be expected that most mutations would lead to a mutations would lead to a loss of functionloss of functionit is possible that a new and important it is possible that a new and important function could result from the mutation:function could result from the mutation:– the mutation creates a new allele:the mutation creates a new allele:

associated with a new functionassociated with a new function

Genetically this will define the mutation Genetically this will define the mutation as a as a dominantdominant

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Mendelian traits, or single gene Mendelian traits, or single gene disordersdisorders

X-linked recessive inheritance:X-linked recessive inheritance:

– the locus :on the X chromosome the locus :on the X chromosome –both alleles : mutant alleles to both alleles : mutant alleles to

express the phenotype in femalesexpress the phenotype in females

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Mendelian traits, or single gene Mendelian traits, or single gene disordersdisorders

X-linked dominant inheritance:X-linked dominant inheritance:

– the locus: on the X chromosomethe locus: on the X chromosome

–only one mutant allele : for only one mutant allele : for expression of the phenotype in expression of the phenotype in femalesfemales

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MitosisMitosis

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MitosisMitosis

Mutations:Mutations: during DNA replication in during DNA replication in mitosismitosisthese mutations:these mutations: in somatic cell diseases, in somatic cell diseases, such as cancersuch as cancermost mitotic divisions/the fastest rate of most mitotic divisions/the fastest rate of growth:growth:– before birth in the relatively protected before birth in the relatively protected

environment of the uterusenvironment of the uterus– Most of us only increase 15 to 30 times Most of us only increase 15 to 30 times

our birth weightour birth weight

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Meiosis (I)Meiosis (I)

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Meiosis (II)Meiosis (II)

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PEDIGREE CONSTRUCTIONPEDIGREE CONSTRUCTION

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AUTOSOMAL AUTOSOMAL RECESSIVE RECESSIVE

INHERITANCEINHERITANCE

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AUTOSOMAL RECESSIVE INHERITANCEAUTOSOMAL RECESSIVE INHERITANCE

affected individuals: normal phenotypes affected individuals: normal phenotypes

one in ten thousand live birthsone in ten thousand live births

heterozygote frequency in the heterozygote frequency in the population: one in fiftypopulation: one in fifty

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The Punnett Square for autosomal The Punnett Square for autosomal recessive diseases with an affectedrecessive diseases with an affected

child in the family child in the family

Within the normal siblings of affected Within the normal siblings of affected individual :individual :

the probability of being a carrier is 2/3the probability of being a carrier is 2/3

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hallmarks of autosomal hallmarks of autosomal recessive inheritancerecessive inheritance

Males and females: equally likely to be affectedMales and females: equally likely to be affected

the recurrence risk to the unborn sibling of an the recurrence risk to the unborn sibling of an affected individual : 1/4affected individual : 1/4

Parents of affected children: may be relatedParents of affected children: may be related

The rarer the trait in the general population, the more The rarer the trait in the general population, the more likely a consanguineous mating is involvedlikely a consanguineous mating is involved

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Autosomal recessive inheritanceAutosomal recessive inheritance

1.

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common autosomal recessive common autosomal recessive diseasesdiseases

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AUTOSOMAL AUTOSOMAL DOMINANT DOMINANT

INHERITANCEINHERITANCE

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Autosomal dominant diseasesAutosomal dominant diseasesusually rareusually rare

To produce a affected homozygote: two To produce a affected homozygote: two affected heterozygotes would have to mateaffected heterozygotes would have to mate

they would have only a 1/4 chance of having a they would have only a 1/4 chance of having a normal offspringnormal offspring

In the extremely rare instances:In the extremely rare instances:– where two affected individuals have mated: where two affected individuals have mated:

the homozygous affected individuals :the homozygous affected individuals :

usually are so severely affected they are usually are so severely affected they are not compatible with lifenot compatible with life

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Autosomal dominant diseasesAutosomal dominant diseases

The mating of very closely related The mating of very closely related individuals: individuals:

– two affected individuals to know each two affected individuals to know each other, other, isn’t forbiddenisn’t forbidden in our society in our society

in most matings: affected individuals : in most matings: affected individuals : heterozygotesheterozygotes

