Human Genetics II

8/3/2019 Human Genetics II

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HUMAN GENETICSHUMAN GENETICS


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Clinical geneticsClinical genetics is a branch of medicineis a branch of medicineconcerned with the diagnosis, testing andconcerned with the diagnosis, testing and

management of diseases caused bymanagement of diseases caused bychanges in the human genome.changes in the human genome.

Human genomeHuman genome project, designed toproject, designed tosequence the entire human genome andsequence the entire human genome andthe new treatment including genethe new treatment including genetherapy will become the standard of caretherapy will become the standard of care

for familial cancers, inborn errors offor familial cancers, inborn errors ofmetabolism .metabolism .


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GENESGENES: Are found at specific loci on: Are found at specific loci onchromosome .chromosome .

AlleleAllele: is a single gene of the gene pairs , when: is a single gene of the gene pairs , whenalleles are similar called homozygous whenalleles are similar called homozygous whenare different called heterozygous.are different called heterozygous.

Chromosomes:Chromosomes: are condensed DNA formed onlyare condensed DNA formed onlyduring cell division , and every human cellduring cell division , and every human cellhas two pairs of similar chromosomes (has two pairs of similar chromosomes (diploid ) = 2N = autosomes ,and two sexdiploid ) = 2N = autosomes ,and two sexchromosomes haploid = single pair ofchromosomes haploid = single pair ofchromosome.chromosome.


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Basic structure of DNA:Basic structure of DNA:

DNA molecule consists ofDNA molecule consists ofa sugar( deoxyribose) anda sugar( deoxyribose) andphosphate backbone withphosphate backbone withbases covalently boundedbases covalently boundedto each deoxyriboseto each deoxyribose

molecule.molecule.

The DNA double helix isThe DNA double helix isformed by two standsformed by two standsrunning in oppositerunning in opposite

directions. Held togetherdirections. Held togetherby hydrogen bondsby hydrogen bondsbetween the bases e.g Abetween the bases e.g A--TT&G&G--CC


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KARYOTYPINGKARYOTYPING

Defined as the study of CHROMOSOMES46 = (22x2) + X + Y

Conventional notation is 46,XY or

46,XX G(iemsa)-banding, 500 bands per

haploid recognizableShort (p-etit) arm = p, other (long)

arm = q


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DISEASESDISEASESGENETICGENETICENVIRONMENTALENVIRONMENTALBOTHBOTH


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Genetic damage can result from:Genetic damage can result from:

11-- ChemicalsChemicals

22-- RadiationRadiation33-- VirusesViruses

Genetic diseases:Genetic diseases:

11--Congenital diseases:Congenital diseases: are present since birth , are classified into:are present since birth , are classified into:

*Genetic disorders: abnormal genetic material*Genetic disorders: abnormal genetic material*Developmental defects: malformations , Agenesis ,Atresia.*Developmental defects: malformations , Agenesis ,Atresia.*Multifactorial disorders.*Multifactorial disorders.

22-- Familial diseases:Familial diseases: running in family, after birth.running in family, after birth.

Example:Example:

Discovering at autopsy that a bowel cancer in young man was causedDiscovering at autopsy that a bowel cancer in young man was causedby familial adenomatous polyposis. So we can testing other familyby familial adenomatous polyposis. So we can testing other familymembers at risk.members at risk.


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MUTATIONMUTATION

PERMANENT change inPERMANENT change inDNADNA

GENOMEGENOME MUTATION: (wholeMUTATION: (wholechromosome)chromosome)

CHROMOSOMECHROMOSOME MUTATION:MUTATION:(visible chromosome change)(visible chromosome change)

GENEGENE MUTATION: (may, and often,MUTATION: (may, and often,

result in a single base error)result in a single base error)


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GENETIC Changes that cause diseases:GENETIC Changes that cause diseases:

It can range from missing or additional the wholeIt can range from missing or additional the whole

chromosome to a change of a single base in the genechromosome to a change of a single base in the genesequence.sequence.

11-- Mutation:Mutation: single gene disorders are caused by changesingle gene disorders are caused by changein DNA resulting in functional or structural abnormality,in DNA resulting in functional or structural abnormality,

DNA damage is more common during stage of cellDNA damage is more common during stage of celldivision , such as embryogenesis.division , such as embryogenesis.

The inheritance of single gene disorder is determinedThe inheritance of single gene disorder is determinedby Mendels law.by Mendels law.

(an autosomal gene is one that is carried on one of(an autosomal gene is one that is carried on one ofthe autosomes or sex linked gene is one that is foundthe autosomes or sex linked gene is one that is foundon the X chromosome).on the X chromosome).

-- If one copy has a mutation called mutant allele.If one copy has a mutation called mutant allele.


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POINT MUTATIONPOINT MUTATION


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GENE MUTATIONGENE MUTATION

POINT MUTATIONPOINT MUTATION within a coding sequence:within a coding sequence:VALVAL--GLUGLU

MUTATIONS in NONMUTATIONS in NON--coding sequencescoding sequencesdefective transcription, regulationdefective transcription, regulation

DELETIONS/INSERTIONSDELETIONS/INSERTIONS frameshiftframeshiftmutation, involvement is NOT a multiple of 3mutation, involvement is NOT a multiple of 3

TriTri--nucleotidenucleotide REPEATSREPEATS, e.g., CGG repeats, e.g., CGG repeatsmany times in fragile X syndromemany times in fragile X syndrome


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GENE MUTATIONSGENE MUTATIONS

