1

TheChromosomalBasisofInheritanceBIOL221

Ch.15

Overview:LocatingGenesAlongChromosomes• Mendel’s“hereditaryfactors” weregenes

• Notknownatthetime

• Todaywecanshowthatgenesarelocatedonchromosomes

• Locationofaparticulargene

• Canbeseenbytaggingisolatedchromosomeswithafluorescent

dyethathighlightsthegene

Fig.15-2

P Generation Yellow-roundseeds (YYRR)

Y

F1 Generation

Y

R R

R Y

´ r

r

r

y

y

y

Meiosis

FertilizationGametes

Green-wrinkledseeds (yyrr)

All F1 plants produceyellow-round seeds (YyRr)

R R

YY

r ry y

Meiosis

R R

Y Y

r r

y y

Metaphase I

Y Y

R Rrr

y yAnaphase I

r r

y Y

Metaphase IIR

Y

R

y

yyy

RR

YY

rrrr

yYY

R R

yRYryrYR1/4 1/4 1/4 1/4

F2 Generation

Gametes

An F1 ´ F1 cross-fertilization

9 : 3 : 3 : 1

LAW OF INDEPENDENTASSORTMENT Alleles of geneson nonhomologouschromosomes assortindependently during gameteformation.

LAW OF SEGREGATIONThe two alleles for each geneseparate during gameteformation.

1

2

33

2

1

2

Morgan’sChoiceofExperimentalOrganism• ThomasHuntMorgan- Embryologist

• Showedgenesareonchromosomes

• Studiedfruitflies

• Convenientorganismforgeneticstudies:

• Theybreedatahighrate

• Agenerationcanbebredeverytwoweeks

• Theyhaveonlyfourpairsofchromosomes

• Wildtype

• Normal,phenotypesthatwerecommoninflypopulations

• Mutantphenotypes

• Traitsalternativetothewildtype

Morgan’sChoiceofExperimentalOrganism

AllelesandBehaviorofaChromosomePair• Matedmaleflieswithwhiteeyes

(mutant)

• Withfemaleflieswithredeyes(wildtype)

• TheF1 generationallhadredeyes

• TheF2 generationshowedthe3:1red:whiteeyeratio

• Butonlymaleshadwhiteeyes

• Thereforewhite-eyedmutantallelemustbeonXchromosome

• Supportedthechromosometheoryofinheritance

PGeneration

Generation

Generation

Generation

Generation

Generation

F1

F2

All offspring had red eyes

SpermEggs

F1

F2

P

SpermEggs

´

´XX

XY

CONCLUSION

EXPERIMENT

RESULTS

w

w

w

w

ww

w w

+

+

+ + +

w

w w w

ww

w

ww

+

++

+ +

+

3

• Inmammals

• twokindsofsexchromosomes- largerX,smallerYchromosome

• RegionsonendsofYchromosome

arehomologouswiththeXchromosome

• TheSRYgeneontheYchromosomecodesforthedevelopmentoftestes

• Someotheranimalshavedifferent

methodsofsexdetermination

• Birds,fish,somecrustaceans,someinsects

• Female:ZW;MaleZZ

Sex-linkedinheritance

InheritanceofSex-LinkedGenes• Sexchromosomes

• Havegenesformany

charactersunrelatedto

sex

• Sex-linkedgene

• Agenelocatedon

eithersex

chromosome

• Inhumans,sex-linked

usuallyreferstoa

geneonthelargerX

chromosome

• CalledX-linked

• Sex-linkedgenesfollowspecificpatternsofinheritance

• Forarecessivesex-linkedtraittobeexpressed

• Afemaleneedstwocopiesoftheallele

• Amaleneedsonlyonecopyoftheallele

• Sex-linkedrecessivedisorders

• Aremuchmorecommoninmalesthaninfemales

Sex-linkedinheritance

(a) (b) (c)