–the other partner will be homozygous the other partner will be homozygous normalnormal

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Autosomal dominant diseasesAutosomal dominant diseasesnew mutations:new mutations:– rare in naturerare in nature

every affected individual:every affected individual: an affected biological parent an affected biological parent

Males and females : Males and females : – an equally likely chance of inheriting the mutant allele an equally likely chance of inheriting the mutant allele

The recurrence risk of each child of an affected parent :The recurrence risk of each child of an affected parent :– 1/21/2

Normal siblings of affected individuals:Normal siblings of affected individuals:– do not transmit the trait to their offspringdo not transmit the trait to their offspring

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The defective product of The defective product of the genethe gene

usually a structural protein, not an enzymeusually a structural protein, not an enzyme

Structural proteins :Structural proteins : usually defective: usually defective:

–one of the allelic products is one of the allelic products is nonfunctionalnonfunctional

enzymes usually :enzymes usually :

– require both allelic products to be require both allelic products to be nonfunctional to produce a mutant nonfunctional to produce a mutant phenotypephenotype

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AUTOSOMAL DOMINANT AUTOSOMAL DOMINANT INHERITANCEINHERITANCE

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AUTOSOMAL DOMINANT AUTOSOMAL DOMINANT INHERITANCEINHERITANCE

Variable Expressivity Variable Expressivity

Late Onset Late Onset

High Recurrent Mutation Rate High Recurrent Mutation Rate

Incomplete Penetrance Incomplete Penetrance

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VARIABLE EXPRESSIVITY (AD)VARIABLE EXPRESSIVITY (AD)One example : Marfan syndromeOne example : Marfan syndromeautosomal dominant diseaseautosomal dominant diseasecaused by:a mutation in collagen formationcaused by:a mutation in collagen formationIt affects about 1/60,000 live birthsIt affects about 1/60,000 live birthsSymptoms of Marfan syndromeSymptoms of Marfan syndrome– skeletalskeletal– OpticalOptical– cardiovascular abnormalitiescardiovascular abnormalitiesSkeletal abnormalities:Skeletal abnormalities:– arachnodactyly (long fingers and toes)arachnodactyly (long fingers and toes)– extreme lengthening of the long bonesextreme lengthening of the long bones

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dislocation of the lens of the eyedislocation of the lens of the eye

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VARIABLE EXPRESSIVITY (AD)VARIABLE EXPRESSIVITY (AD) Marfan syndromeMarfan syndrome

Optical abnormalities:Optical abnormalities:– a dislocation of the lens of the eyea dislocation of the lens of the eyeCardiovascular abnormalities Cardiovascular abnormalities – responsible for the shorter life span of Marfan responsible for the shorter life span of Marfan

syndrome patients syndrome patients Each patient may express all of the symptoms, or only a Each patient may express all of the symptoms, or only a few!few!That is variable expressivityThat is variable expressivityEach patient with the mutant allele for Marfan syndrome:Each patient with the mutant allele for Marfan syndrome:– expresses at least one of the symptomsexpresses at least one of the symptoms

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LATE ONSET (AD)LATE ONSET (AD)Some autosomal dominant diseases :Some autosomal dominant diseases :

do not express themselves until later in lifedo not express themselves until later in life

the disease: passed the mutant allele the disease: passed the mutant allele along to their offspring before they along to their offspring before they themselves know they are affectedthemselves know they are affected

In some cases even grandchildren are In some cases even grandchildren are born born before the affected grandparent before the affected grandparent shows the first signs of the diseaseshows the first signs of the disease

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LATE ONSET (AD)LATE ONSET (AD)Huntington disease (Huntington's Huntington disease (Huntington's Chorea):Chorea): choreic movements expressed choreic movements expressed ProgressiveProgressive a good example of a late onset diseasea good example of a late onset diseaseAge of onset varies from the teens to the Age of onset varies from the teens to the late sixtieslate sixtieswith a mean age of onset between ages with a mean age of onset between ages 35 and 4535 and 45

