Lecture(Chromsomes and Human Genetics) Spr 2009

Chromosomes andChromosomes andHuman GeneticsHuman Genetics

Chromosomes & Cancer Chromosomes & Cancer

• Some genes on chromosomes control Some genes on chromosomes control cell growth and divisioncell growth and division

• If something affects chromosome If something affects chromosome structure at or near these loci, cell structure at or near these loci, cell division may spiral out of controldivision may spiral out of control

• This can lead to cancerThis can lead to cancer

Philadelphia ChromosomePhiladelphia Chromosome

• First abnormal chromosome to be First abnormal chromosome to be

associated with a cancerassociated with a cancer

• Reciprocal translocationReciprocal translocation

• Causes chronic myelogenous Causes chronic myelogenous

leukemia (CML)leukemia (CML)

Genes Genes

• Units of information about heritable Units of information about heritable

traitstraits

• In eukaryotes, distributed among In eukaryotes, distributed among

chromosomeschromosomes

• Each has a particular locus Each has a particular locus – Location on a chromosomeLocation on a chromosome

Homologous Homologous ChromosomesChromosomes

• Homologous autosomes are Homologous autosomes are identical in length, size, shape, and identical in length, size, shape, and gene sequencegene sequence

• Sex chromosomes are nonidentical Sex chromosomes are nonidentical but still homologousbut still homologous

• Homologous chromosomes Homologous chromosomes interact, then segregate from one interact, then segregate from one another during meiosisanother during meiosis

AllelesAlleles

• Different molecular forms of a geneDifferent molecular forms of a gene

• Arise through mutationArise through mutation

• Diploid cell has a pair of alleles at Diploid cell has a pair of alleles at

each locuseach locus

• Alleles on homologous chromosomes Alleles on homologous chromosomes

may be same or differentmay be same or different

Sex ChromosomesSex Chromosomes

• Discovered in late 1800sDiscovered in late 1800s

• Mammals, fruit fliesMammals, fruit flies

– XX is female, XY is maleXX is female, XY is male

• In other groups XX is male, XY femaleIn other groups XX is male, XY female

• Human X and Y chromosomes function Human X and Y chromosomes function

as homologues during meiosisas homologues during meiosis

Karyotype Preparation - Karyotype Preparation - Stopping the Cycle Stopping the Cycle

• Cultured cells are arrested at Cultured cells are arrested at metaphase by adding colchicinemetaphase by adding colchicine

• This is when cells are most This is when cells are most condensed and easiest to identifycondensed and easiest to identify

Karyotype PreparationKaryotype Preparation

• Arrested cells are broken openArrested cells are broken open

• Metaphase chromosomes are Metaphase chromosomes are fixed and stainedfixed and stained

• Chromosomes are photographed Chromosomes are photographed through microscopethrough microscope

• Photograph of chromosomes is Photograph of chromosomes is cut up and arranged to form cut up and arranged to form karyotype diagramkaryotype diagram

1 2 3 4 5 6 7 8 9 10 11 12

13 14 15 16 17 18 19 20 21 22 XX (or XY)

Figure 12.4Page 197

Karyotype DiagramKaryotype Diagram

Sex Sex DeterminatioDetermination n

X

X Y

X

XX

XY

XX

XY

X X

Y

X

x

x

eggs sperm

female(XX)

male(XY)

Figure 12.5Page 198

The Y ChromosomeThe Y Chromosome

• Fewer than two dozen genes Fewer than two dozen genes

identifiedidentified

• One is the master gene for male sex One is the master gene for male sex

determination determination – SRY gene (sex-determining region of Y)SRY gene (sex-determining region of Y)

• SRY present, testes formSRY present, testes form

• SRY absent, ovaries formSRY absent, ovaries form

Effect of YEffect of YChromosomeChromosome

10 weeks

Y present

Y absent

7 weeks

birth approaching

appearance of structuresthat will give rise toexternal genitalia

appearance of “uncommitted” duct system

of embryo at 7 weeks

Y present

Yabsent

testis

ovary

testes ovaries

Figure 12.6Page 199

Androgen DeprivationAndrogen Deprivation

• The “Guevedoces” of the Dominican The “Guevedoces” of the Dominican RepublicRepublic

