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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

Numerical

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

Monosomy
-the absence of a single chromosome Trisomy
-presence of an extra chromosome
-E.g
-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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