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Huntington diseaseHuntington diseaseNearly 100% of the individuals born Nearly 100% of the individuals born with the defective allele will develop with the defective allele will develop the disease by the time they are 70the disease by the time they are 70

The disease : progressive with death The disease : progressive with death usually occurring between four and usually occurring between four and twenty-five years after the first twenty-five years after the first symptoms developsymptoms develop

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Huntington disease (AD)Huntington disease (AD)At the gene level:At the gene level:

the expansion of an unstable trinucleotide the expansion of an unstable trinucleotide repeat sequencerepeat sequence

CAGCAG““POLYGLUTAMINE DISEASES”POLYGLUTAMINE DISEASES”

mutations: expansion of trinucleotide repeat mutations: expansion of trinucleotide repeat sequences sequences

in the coding region of the genein the coding region of the gene to produce a to produce a mutant allelemutant allele

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Other diseases (AD):(AD):

myotonic dystrophy:

an autosomal dominant diseasean autosomal dominant disease

expression is delayed expression is delayed

expansion of unstable trinucleotide expansion of unstable trinucleotide sequencessequences

CTGCTG

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myotonic dystrophy

unstable sequence lies in unstable sequence lies in a non-a non-translated region of the genetranslated region of the gene

the size of the inherited expansion the size of the inherited expansion correlates to the age of onsetcorrelates to the age of onset

or the severity of diseaseor the severity of disease

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Repeats in non-coding sequencesRepeats in non-coding sequences

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HIGH RECURRENT MUTATION HIGH RECURRENT MUTATION RATERATE

Achondroplasia:

the major causes of dwarfismthe major causes of dwarfism

Motor skills may not develop as Motor skills may not develop as quickly as their normal siblingsquickly as their normal siblings

but intelligence is not reducedbut intelligence is not reduced

about 1/10,000 live births about 1/10,000 live births

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Achondroplasia

Almost 85% of the cases : new mutations Almost 85% of the cases : new mutations both parents have a normal phenotypeboth parents have a normal phenotype

The mutation rate for achondroplasia may The mutation rate for achondroplasia may be as much as 10 times the "normal" be as much as 10 times the "normal" mutation rate in humansmutation rate in humans

This high recurrent mutation is largely This high recurrent mutation is largely responsible for responsible for keeping the mutant gene in keeping the mutant gene in the populationthe population at its present rate at its present rate

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INCOMPLETE PENETRANCEINCOMPLETE PENETRANCE It shouldIt should never never be confused with variable be confused with variable expressivityexpressivityvariable expressivity: – the patient always expresses some of the the patient always expresses some of the

symptoms of the diseasesymptoms of the disease–and varies from very mildly affected to very and varies from very mildly affected to very

severely affectedseverely affectedincomplete penetrance:– the person either expresses the disease the person either expresses the disease

phenotype or he/she doesn'tphenotype or he/she doesn't

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Incomplete penetrance and Incomplete penetrance and variable expressivity are variable expressivity are phenomena associated phenomena associated onlyonly with dominant inheritance, with dominant inheritance, nevernever with recessive inheritance with recessive inheritance

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INCOMPLETE PENETRANCEINCOMPLETE PENETRANCE in a known autosomal dominant diseasein a known autosomal dominant disease

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X-LINKED DOMINANT X-LINKED DOMINANT INHERITANCE INHERITANCE

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X-LINKED DOMINANT INHERITANCE X-LINKED DOMINANT INHERITANCE

A single dose of the mutant allele will A single dose of the mutant allele will affect the phenotype of the female!affect the phenotype of the female!