INTERFERE with proteinINTERFERE with proteinsynthesissynthesis

SUPPRESS transcription,SUPPRESS transcription,DNADNARNARNA

PRODUCE abnormal mRNAPRODUCE abnormal mRNA

DEFECTS carried over intoDEFECTS carried over into

TRANSLATIONTRANSLATION ABNORMAL proteins WITHOUTABNORMAL proteins WITHOUT

impairing synthesesimpairing syntheses


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IN SITU HYBRIDIZATIONIN SITU HYBRIDIZATION

Awesome research technique, used oftenAwesome research technique, used oftenin everyday pathology too, fluorescentlyin everyday pathology too, fluorescentlylabels pieces of DNA which connect tolabels pieces of DNA which connect to

the corresponding strand during DNAthe corresponding strand during DNAreplication.replication. In situ hybridizationIn situ hybridization(ISH)(ISH) is a type ofis a type ofhybridizationhybridization that usesthat usesa labeleda labeled complementarycomplementary

DNADNA oror RNARNA strand (i.e.,strand (i.e., probeprobe) to localize) to localizea specific DNA or RNA sequence in aa specific DNA or RNA sequence in aportion or section ofportion or section oftissuetissue ((in situin situ))


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F.I.S.H.F.I.S.H. (gene probes)(gene probes)

greatly enhances Ggreatly enhances G--bandingbanding

Fluorescent In-SituHybridizationUses fluorescentlabelled DNA

fragments,~10,000 basepairs, to bind (ornot bind) to its

complement


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FISHFISH

SUBTLE MICRODELETIONS COMAPLEX TRANSLOCATIONS

AND TELOMERE ALTERATIONS


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MULTIMULTI--FACTORIALFACTORIAL

INHERITANCEINHERITANCE MultiMulti--FACTORIAL, not just multiFACTORIAL, not just multi--

GENICGENIC SOIL theorySOIL theory

Common phenotypic expressionsCommon phenotypic expressionsgoverned by multifactorialgoverned by multifactorialinheritanceinheritance

Hair colorHair color Eye colorEye color

Skin colorSkin color HeightHeight IntelligenceIntelligence Diabetes, type IIDiabetes, type II


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MULTIFACTORIALFEATURESMULTIFACTORIALFEATURES

Expression determined by NUMBER ofgenesOverall 5% chance of 1st degree

relatives having itIdentical twins >>>5%, but WAY lessthan 100%This 5% is increased if more children

have itExpression ofCONTINUOUS traits (e.g.,height) vs. DISCONTINUOUS traits(e.g., diabetes)


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MULTIFACTORIALDISORDERSMULTIFACTORIALDISORDERS

Cleft lip, palateCleft lip, palate Congenital heart diseaseCongenital heart disease Coronary heart diseaseCoronary heart disease HypertensionHypertension GoutGout DiabetesDiabetes

Pyloric stenosisPyloric stenosis MANY, MANY, MANY, MANYMANY, MANY, MANY, MANY

MOREMORE


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22-- Chromosomal abnormality:Chromosomal abnormality:

-- Chromosomal aneuploidy, refers to presenceChromosomal aneuploidy, refers to presenceof an entire extra chromosome, (trisomy) mostof an entire extra chromosome, (trisomy) mostcommon example (trisomy 21) = Downcommon example (trisomy 21) = Downsyndrome or absence of whole chromosomesyndrome or absence of whole chromosome(monosomy).(monosomy).

-- Chromosomal translocations: are exchangesChromosomal translocations: are exchangesof chromosomal material between two or moreof chromosomal material between two or morechromosomes.chromosomes.

-- Chromosomal deletions andChromosomal deletions andmicrodeletions:deletion of a segment of amicrodeletions:deletion of a segment of achromosome.chromosome.


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MORE DEFINITIONSMORE DEFINITIONS


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TRISOMY 21TRISOMY 21


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Most trisomies (monosomies,Most trisomies (monosomies,aneuploidy) are from maternal nonaneuploidy) are from maternal non--disjunctiondisjunction

(non(non--disjunction or anaphase lag aredisjunction or anaphase lag areBOTH possible)BOTH possible)

#1 cause of mental#1 cause of mental

retardationretardation Maternal age relatedMaternal age related

Congenital Heart Defects, risk forCongenital Heart Defects, risk for

acute leukemias, GI atresiasacute leukemias, GI atresias Most LOVABLE of all Gods childrenMost LOVABLE of all Gods children


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Chromosome 22q11.2Chromosome 22q11.2

Deletion Syndrome

Deletion Syndrome

Because of a DELETION, this cannot beBecause of a DELETION, this cannot bedetected by standard karyotyping anddetected by standard karyotyping andneeds FISHneeds FISH

Cardiac defects, DiGeorge syndrome,Cardiac defects, DiGeorge syndrome,velocardiofacial, CATCH*velocardiofacial, CATCH*


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MEDELIAN DISORDERS :MEDELIAN DISORDERS :

Classified into two types autosomal or sex linked:Classified into two types autosomal or sex linked:

A gene disorder can also be dominant or recessive.A gene disorder can also be dominant or recessive.

Autosomal Dominant:Autosomal Dominant: 50% children abnormal, Marfans,50% children abnormal, Marfans,familial hypercholesterolemia.familial hypercholesterolemia.

Autosomal recessive :Autosomal recessive : 25% normal, 50% carriers, 25%25% normal, 50% carriers, 25%affected e.g. cystic fibrosis , sickle cell anemia.affected e.g. cystic fibrosis , sickle cell anemia.

Sex linked :Sex linked : Usually recessive, males affected, femalesUsually recessive, males affected, femalescarrier e.g.carrier e.g. ------------------------------------ Hemophilia A.Hemophilia A.

Dominant, when X gene affected (mutation)Dominant, when X gene affected (mutation) --------------------

will cause death.will cause death.

Human Genetics II

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