Tuesday, January 19, 2016

Bio (7): Mycobacterium tuberculosis facts......

Mtb has GC content pf 65.53%
4% of its genome is PE and PPE genes (proline and glutamic acid rich)
Proline is non-polar, while glutamic acid is acidic (high proline means high stress)
PGRS is GC rich. PGRS genes in M. tuberculosis, which have regions with 80-90% GC content
MPTR has many tandem repeats.
 PE has PGRS . PGRS is GC rich
M. tuberculosis possesses a very high number of toxin-antitoxin (TA) systems in its chromosome, 79 in total, regrouping both well-known (68) and novel (11) families, with some of them being strongly induced in drug-tolerant persisters. IS ORFs are flanked by inverted repeats (IR) and direct repeats (DR).
Beijing clade of East Asian lineage have high number of IS6110 (16-24)
Great option to rearrange genome. Hundreds of insertion points and preferred loci have been found.
Genomic unstable regions are targeted by a variety of mobile genetic elements.
Some IS are stable, some are not.
in vitro conditions might affect IS copy number (M. tuberculosis H37Rv  has 17-19 IS6110 copy numbers)
Intergenic region are not junk, they code for gene expression-changing small RNAs (sRNA)
Two component regulatory system: devR/devS
dosR is a regulatory protein
These proteins control HSP proteins and facilitate adaptation, promote dormancy
IS6110 have been seen to cause overexpression of regulatory gene  dosR
Duplication is common. It can be as long as 350kb
pncA is a lineage marker, rather than resistance marker
Spoligotyping (based on spacers) and MIRU (based on repeat units) are lineage assignment techniques
Beijing clade has both ancient (N) and modern(W) branches (the division based on location of IS6110)
About two-third of the genomeis core genome (about 2,100 genes).
HGT is less common in M. tuberculosis, yet its there. Many antibiotic resistance genes have been found in the isolates.
 Known mutations.........(*Codon for gene; *Position for promoter)
INH resistance
katG gene: S315T, katG315N (polar to polar, just size big)
inhA promoter:  −15C/T
ahpC-oxyR region:
efpA, fadE24, iniA,iniB, iniC, kasA, nat, ndh, Rv1772, Rv1592c, Rv0340, and srmR genes
RIF resistance
 rpoB: rpoB531, rpoB526
FQ resistance
gyrA:Ala90Val, Ser91Pro, Asp94 (Gly/Ala/His/Asn)
gyrB: 495, 516, 533
Lineages (There are 7, out which 4 are most-studied)
The Indo- Oceanic lineage: EAI
East African-Indian lineage: CAS
East Asian lineage: Beijing
Euro-American lineage: Ural, X, Haarlem, LAM, S and T

 TubercuList database is based on the below strain of H37Rv. Mycobacterium tuberculosis H37Rv complete genome
GenBank: AL123456.3
Transposon in Mtb
Tn1721: codes for inducible tetracycline resistance  (1 copy)
Tn10: two genes (tetC and tetD) were identified and located (2 copy)
Lytic phages might be captured by CRISPR, lysogenic might be kept in genome, as  an extra MGE. Sometimes, phages are adjacent, and they are highly polymorphic (17% cover and 55% identity)
Phage capsid family protein
Caudovirus prohead protease
Phage terminase, small subunit
phage T7 F exclusion suppressor FxsA
Putative prophage phiRv2 integrase

Bacterial phages:
Lytic: Enterobacteria phage T2, T4, T6
Lysogenic: phage lambda of E. coli
T4  (ds DNA phage) infects E. coli

Phage therapy: Using phage to kill bacteria (instead of using fungi or Streptomyxes-elaborated polyketides). Lytic phage is more suitable for therapy.
Lysogenic phage can detach and become a plasmid.
Some lesser-known bacterial enzymes and their functions:
Anthranilate synthase: pathway of tryptophan biosynthesis
Isonitrile hydratase: caprolactam degradation

Down-regulation and up-regulation of  genes
RNase III activity lowered by stresses, and cold shock

Adhesin protein expression induced by immune response

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