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Chromosomes Medical Genetics 2 Notes

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CHROMOSOMES Structure of chromosomes
-There are 46 DNA altogether each chromosome has 1 DNA molecule
-nucleus of somatic cells: 46 chromomes- 22 pairs of autosomes and single pair of sex chromosomes
-members of each pair homologs : one member of each pair derived from each parent-gametes: 23 chromosomes
-During interphase- which is the phase where the chromosomes spend the majority of the time the chromosomes are found as a single DNA molecule in a single strand
-chromosomes are best seen during metaphase- During S phase DNA replication has taken place so each chromosome consists of:
-consist of 2 identical strands- chromatids
-joined at the centromere- repetitive DNA and are responsible for movement of chromosomes at cell division
-centromere divides the chromosome into short and long arms. P 'petite' arm is the short arm, q 'grande' arm is the long arm
-chromosomes are classified according to where the centromere is
-acrocentric- centromere is towards the end, sometimes have stalk like appendages 'satellites'
-metacentric-centromere is towards the middle
-submetacentric- centromere is an intermediate position of the chromosome
-tip of each chromosome arm is known as the telomere-seal the ends of chromosomes
-telomeres maintain the structural integrity of chromosomes
-highly conserved tandem repeat sequences-TTAGGG
-telomerase enzyme ensures replication-replaces the 5' end of the leading strand - otherwise telomere becomes progressively shorter and critical length is reached where DNA can no longer be replicated. Cell can no longer divide and becomes senescent- occurs during normal cell ageing. In tumours this process goes worng-cell is immortal

Methods of chromosome analysis Chromosome preparation
-living nucleated cell that undergoes cell division is used to study human chromomes: e.g circulating lymphocytes from peripheral blood
-small sample of peripheral venous blood is added to a small volume of nutrient medium containing phytohemagglutinin- stimulates T lymphocytes to divide
-cells are cultured for three days- then colchicines is added to the culturethis drug prevents the formation of the spindle- arresting cell division at metaphase
-hypotonic solution is then added causing cells to lyse and results in spreading of the chromosomes- chromosomes are then fixed onto a slide Method 1: G banding Chromosomes are treated with trypsin- this denatures their protein content
-it is then stained with DNA binding dye giemsa- this gives each chromosome a characteristic and reproducible pattern of light and dark Active (transcribed) areas stain light
-there is high resolution banding: (6-8 megabases) of DNA Method 2: Fluroescent in-situ hybridisation
-probe: single stranded DNA, conjugated with modified nucleotides, anneals with its complementary target sequence wherever it is located on the metaphase spread. After hybridisation it can be visualised using a fluorescent microscope
-advantage: can be used to study chromosomes in cells that are resting in the interval known as the interphase
-can be used for clinical diagnostic purposes
-centromeric probes made up of repetitive DNA sequences- rapid diagnosis of trisomies 13,18,21- used in non dividing cells in interphase
-used in chromosome painting- mixture of colour labelled probes specific for each chromosome is used- each chromosome is seen as a different colour.

-useful in seeing translocations and identifying origin of additional chromosome material (small super numeray markers/ rings
-comparative genome hybridisationused in cancer genetics to detect regions of allele loss/gene amplification. Tumour DNA is labelled with green paint and normal DNA is labelled with red paint.
-gene amplification shows up green and gene loss shows up red. Chromosome abnormalities Structural


Different cell lines

Translocations Deletions Insertations Inversions Rings Isochromosomes

Aneuploidy Polyploidy

Mosaicism Chimerism

Sex chromosome abnormalities

-chromosomal abnormality account for the vast majority of miscarriages Numerical abnormalities
-loss or gain of one or more chromosomes- aneuploidy (abnormal amount of chromosomes)
-most cases: monosomy in the autosomal chromosomes is not compatible with life: as every chromosome must have 2 copies of each gene otherwise there is haploinsufficiency
-similarity trisomy of an autosomal chromosome is also not compatible with life- as there is excess gene dosage- but there are few viable cases
-aneuploidy results in changes in gene dosage which humans are intolerant to- the number of genes correlates to the product of the genes.
-addition of one or more complete haploid complements- polyploidy (abnormal amount of chromosome sets) Causes Non-dysjunction:

-non-disjunction in meiosis 1 results in the gamete containing both homologs of one chromosome pair
-non disjunction in meiosis 2 results in gamete receiving 2 copies of one homologs of the chromosome pair
-non dysjunction in oocytes is more common in older women as before ovulation meiosis 1 occurs which is often abnormal

-the absence of a single chromosome Trisomy
-presence of an extra chromosome
-Down syndrome, additional number 21 chromosome (1 in 700) - often due to failure of separation of one of the pairs of homologous chromosomes during anaphase of maternal meiosis.- mental retardation, typical face, low muscle tone (tongue poking out), septation in the 1st and 2nd toe thyroid problems
-Patau syndrome- trisomy 13 (1 in 5000)- clefting, finger and toe abnormalities, severe mental retardation, heart and scalp defects.
-Edwards syndrome (trisomy 18)- sever mental retardation, rocker bottom feet, clenched overlappping fingers, cardiac abnormalities Polyploidy
-polyploidy cells contain multiples of the haploid number of chromosomes
-E.g: 69 (triploidy-xxx) : often due to polyspermy- vast majority are miscarried or die shortly after brith - if they do survive after birth it is often due to mixoploidy where there are a mixture of cells containing diploid and triploid cells.
-digyny- extra haploid set comes from the mother- failure of one meiotic division during oogenesis leading to a diploid oocyte or the failure of the polar body to be extruded from the oocyte- asymmetric poorly grown fetus, very small placenta- effects are due to genomic imprinting
-92 (tetraploidy)- very rare Structural abnormalities
-structural chromosome rearrangements result from chromosome breakage and reuninon in a different configuration

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