• Reports from isolated villages asserted Reports from isolated villages asserted that that ”children appearing to be ”children appearing to be girls turned into men at puberty.”girls turned into men at puberty.” (Urological Sciences Research (Urological Sciences Research Foundation)Foundation)

• http://www.usrf.org/news/010308-http://www.usrf.org/news/010308-guevedoces.htmlguevedoces.html

Male Pseudohermaphrodites Male Pseudohermaphrodites

• ““These children appeared to be girls These children appeared to be girls at birth, but at puberty these 'girls' at birth, but at puberty these 'girls' sprout muscles, testes, and a penis. sprout muscles, testes, and a penis. For the rest of their lives they are For the rest of their lives they are men in nearly all respects …. Their men in nearly all respects …. Their underlying pathology was found to underlying pathology was found to be a deficiency of the enzyme, 5-be a deficiency of the enzyme, 5-alpha Reductase. “alpha Reductase. “

MapMap

From the American Journal of From the American Journal of Medicine Medicine (Am. L. Med. 62: 170-191, 1977)(Am. L. Med. 62: 170-191, 1977)

From the American Journal of From the American Journal of Medicine Medicine (Am. L. Med. 62: 170-191, 1977)(Am. L. Med. 62: 170-191, 1977)

• 6. And for the rest of their lives, the 6. And for the rest of their lives, the guevedoces resemble the other Dominican guevedoces resemble the other Dominican men in all respects except:men in all respects except:* Beard growth is scanty.* Beard growth is scanty.* There is no hairline recession.* There is no hairline recession.* None has acne.* None has acne.* The prostate remains small* The prostate remains small

The X ChromosomeThe X Chromosome

• Carries more than 2,300 genesCarries more than 2,300 genes

• Most genes deal with nonsexual Most genes deal with nonsexual traitstraits

• Genes on X chromosome can be Genes on X chromosome can be expressed in both males and femalesexpressed in both males and females

Discovering Discovering Linkage Linkage

homozygous dominant female

recessive male

Gametes:

XX X Y

All F1 have red eyes

x

1/4

1/4

1/4

1/4

1/2

1/2 1/2

1/2

F2

generation:

XX X Y

xGametes:

Figure 12.7Page 200

Linkage GroupsLinkage Groups

• Genes on one type of Genes on one type of chromosomechromosome

• Fruit fliesFruit flies

– 4 homologous chromosomes4 homologous chromosomes

– 4 linkage groups4 linkage groups

• Not all genes on chromosome Not all genes on chromosome are tightly linkedare tightly linked

Full LinkageFull Linkage

x

AB ab

50% AB 50% ab

All AaBb

meiosis, gamete formation

Parents:

F1 offspring:

Equal ratios of two types of gametes:

AB

ab

AB

ab

ab

AB

Figure 12.8aPage 201

Independent AssortmentIndependent Assortment

Metaphase I:

Metaphase II:

Gametes:

1/4 AB 1/4 ab

1/4 Ab

1/4 aB

A A A A

A A A A

AAAA

B B

B B

BB

B B

BBBB

a a a a

aa aa

aaaa

bb b b

bb b b

b b b b

OR

Incomplete LinkageIncomplete Linkage

Parents:

F1 offspring:

Unequal ratios of four types of gametes:

All AaCc

x

meiosis, gamete formation

AC acA

C A

C

AC

a

c

ac

Ac

aC

a

c

parental genotypes

recombinant genotypes

Figure 12.8bPage 201

Crossover FrequencyCrossover Frequency

Proportional to the distance that Proportional to the distance that

separates genesseparates genesA B C D

Crossing over will disrupt linkage Crossing over will disrupt linkage

between between AA and and BB more often than more often than CC

and and DD In-text figurePage 201

Linkage Mapping in HumansLinkage Mapping in Humans

• Linkage maps based on pedigree Linkage maps based on pedigree analysis through generationsanalysis through generations

