The clinical significance of DNA organization and diseases associated

1. Prof (Dr) Viyatprajna Acharya MD,
PhD
KIMS & PBMH Hospital, Bhubaneswar
DNA ORGANISATION-II

2. DNA is compressed 8000 times

3. Histone chaperones help in formation
of Nucleosomes
 After histones bind to DNA with the help of
nuclear chromatin assembly factor,
chaperones separate out
 Phasing- Nucleosomes have affinity for
specific sites of DNA; basis not known
 Phasing is likely related both to the relative
physical flexibility of particular nucleotide
sequences to accommodate the regions of
kinking within the supercoil, as well as the
presence of other DNA-bound factors that

4. Transcriptionally Active regions have
different arrangements
 Transcriptionally active or potentially
active regions have altered nucleosome
structure
 Susceptible to DNase I action- makes
single strand cuts
 Hypersensitive sites- interspersed regions
between active chromatin; even more
susceptible to nuclease action– give
access to Dnase probably
 These sites located immediately upstream
of the genes

5. Euchromatin Vs Heterochromatin
 Euchromatin is replicated
earlier than
heterochromatin
 Heterochromatin- at
centromere and telomere
 Inactive regions- high in
meC DNA content
↓
Lower levels of activating
covalent modifications and
high levels of repressing
histone PTMs

6.  Constitutive- always inactive and
condensed; centromere and telomeres
 Facultative- at times of need they may
transcribe and may be seen as
euchromatin
 XX- one X remains inactive till
gametogenesis
And becomes transcriptionally active during
early embryogenesis

7. Polytene chromosomes
 When multiple cycles of DNA replication
occurs without separation of daughter
strands
 Chironomus & Drosophila- contain giant
chromosomes

8. Telomere- ageing and cancer
 Telo= end
 End of chromosome- TG –rich regions
 5’-TTAGGG-3’ repeats- variable in
number
 Extend up to several kilobases
 Telomerase- resembles viral reverse
transcriptase; multi-subunit RNA
containing complex
 Telomerase synthesises telomere and
maintains length of DNA
 Telomere shortening unchecked-
Ageing
 Telomere lengthening- Cancer- target

9. ~1% DNA codes for about 100,000 proteins
 25,000 protein coding genes present
 Most of the DNA is non-protein coding

11. DNA sequence classes
1. Unique sequence DNA/ non-repetitive
DNA
2. Repetitive –sequence DNA
I. Moderately repetitive
II. Highly repetitive
 More than half are unique- single copy
genes that code for proteins
 In human DNA- at least 30% are repetitive
sequence DNA

12. Highly Repetitive sequences
 In tandems 5-500 bp repeats
 Present in centromere and telomeres
 1-10million copies per haploid genome
 Play a structural role in DNA

13.  <106 copies per haploid genome
 Not clustered; interspersed in unique
sequences
 LINEs- Long interspersed nuclear
elements
 SINEs- Short interspersed nuclear
elements
 They appear to be retroposons - through
an RNA intermediate from one location to
another; reverse transcriptase is involved
 LINEs- Mammalian genome consists of 20-
5ok copies of 6-7 kbp LINEs

14. Alu family is SINEs
 Constitutes ~10% of human genome
 Alu- 500,000 copies /haploid genome
 Highly conserved for species to species
 Transposition may occur
 May lead to mutation due to such transpositions
 Clinical significance: Neurofibromatosis
Insertion of Alu family into a gene
Alu B1 & B2 SINE RNAs- involved in transcription and
splicing of RNA

15. Microsatellite repeat sequences
 Repeat sequences that exist both grouped
and dispersed
 Dinucleotide repeats of AC on one strand and
TG on the opposite strand
 CG, AT, CA may also occur
 AC repeats are maxm- 50,000-1Lakh locations
in the genome
 Heritable trait
 Easy to locate them by PCR- genetic linkage
maps
 Most of the genes linked to some or other
microsatellite- basis of genetic disease can be
studied by studying the Microsatellite
polymorphism

16. Trinucleotide sequences are linked with
genetic instability and diseases
 (CGG)n repeats- Fragile X syndrome
 Huntington’s chorea (CAG)
 Myotonic dydtrophy(CTG)
 Spinobulbar muscular atrophy(CAG)

17. Pseudogenes
 Processed genes that can’t encode for any
functional proteins
 Jumping genes- by transposition
 Gene cross-over, recombination, gene
conversion- change the genetic make-up
and have a role in evolution

18.  No change if the cross-over is
homologous
 Immediately post-S phase of
cell cycle it may take place

19. Gene rearrangement
 Immunoglobulins- IgG
 VL & CL genes - widely separated in the
germ line DNA but move closer in plasma
cell DNA that produces the IgG, separated
by an intron

20. More PPT on Medical Biochemistry
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