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Skrivnostni svet nekodirajočih delov evkariontskih genomov
Kordiš DušanOdsek za biokemijo in molekularno biologijo, IJS, Ljubljana
19
Junk DNAJunk DNAJunk can sometimes be useful:Junk can sometimes be useful:
•• spare parts (spare parts (modulesmodules))
•• motif donors (motif donors (exon exon shufflingshuffling))
•• molds (molds (gene conversiongene conversion))
7
C-value paradox: ComplexityC-value paradox: Complexitydoes not correlate withdoes not correlate withgenome size.genome size.
3.4 10 9 bpHomo sapiens Amoeba dubia
6.7 1011 bp
6
K-value paradox: ComplexityK-value paradox: Complexitydoes not correlate withdoes not correlate withchromosome number.chromosome number.
46 250
Ophioglossum reticulatumHomo sapiens Lysandra atlantica
1260
8
N-value paradox: ComplexityN-value paradox: Complexitydoes not correlate with genedoes not correlate with genenumber.number.
~31,000 genes~31,000 genes ~26,000 genes~26,000 genes ~50,000 genes~50,000 genes
Human vs. Chimpanzee
• A difference every 100 bases.• A new transposon every 50000 bases• Two chromosome in one species fused
compared to the other.
Human vs. Mouse
• In general 40% of bases have changed.• In functional regions only 15% of bases have
changed.• Looking for conserved regions between human
and mouse helps identify functional parts ofhuman genome.
Deletion of a conserved noncoding sequence selectively reduces expression of cytokine genes over a long distance
Percent identity plots comparing human and other sequences at three loci (CNS:red, exons:blue, introns:yellow)
Cis-regulatorna evolucija
gradual, stepwise accumulation of sites that impart quantitatively greater Hox influence over gene regulation
• What are introns?
Stretches of DNA that are transcribed intoRNA, then spliced out during RNA processing.
Contain functional elements such as splicingsignals, regulatory promoters, and other genes.
Evolve very rapidly in size and content.
Constitute 26%, 11%, and 24% of thenematode, fly, and human genomes.
What forces drive the evolution of intron size?
I ntrons are transcribed
Precursor RNA (dotted)hybridized with DNA (red)
Mature mRNA (dotted)hybridized with DNA (red)
I nton Size - 10 to 100,000 nt
I ntrons vary in size and number
Gene numbers do not increase as much as expected with complexity:
- worm and fly gene numbers (12-14,000) are only about twice those of yeast (6,000) and P. aeruginosa (5,500)- mammalian (human, mouse) gene numbers (~30,000) are only about twice those of invertebrates.
The complexity problem
This suggests that:- animals have a relatively stable core proteome, whose components are multitasked in differentiation and development- variations in phenotype occurs mainly by variation in the control architecture (unlike prokaryotes)
Phenotypic variation in mammals is primarily associated with noncodingregions:- only ~10,000 out of ~3,000,000 polymorphisms between individual humans (0.3%) occur in protein coding sequences- only 1% of genes are different between humans and mice.
98% of transcriptional output in humans is noncoding RNA
Four classes of parasitic DNA elements arefound interspersed throughout the human genome
Retrotransposons
Transposons
1.
2.
3.
4.
Do LINEs Mediate Genomic Plasticity ?
12.5%13.1%SINEs
8.3%8.3%LTRs
45.3%20.4%LINEs
Breakpoints(245 Mb)
Whole Genome(3300 Mb)
chromatin remodeling and demethylation during
(a) normal fertilization and
(b) during cloning by nuclear transfer.
epigenetics as process inducing differentiated cellular states
Chromatin as a template of genetic inheritance
Central role for RNAi in genome maintenance: RNAi responds not only to exogenous nucleic acids but also to endogenous DNA parasites
(a) A viral vector delivers a gene encoding a small interfering RNA (siRNA) to silence the mutant allele of a cancer-causing gene. The vector encodes a short RNA hairpin, which is processed in the cytoplasm by the ribonuclease Dicer into the siRNA.
(b) The siRNA acts as a sequence-specific guide for the RNA-induced silencing complex (RISC) to target cleavage of the mRNA from a specific gene, in this case, the mutant allele of an oncogene.
HIV infection and replication have been targeted by RNA interference (RNAi) (red).
preventing HIV entry and subsequent replication: RNAi has also been used to suppress CD4 expression in host cells (blue).