• Color blindness and hemophilia are Color blindness and hemophilia are very closely linked on X chromosome very closely linked on X chromosome

Pedigree Pedigree Symbols Symbols

male

female

marriage/mating

Individual showing trait being studied

sex not specified

generationI, II, III, IV...

offspring in order of birth, from left to right


Pedigree for PolydactylyPedigree for Polydactyly

I

II

III

IV

V

6 7

12

5,5 6,6

5,5 6,6

5,5 6,6

5,5 6,6

5,5 6,6

5,5 6,6

6,6 5,5

6,6 5,5

5,6 6,7

6,6 6,6*Gene not expressed in this carrier.

*

malefemale


Genetic AbnormalityGenetic Abnormality

• A rare, uncommon version of a traitA rare, uncommon version of a trait

• PolydactylyPolydactyly

– Unusual number of toes or fingersUnusual number of toes or fingers

– Does not cause any health problemsDoes not cause any health problems

– View of trait as disfiguring is subjectiveView of trait as disfiguring is subjective

New Bond Girl Proud of New Bond Girl Proud of Her 'Little Oddity‘ Her 'Little Oddity‘ by Jonathan by Jonathan Crow | October 7 , 2008Crow | October 7 , 2008

“Gemma Arterton … has proven herself to be exceptional not only for her English Rose beauty, but also because she was born with six fingers on each hand.”

Genetic DisorderGenetic Disorder

• Inherited conditions that cause mild Inherited conditions that cause mild

to severe medical problemsto severe medical problems

• Why don’t they disappear?Why don’t they disappear?– Mutation introduces new rare allelesMutation introduces new rare alleles

– In heterozygotes, harmful allele is In heterozygotes, harmful allele is

masked, so it can still be passed on to masked, so it can still be passed on to

offspring offspring

Autosomal Recessive Autosomal Recessive Inheritance PatternsInheritance Patterns

• If parents are If parents are

both both

heterozygous, heterozygous,

child will have child will have

a 25% chance a 25% chance

of being of being

affected affected Figure 12.10aPage 204

GalactosemiaGalactosemia

• Caused by autosomal recessive alleleCaused by autosomal recessive allele

• Gene specifies a mutant enzyme in the Gene specifies a mutant enzyme in the pathway that breaks down lactosepathway that breaks down lactose

In-text figurePage 204

galactose-1-phosphate

enzyme 2

lactose galactose

enzyme 1

+glucose

galactose-1-phosphate

enzyme 3

intermediatein glycolysis

One Common Ancestor One Common Ancestor Behind Blue EyesBehind Blue Eyes• People with blue eyes have a single, People with blue eyes have a single,

common ancestor, according to new common ancestor, according to new research. research.

• A team of scientists has tracked down A team of scientists has tracked down a genetic mutation that leads to blue a genetic mutation that leads to blue eyes. The mutation occurred between eyes. The mutation occurred between 6,000 and 10,000 years ago. Before 6,000 and 10,000 years ago. Before then, there were no blue eyes.then, there were no blue eyes.

• http://www.livescience.com/health/080131-blue-eyes.htmlhttp://www.livescience.com/health/080131-blue-eyes.html

from Beals et al., An Introduction to Anthropology, 1965

Percentage Frequency of Light Eyes in and Near Europe

Danish geneticist Hans Danish geneticist Hans Eiberg in the journal Eiberg in the journal Human Human GeneticsGenetics• ““Originally, Eiberg says, everyone in the Originally, Eiberg says, everyone in the

world had brown eyes. But the mutation world had brown eyes. But the mutation acts as a switch that shuts off the OCA2 acts as a switch that shuts off the OCA2 gene, which controls the eye's production gene, which controls the eye's production of melanin. Melanin is the pigment that of melanin. Melanin is the pigment that gives color to eyes and hair.”gives color to eyes and hair.”

