ChromosomesChromosomes

GeneticsGenetics

20052005

Chromosomal Chromosomal AnomaliesAnomalies

CytogeneticsCytogenetics

The subdivision of genetics that The subdivision of genetics that focuses on chromosomes and cell focuses on chromosomes and cell divisiondivision

Abnormal cell divisions can lead Abnormal cell divisions can lead to abnormal chromosomal to abnormal chromosomal numbers or other anomaliesnumbers or other anomalies

Chromosome Chromosome anomaliesanomalies

may cause phenotype may cause phenotype abnormalities. abnormalities.

A chromosome karyotype revealed she carries three A chromosome karyotype revealed she carries three copies of chromosome 21, a condition called trisomy copies of chromosome 21, a condition called trisomy 21.21.

Wendy Weisz has Down syndrome.

KaryotypeKaryotype A chart arranging A chart arranging

chromosome chromosome pictures according pictures according to their size, to their size, grouped by pairs grouped by pairs of homologs.of homologs.

Chromosomes were named in order of their size and centromere position.

Anatomy of a Anatomy of a chromosomechromosomeCentromeres are the largest Centromeres are the largest

constriction of the chromosome constriction of the chromosome •Site of attachment of spindle fibers•100,000s of 171 base pair repeat, called alpha satellite sequences•Centromere associated proteins are bound

Anatomy of a Anatomy of a chromosomechromosome Telomeres are: Telomeres are:

•At the tips of chromosomes •Many repeats of the sequence TTAGGG•Subtelomeres have more varied short repeats

SubtelomeresSubtelomeresThe chromosome region next to the The chromosome region next to the telomere consists of 8,000 - 300,000 bases telomere consists of 8,000 - 300,000 bases including: including: Repeats similar to the telomere sequenceRepeats similar to the telomere sequenceShorter repeatsShorter repeatsMultigene families of genes Multigene families of genes (e.g. olfactory receptor genes)(e.g. olfactory receptor genes)

Anatomy of a Anatomy of a chromosomechromosome

Chromosomes Chromosomes are categorized are categorized by the relative by the relative location of their location of their centromere.centromere.

•At tip - telocentric•Close to tip - acrocentric•At midpoint - metacentric•Displaced from center - submetacentric

Largest,Metacentric

Smallestacrocentric

Sex chromosomesXX (shown)

Karyotype Karyotype Metaphase Metaphase

chromosomes are chromosomes are squashed on a slide and squashed on a slide and

stained with DNA stained with DNA binding dyes. binding dyes.

Banding patterns help Banding patterns help define different define different chromosomes.chromosomes.

Chromosome Spreads

Ideograms

Chromosome #1

Chromosome Map

P arm

Centromere

Q arm

Chromosomal Chromosomal shorthandshorthand

An ideogram An ideogram represents a represents a chromosome chromosome schematically. schematically.

The major banding The major banding regions are indicated regions are indicated with numbers.with numbers.

Sucrose intolerance Sucrose intolerance is located at 3q.26 is located at 3q.26 (chromosome 3, long (chromosome 3, long arm, major band 26)arm, major band 26)

Chromosomes Chromosomes carry different carry different

genesgenes

Chromosomes Chromosomes differ in size differ in size

ChromoChromosomesome

Size Size in in

milliomillion n

basesbases% of % of

genomegenome

55 194194 66

1616 9898 33

1919 6060 22

2121 33.5533.55 11

2222 33.4633.46 11

FISH: fluorescence FISH: fluorescence in situ hybridizationin situ hybridizationDNA probes labelled DNA probes labelled with fluorescing dye with fluorescing dye bind complementary bind complementary

DNADNA

centromeres

telomeres

Metaphase Chromosomes

KaryotypingKaryotyping

Visualizing Visualizing chromosomeschromosomes Obtain tissue from personObtain tissue from person

Fetal tissue: amniocentesisFetal tissue: amniocentesis chorionic villi samplingchorionic villi sampling fetal cell sorting fetal cell sorting Adult tissue: blood (white blood cells)Adult tissue: blood (white blood cells) cheek swab (buccal cheek swab (buccal

cells)cells) skin cells skin cells tissue biopsytissue biopsy

Prepare cells on slide to remove rest of Prepare cells on slide to remove rest of cell mattercell matter