XNXN XnY XNXn´ ´ XNY XNXn ´ XnY

YXnSpermYXNSpermYXnSperm

XNXnEggs XN

XN XNXn

XNY

XNY

Eggs XN

Xn

XNXN

XnXN

XNY

XnY

Eggs XN

Xn

XNXn

XnXn

XNY

XnY

4

• CommonX-linkedconditions- Duetorecessivealleles

• Colorblindness

• Red/greenmostcommon

• Mayinclude19chromosomesand56genes

• Duchennemusculardystrophy

• MutantDystrophingeneXp21

• Hemophilia- Failedbloodclotting

• Threetypes

• TwofoundonXchromosome

Sex-linkedinheritance

XInactivationinFemaleMammals• Mammalianfemales

• OneofthetwoXchromosomes

ineachcellisrandomly

inactivatedduringembryonic

development

• Barrbody

• Thecondensedinactive

X

• Ifafemaleisheterozygousfora

particulargenelocatedontheX

chromosome

• Shewillbeamosaicforthat

character

X chromosomes

Early embryo:

Allele fororange fur

Allele forblack fur

Cell division andX chromosomeinactivationTwo cell

populationsin adult cat:

Active XActive X

Inactive X

Black fur Orange fur

• Eachchromosome

• hashundredsorthousandsofgenes

• linkedgenes

• Geneslocatedonthesamechromosomethattendtobeinherited

togetherarecalled

LinkedGenes

5

HowLinkageAffectsInheritance• Morgandidotherexperimentswithfruitflies

• Toseehowlinkageaffectsinheritanceoftwocharacters

• Crossedflies

• Thatdifferedintraitsofbodycolorandwingsize

b+ vg+

Parents in testcross

Most offspring

b+ vg+

b vg

b vg

b vg

b vg

b vg

b vg

´

or

Fig.15-9-4

EXPERIMENTP Generation (homozygous)

RESULTS

Wild type(gray body,normal wings)

Double mutant(black body,vestigial wings)´

b b vg vg

b b vg vg

Double mutantTESTCROSS

´

b+ b+ vg+ vg+

F1 dihybrid(wild type)

b+ b vg+ vg

Testcrossoffspring Eggs b+ vg+ b vg b+ vg b vg+

Black-normal

Gray-vestigial

Black-vestigial

Wild type(gray-normal)

b vg

Sperm

b+ b vg+ vg b b vg vg b+ b vg vg b b vg+ vgPREDICTED RATIOS

If genes are located on different chromosomes:

If genes are located on the same chromosome andparental alleles are always inherited together:

1

1

1

1

1 1

0 0

965 944 206 185

:

:

:

:

:

:

:

:

:

• Morganfoundthat

• Bodycolorandwingsize

• Areusuallyinheritedtogetherinspecificcombinations

• FailedLawofSegregation

• Reasonedthattheywereonthesamechromosome

• Thereforelinked

• Theclosertogetheronchromosome

• Morelikelytobeinheritedtogether

Linkedinheritance

RESULTS

Testcrossoffspring Eggs b+ vg+ b vg b+ vg b vg+

Black-normal

Gray-vestigial

Black-vestigial

Wild type(gray-normal)

b vg

Sperm

b+ b vg+ vg b b vg vg b+ b vg vg b b vg+ vg

PREDICTED RATIOSIf genes are located on different chromosomes:

If genes are located on the same chromosome andparental alleles are always inherited together:

1

1

1

1

1 1

0 0

965 944 206 185

:

:

:

:

:

:

:

:

:

6

• Afewnon-parentalphenotypeswerealsoproduced

• Geneticrecombination

• Theproductionofoffspringwithcombinationsoftraits

• Differingfromeitherparent

• Ienotgray/normalorblack/vestigial

• Butgray/vestigialorblack/normal

Linkedinheritance

RESULTS

Testcrossoffspring Eggs b+ vg+ b vg b+ vg b vg+

Black-normal

Gray-vestigial

Black-vestigial

Wild type(gray-normal)

b vg

Sperm

b+ b vg+ vg b b vg vg b+ b vg vg b b vg+ vg

PREDICTED RATIOSIf genes are located on different chromosomes:

If genes are located on the same chromosome andparental alleles are always inherited together:

1

1

1

1

1 1

0 0

965 944 206 185

:

:

:

:

:

:

:

:

:

IndependentAssortmentofChromosomes• Mendel- Combinationsoftraitsinsomeoffspringdifferfromeitherparent

