© 2009 nhs national genetics education and development centregenetics and genomics for healthcare ...

© 2009 NHS National Genetics Education and Development Centre

Genetics and Genomics for Healthcarewww.geneticseducation.nhs.uk

ChromosomesAn overview

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Chromosomes

This presentation includes:

• The anatomical structure of chromosomes• Classification of chromosomal anomalies• Description of chromosomal anomalies• Examples of chromosomal anomalies• Explanation of normal and abnormal karyotypes• Chromosomal findings in early miscarriages.



Chromosomes

• Chromosomes are made of DNA.

• Each contains genes in a linear order.

• Human body cells contain 46 chromosomes in 23 pairs – one of each pair inherited from each parent

• Chromosome pairs 1 – 22 are called autosomes.

• The 23rd pair are called sex chromosomes: XX is female, XY is male.

Gene for sickle cell disease (chromosome 11)

Gene for cystic fibrosis (chromosome 7)



Chromosomes

pp

CentromereCentromere

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Chromosome 5Chromosome 5



CentromereJoins sister chromatids

Essential for chromosome segregation at cell division100s of kilobases of repetitive DNA: some non-specific, some chromosome specific

Dark (G) bands Replicate lateContain condensed chromatinAT rich

Short armp (petit)

Long armq

Light bands Replicate early in S phaseLess condensed chromatinTranscriptionally activeGene and GC rich

TelomereDNA and protein capEnsures replication to tipTether to nuclear membrane

Telomere

Chromosomes as seen at metaphase during cell division



Different chromosome banding resolutions can resolve bands, sub-bands and sub-sub-bands

Chromosome 1

Human chromosome banding patterns seen on light microscopy



A pair of homologous chromosomes (number 1) as seen at metaphase

Locus (position of a gene or DNA marker)

Allele (alternative form of a gene/marker)



Total Genes On Chromosome: 723373 genes in region marked red, 20 are shown

FZD2AKAP10ITGB4KRTHA8WD1SOST

MPP3

MLLT6

STAT3

BRCA1breast cancer 1, early onsetGFAPNRXN4NSF

NGFR

CACNB1HOXB9HTLVRABCA5CDC6ITGB3

Chromosome 17source: Human Genome Project

Genes are arranged in linear order on chromosomes



Chromosome anomalies

• Cause their effects by altering the amounts of products of the genes involved.

– Three copies of genes (trisomies) = 1.5 times normal amount.

– One copy of genes (deletions)= 0.5 times normal amount.

– Altered amounts may cause anomalies directly or may alter the balance of genes acting in a pathway.



Classification of chromosomal anomalies

• Numerical (usually due to de novo error in meiosis)Aneuploidy - monosomy

- trisomyPolyploidy - triploidy

• Structural (may be due to de novo error in meiosis or inherited) Translocations - reciprocal

- Robertsonian (centric fusion)DeletionsDuplicationsInversions

• Different cell lines (occurs post-zygotically) Mosaicism



Anomalies of chromosome structure

• Translocations

• Deletions• Duplications• Ring chromosomes

RobertsonianReciprocal



Chromosomal deletions and duplications

(not caused by translocations)• Are usually “one off”/de novo events occurring in meiosis.

• Have a very low recurrence risk in future pregnancies.



Most frequent numerical anomalies in liveborn

AutosomesDown syndrome (trisomy 21: 47,XX,+21)

Edwards syndrome (trisomy 18: 47,XX,+18) Patau syndrome (trisomy 13: 47,XX+13)

Sex chromosomesTurner syndrome 45,X

Klinefelter syndrome 47,XXY

All chromosomesTriploidy (69 chromosomes)



The Karyotype

A normal male chromosome pattern would be described as:

46,XY.

46 = total number of chromosomesXY = sex chromosome constitution

(XY = male, XX = female).

Any further description would refer to any abnormalities orvariants found (see following slide for examples).



Total number of chromosomes,

Sex chromosome constitution,

Anormalies/variants.

46,XY47,XX,+2147,XXX69,XXY45,XX,der(13;14)(q10;q10)46,XY,t(2;4)(p12;q12)46,XX,del(5)(p25)46,XX,dup(2)(p13p22)46,XY,inv(11)(p15q14)46,XY,fra(X)(q27.3)46,XY/47,XXY

The Karyotype: an international description



Total number of chromosomes,

Sex chromosome constitution,

Anomalies/variants.46,XY47,XX,+21 Trisomy 21 (Down syndrome)47,XXX Triple X syndrome69,XXY Triploidy

45,XX,der(13;14)(p11;q11) Robertsonian translocation46,XY,t(2;4)(p12;q12) Reciprocal translocation

46,XX,del(5)(p25) Deletion tip of chromosome 546,XX,dup(2)(p13p22) Duplication of part of short arm

Chr 246,XY,inv(11)(p15q14) Pericentric inversion

chromosome 1146,XY,fra(X)(q27.3) Fragile X syndrome46,XY/47,XXY Mosaicism normal/Klinefelter syndrome

The Karyotype: an international description



Chromosomal findings in early miscarriages

40% apparently normal

60% abnormal:Trisomy (47 chromosomes – one extra)30%

45,X (45 chromosomes – one missing)10%

Triploidy (69 chromosomes – three sets)10%

Tetraploidy (92 chromosomes – four sets) 5%

Other chromosome anomalies 5%(e.g. structural anomalies)



Summary of Chromosome Anomalies

• Change in numbere.g. trisomy 21 Down syndrome;

Edwards’ syndrome; Turner syndrome.

Usually an isolated occurrence.

• Change in structuree.g. translocationsMay be inherited.

Trisomy 21

© 2009 nhs national genetics education and development centregenetics and genomics for healthcare ...

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