Stain DNA with dyes or DNA probes to Stain DNA with dyes or DNA probes to visualize DNAvisualize DNA

Evaluate chromosomes in comparison to Evaluate chromosomes in comparison to known informationknown information

The normal The normal karyotype: karyotype: 23 diploid 23 diploid

chromosomchromosomeses Human somatic cells contain 46 Human somatic cells contain 46

chromosomes: chromosomes: paired homologs of chromosomes 1 paired homologs of chromosomes 1

to 22 and to 22 and sex chromosomes (XX or XY)sex chromosomes (XX or XY)

•• DiploidDiploid refers to the presence refers to the presence of two copies of each different of two copies of each different chromosome.chromosome.

Gametes have one set of each Gametes have one set of each chromosome and are called chromosome and are called haploidhaploid..

Cells which contain a normal Cells which contain a normal chromosome constitution are calledchromosome constitution are called euploideuploid..

Chromosome Chromosome AbnormalitiesAbnormalities

PolyploidyPolyploidyAneuploidyAneuploidy monosomymonosomy trisomytrisomyDeletionDeletionDuplicationDuplicationInversionInversionTranslocationTranslocation

Iso Iso chromosomechromosomeRing Ring chromosomechromosome

Extra chromosome setExtra chromosome setExtra or missing chromosomeExtra or missing chromosome one chromosome absentone chromosome absent one chromosome extraone chromosome extraPart of a chromosome missingPart of a chromosome missingPart of a chromosome present Part of a chromosome present twicetwiceSegment of chromosome Segment of chromosome reversedreversedTwo chromosome arms Two chromosome arms exchanged exchanged in part or entirelyin part or entirelyA chromosome with identical A chromosome with identical armsarmsA chromosome that forms a A chromosome that forms a ring ring due to deletions in telomeres, due to deletions in telomeres, which cause ends to adherewhich cause ends to adhere

Chromosomal Chromosomal shorthandshorthandAbbreviatioAbbreviatio

nnWhat it meansWhat it means

46, XY46, XY Normal maleNormal male

46, XX46, XX Normal femaleNormal female

45, X45, X Turner syndrome femaleTurner syndrome female

47, XXY47, XXY Klinefelter syndrome Klinefelter syndrome malemale

47, XYY47, XYY Jacobs syndrome maleJacobs syndrome male

46, XY del 46, XY del (7q)(7q)

Male missing part of long Male missing part of long arm of chromosome 7arm of chromosome 7

47, XX+2147, XX+21 Female with trisomy 21Female with trisomy 21

46, XY t 46, XY t (7;9) (7;9) (p21.1;q34.(p21.1;q34.1)1)

Male with translocation Male with translocation between short arm of between short arm of chromosome 7 band 21.1 chromosome 7 band 21.1 and long arm of and long arm of chromosome 9 band 34.1chromosome 9 band 34.1

PolyploidyPolyploidyIndividuals with three Individuals with three copies of each copies of each chromosome are chromosome are triploid. triploid.

Polyploidy accounts Polyploidy accounts for 17% of all for 17% of all spontaneous abortions spontaneous abortions and 3% of and 3% of stillbirths/newborn stillbirths/newborn deaths.deaths.

Result of:Result of:Two sperm fertilize Two sperm fertilize one egg.one egg.Haploid sperm Haploid sperm fertilizes diploid egg.fertilizes diploid egg.

AneuploidyAneuploidy

Cells with extra or missing chromosomes are aneuploid.

•Nondisjunction is a common cause of aneuploidy resulting in a gamete with one extra chromosome and another gamete with one missing chromosome.

•Nondisjunction during the first meiotic division results in a copy of each homolog in the gamete.

•Nondisjunction during the second meiotic division results in a both sister chromatids in one gamete.