• http://www.spiegel.de/international/http://www.spiegel.de/international/world/0,1518,532346,00.htmlworld/0,1518,532346,00.html

““Inbred Mutants”Inbred Mutants”

“Brad Pitt's squinting a bit in the light of the flashbulbs, but he has blue eyes. A new study suggests he shares a common ancestor with all the world's other blue-eyed denizens.”

Pitt, Diaz, and Sinatra

HeteroHeterochromiachromia

• Heterochromia is an ocular condition Heterochromia is an ocular condition in which one iris is a different color in which one iris is a different color from the other iris (complete from the other iris (complete heterochromia), or where the part of heterochromia), or where the part of one iris is a different color from the one iris is a different color from the remainder (partial heterochromia or remainder (partial heterochromia or sectoral heterochromia). sectoral heterochromia).

http://en.wikipedia.org/wiki/Eye_color

Complete and Sectoral Complete and Sectoral HeterochromiaHeterochromia

http://en.wikipedia.org/wiki/Eye_color

Causes of HeterochromiaCauses of Heterochromia

• Chimeras and Waardenburg Chimeras and Waardenburg syndromesyndrome

• Injury or medicationInjury or medication

Autosomal Autosomal Dominant InheritanceDominant Inheritance

Trait typically Trait typically appears in appears in every every generationgeneration


Huntington DisorderHuntington Disorder

• Autosomal dominant alleleAutosomal dominant allele

• Causes involuntary movements, nervous Causes involuntary movements, nervous system deterioration, deathsystem deterioration, death

• Symptoms don’t usually show up until Symptoms don’t usually show up until person is past age 30person is past age 30

• People often pass allele on before they People often pass allele on before they know they have itknow they have it

AchondroplasiaAchondroplasia

• Autosomal dominant alleleAutosomal dominant allele

• In homozygous form usually leads to In homozygous form usually leads to stillbirthstillbirth

• Heterozygotes display a type of Heterozygotes display a type of dwarfismdwarfism

• Have short arms and legs relative to Have short arms and legs relative to other body partsother body parts

AchondroplasiaAchondroplasia

X-Linked Recessive X-Linked Recessive InheritanceInheritance

• Males show Males show disorder more disorder more than femalesthan females

• Son cannot Son cannot inherit disorder inherit disorder from his fatherfrom his father


Examples of X-Linked TraitsExamples of X-Linked Traits

• Color blindnessColor blindness– Inability to distinguish among some of all Inability to distinguish among some of all

colorscolors

• HemophiliaHemophilia– Blood-clotting disorderBlood-clotting disorder

– 1/7,000 males has allele for hemophilia A1/7,000 males has allele for hemophilia A

– Was common in European royal familiesWas common in European royal families

Royal HemophiliaRoyal Hemophilia

http://www.people.virginia.edu/~rjh9u/roylhema.html

• A Pedigree of Hemophilia in the Royal A Pedigree of Hemophilia in the Royal Families of EuropeFamilies of Europe

• • Selected members of the pedigreeSelected members of the pedigree • I-1 = King George III I-1 = King George III • III-1 and III-2 = Prince Albert and Queen Victoria III-1 and III-2 = Prince Albert and Queen Victoria • IV-5 and IV-6 = Alice of Hesse and Ludwig IV of IV-5 and IV-6 = Alice of Hesse and Ludwig IV of

Hesse Hesse • V-13 and V-14 = V-13 and V-14 = Alix and Nicholas II (Tsar of (Tsar of