• Parentaltypes

• Offspringwithaphenotypematchingoneoftheparentalphenotypes

• Recombinants

• Offspringwithnonparentalphenotypes

• newcombinationsoftraits

• A50%frequencyofrecombinationobservedforanytwogenesondiffchromosomes

• Dueentirelytoindependentassortmentinmetaphase1

YyRr

Gametes from green-wrinkled homozygousrecessive parent ( yyrr)

Gametes from yellow-roundheterozygous parent (YyRr)

Parental-type

offspring

Recombinantoffspring

yr

yyrr Yyrr yyRr

YR yr Yr yR

RecombinationofLinkedGenes:CrossingOver• Morgandiscoveredthatgenescanbelinked

• Butthelinkagewasincomplete

• Evidentfromrecombinantphenotypes

• Proposedthatsomeprocessmustsometimesbreakthephysical

connectionbetweengenesonthesamechromosome

• crossingoverofhomologouschromosomeswasthatmechanism

7

MappingtheDistanceBetweenGenes• AlfredSturtevant

• StudentofMorgan

• Constructedageneticmap

• anorderedlistofthegeneticloci

alongaparticularchromosome

• Predictedthat

• Thefartheraparttwogenesare

• thehighertheprobabilitythatacrossoverwilloccurbetween

them

• andthereforethehighertherecombinationfrequency

Recombinationfrequencies

Chromosome9% 9.5%

17%

b cn vg

• Linkagemap

• geneticmapofachromosome

basedonrecombinationfrequencies

• Mapunits

• Expressionofdistancesbetweengenes

• onemapunit,or

centimorgan,representsa1%recombination

frequency

• Mapunitsindicaterelativedistanceandorder,notpreciselocationsof

genes

LinkageMap

• Genesthatarefarapartonthesame

chromosome

• Canhavearecombination

frequencynear50%

• Suchgenesarephysicallylinked,but

geneticallyunlinked,

• Andbehaveasiffoundon

differentchromosomes

LinkageMap

8

• Sturtevant- usedrecombinationfrequenciestomakelinkagemapsoffruitflygenes

• Chromosomalbanding

• Stainingmethodtoidentifyregionsofchromosomes

• Geneticistscandevelopcytogeneticmapsofchromosomes

• Cytogeneticmaps

• Indicatethepositionsofgeneswithrespecttochromosomalfeatures

• Ie– bandsduetodenselypackagedgene-freeregionsofchromosomes

GeneMapping

Mutant phenotypesShortaristae

Blackbody

Cinnabareyes

Vestigialwings

Browneyes

Redeyes

Normalwings

Redeyes

Graybody

Long aristae(appendageson head) Wild-type phenotypes

0 48.5 57.5 67.0 104.5

Meiosis I

Nondisjunction

(a) Nondisjunction of hom ologouschrom osom es in m eiosis I

(b) Nondisjunction of sisterchrom atids in m eiosis II

Meiosis II

Nondisjunction

Gam etes

Num ber of chrom osom es

n + 1 n + 1 n + 1n – 1 n – 1 n – 1 n n

Alterationsofchromosomenumberorstructure• Large-scalechromosomalalterations

• Oftenleadtospontaneousabortions(miscarriages)

• Orcauseavarietyofdevelopmentaldisorders

• Nondisjunction

• Pairsofhomologouschromosomesor sisterchromatidsdonotseparatenormallyduringmeiosis

• Asaresultonegametereceivestwoofthesametypeofchromosome

• Andanothergametereceivesnocopy

• Aneuploidy

• Resultsfromthefertilizationofgametesinwhichnondisjunction

occurred

• Offspringwiththisconditionhaveanabnormalnumberofaparticular

chromosome

AbnormalChromosomeNumber

9

• Monosomiczygote

• hasonlyonecopyofaparticularchromosome

• Trisomiczygote

• hasthreecopiesofaparticularchromosome

AbnormalChromosomeNumber

• Polyploidy

• conditioninwhichanorganismhas

morethantwocompletesetsof

chromosomes

• Triploidy(3n)isthreesetsof

chromosomes

• Tetraploidy(4n)isfoursetsof

chromosomes

• commoninplants

• butnotanimals

• Polyploidsaremorenormalinappearance

thananeuploids

ChromosomeNumber

AlterationsofChromosomeStructure• Breakageofachromosomecanleadtofourtypesofchangesinchromosome

structure:

• Deletionremovesachromosomalsegment

• Duplicationrepeatsasegment

• Inversionreversesasegmentwithinachromosome

• Translocationmovesasegmentfromonechromosometoanother

DeletionA B C D E F G H A B C E F G H(a)

(b)

(c)

(d)

Duplication

Inversion

Reciprocaltranslocation

A B C D E F G H

A B C D E F G H

A B C D E F G H

A B C B C D E F G H

A D C B E F G H

M N O C D E F G H

M N O P Q R A B P Q R

10

AneuploidyDownSyndrome(Trisomy21)• Downsyndrome

• Aneuploidconditionthatresultsfromthreecopiesofchromosome21

• Affectsaboutoneoutofevery700children

• IntheUnitedStates

• ThefrequencyofDownsyndromeincreaseswiththeageofthemother

• Acorrelationthathasnotbeenexplained

AneuploidyofSexChromosomes• Nondisjunctionofsexchromosomes

• Producesavarietyofaneuploidconditions

• Klinefeltersyndrome

• XXYmale

• Sterile,smalltestes,somefemalesecondarysexualcharacteristics

• MonosomyX,Turnersyndrome

• X0female

• sterile

• itistheonlyknownviablemonosomyinhumans

StructurallyAlteredChromosomes• criduchat(“cryofthecat”)

• specificdeletioninchromosome5

• mentalretardation

• catlikecry

• usuallydieininfancyorearlychildhood

• Translocationsofchromosomes

• Certaincancers,includingchronic

myelogenousleukemia(CML)

Normal chromosome 9

Normal chromosome 22

Reciprocaltranslocation Translocated chromosome 9

Translocated chromosome 22(Philadelphia chromosome)

11

GenomicImprinting• Genomicimprinting

• Variationinphenotype

• dependsonwhichparentpassedalongtheallelesforthosetraits

• Involvesthesilencingofcertaingenes

• thatare“stamped” withanimprintduringgameteproduction

• GenomicImprinting

• Oneformofepigenetics

• Theresultofthemethylation(additionof–CH3)ofDNA

• Thoughttoaffectonlyasmallfractionofmammaliangenes

• Mostimprintedgenesarecriticalforembryonicdevelopment

Norm al Igf2 alleleis expressed

Paternalchrom osom e

Maternalchrom osom e

Norm al Igf2 alleleis not expressed

Mutant Igf2 alleleinherited from m other

(a) Hom ozygote

W ild-type m ouse(norm al size)

Mutant Igf2 alleleinherited from father

Norm al size m ouse(wild type)

Dwarf m ouse(m utant)

Norm al Igf2 alleleis expressed

Mutant Igf2 alleleis expressed

Mutant Igf2 alleleis not expressed

Norm al Igf2 alleleis not expressed

(b) Heterozygotes

InheritanceofOrganelleGenes• Extranucleargenes(orcytoplasmicgenes)

• genesfoundinorganellesinthecytoplasm

• Mitochondria,chloroplasts,andotherplantplastidscarrysmallcircularDNAmolecules

• Extranucleargenes

• inheritedmaternally

• zygote’scytoplasmcomesfromtheegg

• Thefirstevidenceofextranucleargenes

• camefromstudiesontheinheritanceofyelloworwhitepatchesonleaves

• Variegation

• Somedefectsinmitochondrial

genes

• Preventcellsfrommaking

enoughATP

• Andresultindiseases

thataffectthemuscular

andnervoussystems

• Forexample,

mitochondrialmyopathy

andLeber’shereditaryopticneuropathy

• Failureofoxidative

phosphorylation

InheritanceofOrganelleGenes

12

Youshouldnowbeableto:

1. Explainthechromosomaltheoryofinheritanceanditsdiscovery

2. Explainwhysex-linkeddiseasesaremorecommoninhumanmalesthanfemales

3. Distinguishbetweensex-linkedgenesandlinkedgenes

4. Explainhowmeiosisaccountsforrecombinantphenotypes

5. Explainhowlinkagemapsareconstructed

6. Explainhownondisjunctioncanleadtoaneuploidy

7. Definetrisomy,triploidy,andpolyploidy

8. Distinguishamongdeletions,duplications,inversions,andtranslocations

9. Explaingenomicimprinting

10. ExplainwhyextranucleargenesarenotinheritedinaMendelianfashion