Nondisjunctionin meiosis I Anaphase INondisjunctionin meiosis I

Anaphase II

Nondisjunctionin meiosis II

Gametes

Abnormal gametes Abnormal gametesNormal gametes

Nondisjunction causes aneuploidy

Nondisjunction in meiosis I

Anaphase II

Gametes

Abnormal gametes

Anaphase I

Homologs of small chromosome fail to separate

Sister chromatids separate normally

trisomic monosomic

Nondisjunction in meiosis II

Gametes

Abnormal gametesNormal gametes

trisomicmonosomic

Anaphase II

Anaphase I

Homologs segregate normally

Sister chromatids fail to separate (left)

Sex Chromosome Sex Chromosome AneuploidyAneuploidy

SituationSituation OocOocyteyte

SpeSpermrm

ConsequenceConsequence

NormalNormal XX YY 46, XY normal male46, XY normal male

XX XX 46, XX normal female46, XX normal female

Female Female NondisjuNondisjunctionnction

XXXX YY 47, XXY Klinefelter 47, XXY Klinefelter syndromesyndrome

XXXX XX 47, XXX triplo-X47, XXX triplo-X

YY 45, Y nonviable45, Y nonviable

XX 45, X Turner 45, X Turner syndromesyndrome

Male Male NondisjuNondisjunction nction (meiosis (meiosis I)I)

XX 45, X Turner 45, X Turner syndromesyndrome

XX XXXX 47, XXX triplo-X47, XXX triplo-X

Male Male nondisjunnondisjunction ction (meiosis (meiosis II)II)

XX YYYY 47, XYY Jacobs 47, XYY Jacobs syndromesyndrome

X X 45, X Turner 45, X Turner syndromesyndrome

Turner syndromeTurner syndrome 45, X 45, X

1 in 2,000 female 1 in 2,000 female births births

99% of Turner die in 99% of Turner die in uteroutero

Absence of Y leads to Absence of Y leads to development as a development as a female.female.

Absence of two copies Absence of two copies of X-linked genes in a of X-linked genes in a female results in Turner female results in Turner syndrome.syndrome.

Phenotypes include Phenotypes include short stature, webbing short stature, webbing at back of neck, at back of neck, incomplete sexual incomplete sexual development, hearing development, hearing impairment. impairment.

Relative risk of Relative risk of disease among disease among

Turner syndrome Turner syndrome adultsadults

Triplo-X aneuploidyTriplo-X aneuploidy 47, XXX 47, XXX

1 in 1,000 female births1 in 1,000 female births Extra copy of every X-linked geneExtra copy of every X-linked gene

Few modest effects on Few modest effects on phenotype include tallness, phenotype include tallness, menstrual irregularities and slight menstrual irregularities and slight impact on intelligenceimpact on intelligence

X-inactivation of two X X-inactivation of two X chromosomes occurs while third chromosomes occurs while third remains active seems to remains active seems to compensate for presence of extra compensate for presence of extra X.X.

Klinefelter Klinefelter syndromesyndrome 47, XXY47, XXY

1 in 1,000 male births1 in 1,000 male births Extra copy of each X-linked geneExtra copy of each X-linked gene Phenotypes include incomplete Phenotypes include incomplete

sexual development (rudimentary sexual development (rudimentary testes and prostate), long limbs, testes and prostate), long limbs, large hands and feet, some breast large hands and feet, some breast tissue development.tissue development.

Some cases are not diagnosed until Some cases are not diagnosed until fertility problems arise or remain fertility problems arise or remain undiagnosed.undiagnosed.

XYY syndromeXYY syndrome 47, XYY47, XYY 1 in 1,000 male births1 in 1,000 male births Extra Y chromosomeExtra Y chromosome

96% phenotypically normal96% phenotypically normal Modest phenotypes may Modest phenotypes may

include great height, acne and include great height, acne and minor speech and reading minor speech and reading problems. problems.

Studies suggesting some Studies suggesting some increase in aggressive increase in aggressive behaviors remain controversial.behaviors remain controversial.

Trisomies

Trisomies and Trisomies and MonosomiesMonosomies One extra or one missing chromosome One extra or one missing chromosome

results in extra or missing copies of all of results in extra or missing copies of all of the genes on that chromosome.the genes on that chromosome.

Most trisomies and monosomies produce Most trisomies and monosomies produce inviable embryos.inviable embryos.