A recessive X-linked gene:A recessive X-linked gene:–requires two doses of the mutant requires two doses of the mutant

allele to affect the female allele to affect the female phenotypephenotype

–The trait is never passed from The trait is never passed from father to sonfather to son

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X-LINKED DOMINANT X-LINKED DOMINANT INHERITANCEINHERITANCE

All daughters of an affected male and a normal female All daughters of an affected male and a normal female are affected (100%)are affected (100%)

All sons of an affected male and a normal female are All sons of an affected male and a normal female are normal (100%)normal (100%)

Mating of affected females and normal males produce Mating of affected females and normal males produce 1/2 the sons affected and 1/2 the daughters affected 1/2 the sons affected and 1/2 the daughters affected (50% :50%)(50% :50%)

Males are usually more severely affected than femalesMales are usually more severely affected than females

The trait may be lethal in malesThe trait may be lethal in males

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X-LINKED DOMINANT INHERITANCEX-LINKED DOMINANT INHERITANCE

in each affected female: there is one in each affected female: there is one normal allele producing a normal gene normal allele producing a normal gene productproduct

and one mutant allele producing the non-and one mutant allele producing the non-functioning productfunctioning product

while in each affected male there is only while in each affected male there is only the mutant allele with its non-functioning the mutant allele with its non-functioning product and the Y chromosome, no normal product and the Y chromosome, no normal gene product at allgene product at all

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X-LINKED DOMINANT INHERITANCEX-LINKED DOMINANT INHERITANCE

All daughters are affected (100%) / All sons are normal (100%)All daughters are affected (100%) / All sons are normal (100%)

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key for determining: X-L D/ADkey for determining: X-L D/AD

to look at the offspring of the mating of an to look at the offspring of the mating of an affected male and a normal femaleaffected male and a normal female

If the affected male has an affected son:If the affected male has an affected son:– then the disease is not X-linkedthen the disease is not X-linked

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One example of an X-linked One example of an X-linked dominant: incontinentia pigmenti (IPdominant: incontinentia pigmenti (IP))

extremely rareextremely rareThe main features occur in the skin where a blistering The main features occur in the skin where a blistering rash occurs in the newborn periodrash occurs in the newborn periodbrown swirls brown swirls a "marble cake-like" appearance on the skin a "marble cake-like" appearance on the skin the eyesthe eyescentral nervous systemcentral nervous systemTeethTeethnails, and hairnails, and hairThe severity varies from person to personThe severity varies from person to person

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incontinentia pigmentiincontinentia pigmenti

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What happens when males are so severely What happens when males are so severely affected that they can't reproduce?affected that they can't reproduce?

This is not uncommon in X-linked This is not uncommon in X-linked dominant diseasesdominant diseasesThere are no affected males:There are no affected males:– to test for X-linked dominant to test for X-linked dominant

inheritance to see if the produce all inheritance to see if the produce all affected daughters and no affected affected daughters and no affected sons !!!sons !!!

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What happens when males are so What happens when males are so severely affected that they can't severely affected that they can't

reproduce?reproduce?

Next pedigree shows the effects of Next pedigree shows the effects of such a disease in a familysuch a disease in a family

There are no affected malesThere are no affected males

only affected females, in the only affected females, in the population!population!

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X-linked dominant X-linked dominant inheritance (severe)inheritance (severe)

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X-LINKED X-LINKED RECESSIVE RECESSIVE

INHERITANCEINHERITANCE

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X-LINKED RECESSIVE X-LINKED RECESSIVE INHERITANCEINHERITANCE

They are, in general, rareThey are, in general, rare

Hemophilia (A/B)Hemophilia (A/B)

Duchenne muscular dystrophyDuchenne muscular dystrophy

Becker muscular dystrophyBecker muscular dystrophy

Lesch-Nyhan syndrome Lesch-Nyhan syndrome

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X-LINKED RECESSIVE X-LINKED RECESSIVE INHERITANCEINHERITANCE

More common traits:

glucose-6-phosphate dehydrogenase glucose-6-phosphate dehydrogenase deficience deficience

color blindnesscolor blindness

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A rare X-linked recessive diseaseA rare X-linked recessive disease

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The hallmarks of X-linked The hallmarks of X-linked recessive inheritancerecessive inheritance

the disease is never passed from father to sonthe disease is never passed from father to son

Males are much more likely to be affected than Males are much more likely to be affected than femalesfemales

All affected males in a family are related through All affected males in a family are related through their motherstheir mothers