Russia) Russia) • VI-16 = Alexei VI-16 = Alexei • VIII-1 = Prince CharlesVIII-1 = Prince Charles

http://www.people.virginia.edu/~rjh9u/tsar.html

Fragile X SyndromeFragile X Syndrome

• An X-linked recessive disorderAn X-linked recessive disorder

• Causes mental retardationCauses mental retardation

• Mutant allele for gene that specifies Mutant allele for gene that specifies

a protein required for brain a protein required for brain

developmentdevelopment

• Allele has repeated segments of DNAAllele has repeated segments of DNA

Fragile X SyndromeFragile X Syndrome

http://www.tokyo-med.ac.jp/genet/index-e.htmo

Photomicrograph Fragile X Photomicrograph Fragile X ChromosomeChromosome

Hutchinson-Gilford ProgeriaHutchinson-Gilford Progeria

• Mutation causes accelerated agingMutation causes accelerated aging

• No evidence of it running in familiesNo evidence of it running in families

• Appears to be dominantAppears to be dominant

• Seems to arise as spontaneous Seems to arise as spontaneous

mutationmutation

• Usually causes death in early teens Usually causes death in early teens

Hutchinson-Gilford ProgeriaHutchinson-Gilford Progeria

ProgeriaProgeria

• ““It is caused by mutations in a LMNA It is caused by mutations in a LMNA (Lamin A protein) gene on (Lamin A protein) gene on chromosome 1”chromosome 1”

• Patients age 6 to 8 times faster, but Patients age 6 to 8 times faster, but no unusual cancer rates or neuro-no unusual cancer rates or neuro-degenerative abnormalities appear degenerative abnormalities appear

• Associated with mal-formed nuclei Associated with mal-formed nuclei which are also seen in the elderly. which are also seen in the elderly. http://en.wikipedia.org/wiki/Progeria

DuplicationDuplication

• Gene sequence that is repeated Gene sequence that is repeated

several to hundreds of times several to hundreds of times

• Duplications occur in normal Duplications occur in normal

chromosomeschromosomes

• May have adaptive advantageMay have adaptive advantage– Useful mutations may occur in copyUseful mutations may occur in copy

DuplicationDuplication

normal chromosome

one segment repeated

three repeats

InversionInversion

A linear stretch of DNA is reversed A linear stretch of DNA is reversed

within the chromosomewithin the chromosome

segments G, H, I become inverted

In-text In-text figurefigurePage 206Page 206

TranslocationTranslocation

• A piece of one chromosome becomes A piece of one chromosome becomes attached to another nonhomologous attached to another nonhomologous chromosomechromosome

• Most are reciprocalMost are reciprocal

• Philadelphia chromosome arose from Philadelphia chromosome arose from a reciprocal translocation between a reciprocal translocation between chromosomes 9 and 22chromosomes 9 and 22

Philadelphia ChromosomePhiladelphia Chromosome

http://gslc.genetics.utah.edu/units/disorders/karyotype/reciprocal.cfm

Philadelphia KaryotypePhiladelphia Karyotype

http://gslc.genetics.utah.edu/units/disorders/karyotype/reciprocal.cfm

In-text figurePage 206

TranslocationTranslocation

one chromosome

a nonhomologouschromosome

nonreciprocal translocation

In-text In-text figurefigurePage 206Page 206

DeletionDeletion

• Loss of some segment of a chromosomeLoss of some segment of a chromosome

• Most are lethal or cause serious disorderMost are lethal or cause serious disorder

AneuploidyAneuploidy

• Individuals have one extra or Individuals have one extra or less chromosome less chromosome

• (2(2nn + 1 or 2 + 1 or 2nn - 1) - 1)

• Major cause of human Major cause of human reproductive failurereproductive failure

• Most human miscarriages are Most human miscarriages are aneuploids aneuploids

PolyploidyPolyploidy

• Individuals have three or more of Individuals have three or more of each type of chromosome (3each type of chromosome (3nn, 4, 4nn))