Some fetuses with trisomy of smaller Some fetuses with trisomy of smaller autosomes survive to birth with syndromic autosomes survive to birth with syndromic conditions:conditions:

trisomy trisomy (syndro(syndrome)me) Incidence at Incidence at

birthbirth

% % conceptions conceptions that survive that survive >1 year>1 year

13 13 (Patau)(Patau)

1/12,500 to 1/12,500 to 1/21,7001/21,700 < 5 %< 5 %

18 18 (Edwar(Edward)d)

1/6,000 to 1/6,000 to 1/10,0001/10,000 < 5%< 5%

21 21 (Down)(Down)

1/800 to 1/800 to 1/8261/826 85%85%

Down Syndrome – Trisomy, 21

EDWARDS SYNDROME

Three FormsThree Forms Full formFull form (severe) - in this every cell in (severe) - in this every cell in

the body has three no.18 chromosomes the body has three no.18 chromosomes instead of two. instead of two.

Mosaic formMosaic form (less severe) - in this (less severe) - in this some cells have two no.18 some cells have two no.18 chromosomes while others have three. chromosomes while others have three. The extent and severity of the condition The extent and severity of the condition will depend upon the ratio of normal to will depend upon the ratio of normal to abnormal cells. abnormal cells.

Partial formPartial form - in some cases there may - in some cases there may be an extra copy of part of chromosome be an extra copy of part of chromosome 18. This is referred to as partial trisomy 18. This is referred to as partial trisomy 18. The effects of this may be milder 18. The effects of this may be milder and would require further medical and would require further medical advice. advice.

Unusually large uterus during pregnancy Low birth weight infant

Mental deficiency Low-set ears Small jaw

Clenched hands Hypoplastic fingernails

Umbilical hernia or inguinal hernia Diastasis recti Cryptorchidism

Crossed legs (preferred position) Congenital heart disease

VSD (ventricular septal defect) ASD (atrial septal defect)

PDA (patent ductus arteriosus) Congenital kidney abnormalities

Horseshoe kidney Hydronephrosis

Polycystic kidney Coloboma of iris

Microcephaly Motormental retardation

Pectus carinatum

Ventricular Septal Defect - A hole between the lower chambers of the heart which prevents the heart from pumping blood correctly; a heart murmur is generally heard with this congenital defect. Atrial Septal Defect - A hole between the two upper chambers of the heart which makes it difficult for the heart to pump sufficient oxygen-rich blood to the bodys tissues; a heart murmur can be heard. Patent Ductus Arteriosus - A congenital heart defect in which closure of  a duct fails to occur, resulting in abnormal direction of blood flow.

Diagnosis in uteroDiagnosis in utero Examination of the pregnant Examination of the pregnant

woman may show woman may show polyhydramnios. At the birth polyhydramnios. At the birth of the child, an unusually of the child, an unusually small placenta may be noted.small placenta may be noted.

Physical examination may Physical examination may show an excess of arched show an excess of arched type finger print patterns. X-type finger print patterns. X-rays may reveal a short breast rays may reveal a short breast bone. Chromosome studies bone. Chromosome studies show trisomy 18, partial show trisomy 18, partial trisomy, or translocation.trisomy, or translocation.

Patau’s SyndromePatau’s Syndrome

Living with Living with Chromosome 13Chromosome 13

Josiah is diagnosed as Josiah is diagnosed as a Trisomy 13 with a Trisomy 13 with holoprosencephaly and holoprosencephaly and a Dandy-Walker cyst. a Dandy-Walker cyst. His left eye has a His left eye has a coloboma and he is coloboma and he is now fitted with (the now fitted with (the cutest little) glasses. cutest little) glasses. He has hearing aids, a He has hearing aids, a "flattened" windpipe, "flattened" windpipe, and one vocal cord is and one vocal cord is paralyzed. His cleft paralyzed. His cleft palate has not been palate has not been repaired yet, but his lip repaired yet, but his lip has. A V.S.D. is in past, has. A V.S.D. is in past, and has dextrocardia. and has dextrocardia. He still uses a G-tube, He still uses a G-tube, and is just the stoutest and is just the stoutest little thing ever. Last little thing ever. Last but not least, he has but not least, he has the cutest sixth toe on the cutest sixth toe on his left foot.his left foot.

Risk of Patau’s Risk of Patau’s SyndromeSyndrome

Trisomy 13 occurs in approximately 1 in Trisomy 13 occurs in approximately 1 in 12,000 live births. In many cases, 12,000 live births. In many cases, spontaneous abortion (miscarriage) spontaneous abortion (miscarriage) occurs and the fetus does not survive. occurs and the fetus does not survive. The risks of trisomy 13 seem to increase The risks of trisomy 13 seem to increase with the mother's age, particularly if she with the mother's age, particularly if she is older than her early 30s. Male and is older than her early 30s. Male and female children are equally affected, and female children are equally affected, and the syndrome occurs in all races.the syndrome occurs in all races.