Trait or disease is typically passed from an affected:Trait or disease is typically passed from an affected:– grandfather, through his carrier daughters, to half grandfather, through his carrier daughters, to half

of his grandsonsof his grandsons

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X-linked recessive inheritanceX-linked recessive inheritance

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SEX LIMITED SEX LIMITED INHERITANCE INHERITANCE

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SEX LIMITED INHERITANCESEX LIMITED INHERITANCEIn some X-linked dominant traits, such as In some X-linked dominant traits, such as incontinentia pigmenti :incontinentia pigmenti :– expression is limited to femalesexpression is limited to females– males do not survive to termmales do not survive to term

There are autosomal diseases that are There are autosomal diseases that are limitedlimited to to expression in only one sex:expression in only one sex:– Precocious puberty / beard growth are Precocious puberty / beard growth are

factors expressed only in malesfactors expressed only in males– The hereditary form of prolapsed uterus is The hereditary form of prolapsed uterus is

expressed only in femalesexpressed only in females

incontinentia incontinentia pigmentipigmenti

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MITOCHONDRIAL MITOCHONDRIAL INHERITANCE INHERITANCE

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MITOCHONDRIAL INHERITANCEMITOCHONDRIAL INHERITANCE

• A few human diseases:• to be associated with mitochondrial inheritance

• Leber optic atrophy : a disease of mitochondrial DNA

• The ovum, originating in the female• 100,000 copies of mitochondrial DNA

• the sperm, originating in the male• has fewer than 100 copies, and these are probably

lost at fertilization• Virtually all of ones mitochondria come from his, or

her, mother• Affected fathers produce no affected offspring

• while the offspring of affected mothers are affected

The DNA of mitochondria contains about ten

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Mitochondrial inheritance patternMitochondrial inheritance pattern

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IMPRINTINGIMPRINTING

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IMPRINTINGIMPRINTING1/10,000 and 1/30,000 live births1/10,000 and 1/30,000 live birthsfor some genes: the for some genes: the origin of the geneorigin of the gene may be importantmay be importantFor some loci:For some loci:– the gene inherited from the father the gene inherited from the father –acts differently from the gene inherited acts differently from the gene inherited

from the motherfrom the mother–even though they may have the same even though they may have the same

DNADNA

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Prader-Willi syndrome

About 75% of patients with Prader-Willi About 75% of patients with Prader-Willi syndrome :syndrome :

– a small deletion of the long arm of a small deletion of the long arm of chromosome 15chromosome 15

this deletion is on the this deletion is on the paternal paternal chromosome (the father's genes are chromosome (the father's genes are missing)missing)

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Prader-Willi syndromePrader-Willi syndrome

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Angelman syndrome Angelman syndrome

When this deletion is on the When this deletion is on the maternalmaternal chromosome (the mother's genes are chromosome (the mother's genes are missing) Angelman syndrome resultsmissing) Angelman syndrome results

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Angelman syndrome Angelman syndrome

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uniparental disomyuniparental disomy

The two diseases have very different The two diseases have very different clinical symptomsclinical symptomsa rare chromosomal event in which both a rare chromosomal event in which both chromosomes come from a single parent chromosomes come from a single parent (mother or father)(mother or father)both chromosomes 15 are derived from both chromosomes 15 are derived from the mother: Prader-Willi syndrome the mother: Prader-Willi syndrome When both chromosomes 15 are derived When both chromosomes 15 are derived from the father: Angelman syndromefrom the father: Angelman syndrome

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normal development an normal development an individualindividual

inherit one copy of this chromosomal region from inherit one copy of this chromosomal region from his or her father and one from his or her motherhis or her father and one from his or her mother Several other regions : show uniparental disomy Several other regions : show uniparental disomy without this effect on the phenotype!without this effect on the phenotype!Small deletions usually affect the phenotype but Small deletions usually affect the phenotype but they produce the same phenotype whether of they produce the same phenotype whether of maternal or paternal originmaternal or paternal origin

Imprinting represents an Imprinting represents an exceptionexception to Mendel's to Mendel's laws and remains an important area of research laws and remains an important area of research

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