human snps in microrna target sites
DESCRIPTION
Human SNPs in microRNA Target Sites by Brian Magnuson and Yasin SenbabaogluTRANSCRIPT
SNPs in the human genomethat lie within predicted miRNA
target sites
MiRkat Manor presents
19 December, 2007
Yasin“Yossarian”
Şenbabaoglu
Brian“Zaphod”Magnuson.
_
Introduction to microRNAs
subclass of small, non-coding RNA
mature miRs: 19-23nt ssRNA
regulates gene expressionat the level of translation
binds to mRNAmRNA degradation (plants)blocks translation (animals)
miRNA processing
1. transcription of gene (pri-miRNA)
2. pre-processing by Drosha (pre-miRNA)
3. nuclear export
4. post-processing by Dicer (mature miRNA)
5. RISC complex formation
6. target mRNA binding
7. translational inhibition
miRNA processing
images from Ambion, Inc. (www.ambion.com)
miRNA processing
miRNA processing
miRNA processing
miRNA processing
miRNA processing
miRNA processing
miRNA processing
miRNA structure
5' 3'
8mer seed region
highly conserved
target sitecomplementationcrucial
variable-lengthnon-seed region
less conserved
less complementation
Hypotheses
1. If SNPs in human populations existin miR target sites, there may be a real, functional effect in vivo.
2. Given the importance of the 8mer seed,SNPs in target site may show a bias towardbeing within the seed region.
miRtarget
s(miRBas
e)
SNPs(HapMap
)datasources
Generating a set of SNPs in miR targets
miRBasehttp://microrna.sanger.ac.uk/Wellcome Trust Sanger Institute
algorithm: miRanda 3.0targets: v5 (12 November 2007)miR source: miRNA Registry
release 9.0genome source: Ensembl 40
3'UTRs
International HapMap Projecthttp://hapmap.org/Release 22genome source: NCBI build 36Populations:YRI – Yoruban in Ibadan, NigeriaCHB – Han Chinese in BeijingJPT – Japanese in TokyoCEU – European descent in Utah
miRtarget
s(miRBas
e)
SNPs(HapMap
)filters filters
hsa targets
hsa miRs
unique targets
3'UTR
frequencycutoff
split bychromosome
split bychromosome
datasources
filteredtargets
filteredSNPs
Generating a set of SNPs in miR targets
miRtarget
s(miRBas
e)
SNPs(HapMap
)filters filters
hsa targets
hsa miRs
unique targets
3'UTR
frequencycutoff
split bychromosome
split bychromosome
datasources
filteredtargets
filteredSNPs
merge via chromosomal coordinates
tarSNPs
Generating a set of SNPs in miR targets
miRtarget
s(miRBas
e)
SNPs(HapMap
)filters filters
hsa targets
hsa miRs
unique targets
3'UTR
frequencycutoff
split bychromosome
split bychromosome
datasources
filteredtargets
filteredSNPs
merge via chromosomal coordinates
tarSNPs
STATISTICSseed
nonseed
Generating a set of SNPs in miR targets
5' 3'
Z-scores and Hypothesis Testing
For each chromosome of each population, we need to determine whether the target site SNPs have a bias to be inside or outside the seed region (8-mer)
We find the proportion of SNPs within seed regions and standardize them using z-scores. But, is the normality assumption valid?
Z-score:
Distributional Model Chromosome I
for population J
XIJK ~ Bernoulli(p)
Distributional Model Chromosome I
for population J
XIJK ~ Bernoulli(p)
miRNA structure
5' 3'
8mer seed region
highly conserved
target sitecomplimentationcrucial
variable-lengthnon-seed region
less conserved
less complimentation
Further studies
Compare free energy of binding of different allelic variants
Compare predicted target sites to experimentally verified sitesCompare known genes to predicted genesCompare 3'UTR SNPs in and out of target binding sitesExplore conservation across speciesGroup target SNPs intelligently (specific cellular processes,
tissue and system specific, human health conditions)Apply methods to specialized polymorphism data,
such as cancer SNPs
Acknowledgments
Chris Maherpost-doc in Arul Chinnayan's Lab (Pathology)
Animal Planet
vegetables