Patau syndrome is caused by the Patau syndrome is caused by the presence of three copies of chromosome presence of three copies of chromosome 13. The presence of these three copies---13. The presence of these three copies---rather then the normal two--is a random rather then the normal two--is a random error and cannot be attributed to any error and cannot be attributed to any action or lack of action on the part of the action or lack of action on the part of the parents.parents.

Segregation of a Segregation of a Robertsonian Robertsonian translocationtranslocation

Reciprocal Reciprocal translocationtranslocationExchange of material from one Exchange of material from one

chromosome arm to another is called a chromosome arm to another is called a reciprocal translocation. reciprocal translocation.

Rearrangement of the genetic material Rearrangement of the genetic material results in an individual who carries a results in an individual who carries a translocation but is not missing any translocation but is not missing any genetic material unless a translocation genetic material unless a translocation breakpoint interrupts a gene.breakpoint interrupts a gene.

IsochromosomesIsochromosomes

Chromosomes Chromosomes with identical with identical arms form when arms form when centromeres centromeres divide along the divide along the incorrect plane incorrect plane during meiosis.during meiosis.

UniparenUniparental tal

disomydisomyInheritance of two Inheritance of two chromosomes from chromosomes from one parent is called one parent is called uniparental disomy.uniparental disomy.

May occur when May occur when nondisjunction nondisjunction occurs in both occurs in both parents (one parents (one disomic gamete and disomic gamete and one without one without homolog)homolog)

Loss or Loss or nondisjunction of nondisjunction of one homolog in one homolog in early embryo early embryo followed by followed by reduplication of reduplication of remaining homolog.remaining homolog.

Chromosome Chromosome structural structural

abnormalitiesabnormalities

Chromosomal deletions or Chromosomal deletions or duplications result in extra or duplications result in extra or missing copies of genes in the missing copies of genes in the involved segment. involved segment.

PolyploidyPolyploidy Error in cell division in which all Error in cell division in which all chromatids fail to separate at chromatids fail to separate at anaphase. Multiple anaphase. Multiple fertilizations.fertilizations.

AneuploidyAneuploidy Nondisjunction leading to extra Nondisjunction leading to extra or lost chromosomesor lost chromosomes

Deletions Deletions and and

duplicationsduplications

Translocations.Translocations.

Crossover between a Crossover between a pericentric inversion and pericentric inversion and normal homologuenormal homologue

TranslocatioTranslocationn

Recombination between Recombination between nonhomologous chromosomesnonhomologous chromosomes

InversionInversion Breakage and reunion with Breakage and reunion with wrong orientationwrong orientation

Dicentric or Dicentric or acentric acentric

fragmentsfragments

Crossover between paracentric Crossover between paracentric inversion and normal inversion and normal homologue.homologue.

IsochromosIsochromosomeome

Division of centromeres on Division of centromeres on wrong planewrong plane

Ring Ring chromosomchromosom

ee

Loss of telomeres and fusion of Loss of telomeres and fusion of endsends

Causes of chromosomal Causes of chromosomal abnormalitiesabnormalities

Cri du ChatCri du Chat

Cri Du Chat SyndromeCri Du Chat Syndrome results results from the loss or deletion of a from the loss or deletion of a significant portion of the genetic significant portion of the genetic material from the short arm of material from the short arm of one of the pair of number five one of the pair of number five chromosomes. chromosomes.

Cri Du Chat SyndromeCri Du Chat Syndrome is also is also known as 5P Minus syndrome, known as 5P Minus syndrome, Le Jeune's syndrome and Cat's-Le Jeune's syndrome and Cat's-cry syndrome. cry syndrome.

Cri du Chat Cri du Chat IncidenceIncidence

It is a relatively rare genetic It is a relatively rare genetic condition with an estimated condition with an estimated incidence of between around incidence of between around 1:25,000 to 1:50,000 births. 1:25,000 to 1:50,000 births. There are more children being There are more children being diagnosed now that genetic diagnosed now that genetic testing is carried out more testing is carried out more frequently and is more frequently and is more accurate. In addition,  since accurate. In addition,  since records of this nature are not records of this nature are not kept in most countries, the kept in most countries, the actual incidence is not known. actual incidence is not known.