• Common in flowering plantsCommon in flowering plants

• Lethal for humansLethal for humans– 99% die before birth99% die before birth

– Newborns die soon after birthNewborns die soon after birth

NondisjunctionNondisjunction

n + 1

n + 1

n - 1

n - 1chromosome alignments at metaphase I

nondisjunction at anaphase I

alignments at metaphase II anaphase II

Figure 12.17Page 208

Down SyndromeDown Syndrome

• Trisomy of chromosome 21Trisomy of chromosome 21

• Mental impairment and a variety of Mental impairment and a variety of additional defectsadditional defects

• Can be detected before birthCan be detected before birth

• Risk of Down syndrome increases Risk of Down syndrome increases dramatically in mothers over age 35dramatically in mothers over age 35

Trisomy 21Trisomy 21

Non-disjunctionNon-disjunction

Karotype Trisomy 21Karotype Trisomy 21

Mother’s AgeMother’s Age

Age = 35

Incidence/100

0births

Boy with Down’s SyndromeBoy with Down’s Syndrome

Turner SyndromeTurner Syndrome

• Inheritance of only one X (XO)Inheritance of only one X (XO)

• 98% spontaneously aborted98% spontaneously aborted

• Survivors are short, infertile femalesSurvivors are short, infertile females– No functional ovariesNo functional ovaries

– Secondary sexual traits reducedSecondary sexual traits reduced

– May be treated with hormones, surgeryMay be treated with hormones, surgery

MonosomyMonosomy(Having only one X chromsome (Having only one X chromsome per cell)per cell)

Turner’s SyndromeTurner’s Syndrome

Klinefelter SyndromeKlinefelter Syndrome

• XXY conditionXXY condition

• Results mainly from nondisjunction in Results mainly from nondisjunction in mother (67%)mother (67%)

• Phenotype is tall malesPhenotype is tall males– Sterile or nearly soSterile or nearly so– Feminized traits (sparse facial hair, Feminized traits (sparse facial hair,

somewhat enlarged breasts)somewhat enlarged breasts)– Treated with testosterone injectionsTreated with testosterone injections

KlinefelterKlinefelter

http://www.tokyo-med.ac.jp/genet/index-e.htmo

XYY ConditionXYY Condition

• Taller than average malesTaller than average males

• Most otherwise phenotypically Most otherwise phenotypically normalnormal

• Some mentally impairedSome mentally impaired

• Once thought to be predisposed to Once thought to be predisposed to criminal behavior, but studies now criminal behavior, but studies now discreditdiscredit

Phenotypic TreatmentsPhenotypic Treatments

• Symptoms of many genetic disorders Symptoms of many genetic disorders

can be minimized or suppressed bycan be minimized or suppressed by– Dietary controlsDietary controls

– Adjustments to environmental Adjustments to environmental

conditionsconditions

– Surgery or hormonal treatmentsSurgery or hormonal treatments

Genetic ScreeningGenetic Screening

• Large-scale screening programs Large-scale screening programs detect affected persons detect affected persons

• Newborns in United States Newborns in United States routinely tested for PKUroutinely tested for PKU– Early detection allows dietary Early detection allows dietary

intervention and prevents brain intervention and prevents brain impairmentimpairment

Prenatal DiagnosisPrenatal Diagnosis

• AmniocentesisAmniocentesis

• Chorionic villus samplingChorionic villus sampling

• FetoscopyFetoscopy

• All methods have some risksAll methods have some risks

AmniocentesisAmniocentesis

Pedigree AnalysisPedigree Analysis

Preimplantation DiagnosisPreimplantation Diagnosis

• Used with in-vitro fertilizationUsed with in-vitro fertilization

• Mitotic divisions produce ball of 8 cellsMitotic divisions produce ball of 8 cells

• All cells have same genesAll cells have same genes

• One of the cells is removed and its genes One of the cells is removed and its genes

analyzedanalyzed

• If cell has no defects, the embryo is If cell has no defects, the embryo is

implanted in uterusimplanted in uterus

Preimplant DiagnosisPreimplant Diagnosis

http://www.layyous.com/book/book%20images/Untitled-196b.jpg

Lecture(Chromsomes and Human Genetics) Spr 2009

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