Javad Jamshidi Fasa University of Medical Sciences, October 2014 Session 3 Medical Genetics Chromosomes And Cell division

2 What do Chromosomes do?

3 p arm q arm

4 Classified according to position of centromere Metacentric: Central centromere Acrocentric: Sub-terminal centromere Submetacentric: Intermediate centromere

5 Autosomes are numbered from largest to smallest, except that chromosome 21 is slightly smaller than chromosome 22

6 The X and Y chromosomes are known as the sex chromosomes because of their crucial role in sex determination. The Y chromosome is much smaller than the X and carries only a few genes, most notably the SRY. In the female each ovum carries an X chromosome, whereas in the male each sperm carries either an X or a Y chromosome.

7 Karyotype Analysis G banding Q banding R banding C banding Molecular Cytogenetics FISH CGH Array CGH

8 Image from: Emery's Elements of Medical Genetics, 14th Edition, by Peter D. Turnpenny and Sian Ellard, (2012)

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10 Image from: Emery's Elements of Medical Genetics, 14th Edition, by Peter D. Turnpenny and Sian Ellard, (2012)

11 Is used most commonly. The chromosomes are treated with trypsin, which denatures their protein content, and then stained Giemsa Approximately 400 to 500 bands per haploid set. Each band corresponds on average to approximately 6 to 8 Mb High-resolution banding, up to 800 bands per haploid set

12 Q banding Similar pattern to G banding, Needs fluorescent microscope R banding Light and dark bands are reversed C banding Used to identify centromeres / heterochromatin

13 Based on the ability a single-stranded DNA to anneal with its complementary target DNA probe is labeled with a fluorochrome Has been widely used for clinical diagnostic and there are a number of different types of probes

14 Used for rapid diagnosis of the common aneuploidy syndromes using non-dividing cells in interphase

15 Useful for identifying tiny submicroscopic deletions and duplications

16 Useful for characterizing complex rearrangements, such as subtle translocations

17 Spectral karyotyping (SKY)

18 For detection of regions of allele loss and gene amplification Useful in study tumors

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20 Image from: Emery's Elements of Medical Genetics, 14th Edition, by Peter D. Turnpenny and Sian Ellard, (2012)

21 Each chromosome arm is divided into regions and each region is subdivided into bands Numbering always from the centromere outwards

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24 Normal male 46,XY Normal female 46,XX A male with Down syndrome 47,XY,+21 female with cri du chat syndrome 46,XX,del(5p) male with a reciprocal translocation involving 2p23 and 4q25 46,XY,t(2;4)(p23;q25)

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26 Meiosis

27 It facilitates halving of the diploid number of chromosomes Provides an extraordinary potential for generating genetic diversity bivalents separate independently, likelihood of two gametes with the same chromosomes is 1 in 2 23, or approximately 1 in 8 million crossing over, each chromatid contains portions of DNA from both parental homologous chromosomes

28 Table from: Emery's Elements of Medical Genetics, 14th Edition, by Peter D. Turnpenny and Sian Ellard, (2012)

29 Numerical Aneuploidy Monosomy Trisomy Tetrasomy Polyploidy Triploidy Tetraploidy Structural Translocations Reciprocal Robertsonian Deletions Insertions Inversions Paracentric Pericentric Rings Isochromosome s Different Cell Lines (Mixoploidy) Mosaicism Chimerism

30 Aneuploidy: loss or gain of one or more chromosomes Trisomy, Tetrasomy Monosomy Polyploidy: addition of one or more complete haploid complements Triploidy

31 Autosomal trisomies compatible with survival to term: Down syndrome (trisomy 21) Patau syndrome (trisomy 13) Edwards syndrome (trisomy 18) Most other autosomal trisomies result in early pregnancy loss Trisomy 16 a particularly common finding in first-trimester spontaneous miscarriages An additional sex chromosome (X or Y) has only mild phenotypic effects

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33 Chromosome AbnormalityPaternal (%)Maternal (%) Trisomy Trisomy Trisomy ,X ,XXX595 47,XXY ,XYY1000 Table from: Emery's Elements of Medical Genetics, 14th Edition, by Peter D. Turnpenny and Sian Ellard, (2012)

34 The absence of a single chromosome Autosomal monosomy is almost always incompatible with survival to term Monosomy of sex chromosome is viable, Turner syndrome 45,X Can result from non-disjunction or anaphase lag in meiosis.

35 Polyploid cells contain multiples of the haploid number of chromosomes such as 69, triploidy, or 92, tetraploidy Triploidy is found relatively often in spontaneous miscarriages Survival beyond mid-pregnancy is rare. Only a few triploid live births have been described and all died soon after birth

36 Origins of triploidy and tetraploidy

37 Result from chromosome breakage with subsequent reunion in a different configuration Balanced: no loss or gain of genetic material generally harmless, but some exceptions carriers are at risk of producing children with an unbalanced chromosomal complement. Unbalanced: contains an incorrect amount of chromosome material The clinical effects are usually serious.

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43 Loss of part of a chromosome and results in monosomy for that segment of the chromosome Loss of more than 2% of the total haploid genome will have a lethal outcome Large deletions Wolf-Hirschhorn and cri du chat Micro delitions Prader-Willi and Angelman syndromes

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What did you learn? Chromosomes Structure Nomenclature Classification Methods of Chromosome Analysis Karyotype Fish Chromosome abnormalities Numerical Structural 47