Features of the Features of the DiseaseDisease

The gene causing the cry has been The gene causing the cry has been located in band 15.3. This would located in band 15.3. This would explain why some babies with explain why some babies with other features of the syndrome do other features of the syndrome do not have the characteristic cry and not have the characteristic cry and some babies have the cry but not some babies have the cry but not the other characteristics.  the other characteristics. 

In most cases the deletion is In most cases the deletion is spontaneous and no specific cause spontaneous and no specific cause can be identified. The parents did can be identified. The parents did nothing wrong to cause it to nothing wrong to cause it to happen. happen.

Ring chromosomesRing chromosomes Chromosomes shaped like a ring Chromosomes shaped like a ring

occur in 1 of 25,000 conceptions.occur in 1 of 25,000 conceptions.

May arise when telomeres are lost May arise when telomeres are lost and sticky chromosome end fuse.and sticky chromosome end fuse.

Ring chromosomes have Ring chromosomes have phenotypes associated with the phenotypes associated with the loss or addition of genetic loss or addition of genetic material.material.

Ring chromosomesRing chromosomes By two DNA breaks, one in each arm of By two DNA breaks, one in each arm of

the same chromosome, followed by the same chromosome, followed by fusion of the proximal broken ends. The fusion of the proximal broken ends. The causes of these DNA breaks are usually causes of these DNA breaks are usually unknown and so is the mechanism unknown and so is the mechanism behind ligation of the ends. It is possible behind ligation of the ends. It is possible that the non-homologous end-joining that the non-homologous end-joining machinery plays a role in this process machinery plays a role in this process (Smith et al. 2001). A ring can also be (Smith et al. 2001). A ring can also be formed by fusion at two breakpoints in formed by fusion at two breakpoints in the same chromosome arm. However, the same chromosome arm. However, only few examples of such rings have only few examples of such rings have been described. Most probably, this is been described. Most probably, this is because they are acentric and will lack because they are acentric and will lack attachment point for the cell division attachment point for the cell division machinery. Unless there is a different machinery. Unless there is a different anchorage sequence for the kinetochore anchorage sequence for the kinetochore complex they will be lost in subsequent complex they will be lost in subsequent mitoses mitoses

Ring ChromosomeRing Chromosome

Formation of the Formation of the RingRing

TranslocationTranslocationDifferent nonhomologous chromosome Different nonhomologous chromosome exchange portions of chromosomes. exchange portions of chromosomes.

Two major types:Two major types:Robertsonian translocationRobertsonian translocation Two nonhomologous acrocentric Two nonhomologous acrocentric chromosomes break at the centromere chromosomes break at the centromere and long arms fuse. The short arms are and long arms fuse. The short arms are often lost. often lost. 5% of Down syndrome results from a 5% of Down syndrome results from a Robertsonian translocation between chr Robertsonian translocation between chr 21 and chr 14 .21 and chr 14 .

Reciprocal translocation Reciprocal translocation Two nonhomologous chromosomes Two nonhomologous chromosomes exchange a portion of their exchange a portion of their chromosome arms.chromosome arms.

Segregation of a Segregation of a pericentric pericentric inversioninversion

Segregation of a Segregation of a paracentric paracentric inversioninversion

Chromosome Chromosome structure structure

abnormalitiesabnormalities Larger regions of deletion or Larger regions of deletion or

duplication increase the duplication increase the likelihood that there will be likelihood that there will be an associated phenotype.an associated phenotype.

InversionsInversions Inverted chromosomes have a region Inverted chromosomes have a region

flipped in orientation compared to wildtype flipped in orientation compared to wildtype chromosomes.chromosomes.

5-10% cause health problems probably due 5-10% cause health problems probably due to disruption of genes at the breakpoints.to disruption of genes at the breakpoints.

Crossing over within the inverted segments Crossing over within the inverted segments leads to genetically imbalanced gametes.leads to genetically imbalanced gametes.

Two types of inversions occur:Two types of inversions occur: Paracentric inverted region does NOT Paracentric inverted region does NOT

include centomereinclude centomere Pericentric inverted region includes Pericentric inverted region includes

centromerecentromere