linkstream2 microblog

Server for predicting damaging missense #mutations
http://www.nature.com/nmeth/journal/v7/n4/full/nmeth0410-248.html Polyphen2 uses both structure & sequence (eg ASA & conservation)

http://www.ncbi.nlm.nih.gov/pubmed/20354512

Polyphen2 includes both structural and sequence features to predict the effect of nonsynonymous substitutions on protein function. Similar to many other methods, Polyphen2 uses evolutionary conservation as one of the features to identify functionally important residues. Integration of 3D-structure, membrane-specific features (PHAT matrix for TM regions) and other features such as protein-domain and active-site are the strengths of Polyphen2 compared to other sequence-based software making it a good tool for prediction.

Where Do #Introns Come From? A suggestion: exons with premature stops; has implications for #pseudogene formation http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0060283

QT:{{
We have proposed a novel hypothesis for the origin of spliceosomal
introns, invoking endogenous production within translatable sequences
(at least in the case of protein-coding genes), facilitated by the
activity of cellular surveillance mechanisms. Despite the mutational
hazard associated with intron presence and proliferation [136], we
argue that, at least initially, introns might represent a favorable
life line for an allele that has acquired an ORF-disrupting mutation.
In this sense, in-frame stop codons need not be dead ends, as often
believed, but rather sequences that occasionally facilitate the
evolution of eukaryotic gene structure, possibly favoring not only
intronization, but also processes such as exonization (following a PTC
loss [137]). Further experimental validation of our hypothesis would
not only support the idea that intron birth/death rates depend on both
the population-genetic [136] and the intracellular environment, but
also shed light on a surprising aspect of the evolution of eukaryotic
gene structure, i.e., the ongoing, stochastic process of mutual
conversion between exons and introns within genes.
"}}

Inheritance Modes in… #Network Challenges… Guilt-by-Association http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710751 #Diseases of recessive interface SNVs predictable

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710751/

surprisingly, no positional effects on LOF mutations … significant proportion of truncation alleles give rise to functional products

“guilt by assoc works”

signif. number dom mut give rise to func products

Activating Mutations Cluster in… Regions of… #Kinases & Do Not Associate with Conserved or Catalytic Residues
http://onlinelibrary.wiley.com/doi/10.1002/humu.22493/abstract

related to Kin-Driver – a database of driver mutations, which can be used as a gold std in driver predictions

http://www.broadinstitute.org/oncotator
https://github.com/broadinstitute/oncotator

Useful listing of data sources, viz:

QT:{{”

Protein Annotations

Site-specific protein annotations from UniProt.
Druggable target data from DrugBank.
Functional impact predictions from PolyPhen-2.

Cancer Annotations

Observed cancer mutation frequency annotations from COSMIC.
Cancer gene and mutation annotations from the Cancer Gene Census. Significant amplification/deletion region annotations from Tumorscape and theTCGA Copy Number Portal.
Overlapping Oncomap mutations from the Cancer Cell Line Encyclopedia. Significantly mutated gene annotations aggregated from published MutSiganalyses. Cancer gene annotations from the Familial Cancer Database.
Human DNA Repair Gene annotations from Wood et al.

“}}

Uses bamboo testing software
https://www.atlassian.com/software/bamboo

Below is key ref.

## From Brenner talk at ISMB:

Argues that domain trunc prot have a dom. neg pheno.
(ex binding domain for reg & tf or sox10)

NMD fixes this; truncated case now looks like hemizyg.

## Related twitter dialogue:

Brenner: expl. how premature truncation is often a dominant neg. (ex SOX10), providing a rationalization for the purpose of NMD #ISMB #LBR01

@rtraborn · Jul 13
Why would cells generate mRNA that are then immediately degraded by NMD? Brenner suggests that this process has a regulatory function #ISMB

@raarjr · Jul 13
Brenner: 50 nt rule accurately predicts NMD, and is prevalent in auto regulation.so what’s our ruler? #ismb

## REF

http://www.ncbi.nlm.nih.gov/pubmed/9862469

Mol Gen Genet. 1998 Nov;260(2-3):176-84.

mRNA surveillance mitigates genetic dominance in Caenorhabditis elegans.

Cali BM, Anderson P.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710751/

surprisingly, no positional effects on LOF mutations … significant proportion of truncation alleles give rise to functional products

“guilt by assoc works”

signif. number dom mut give rise to func products

Variant Association Tools for Quality Control and Analysis of Large-Scale Sequence and Genotyping Array Data

http://www.cell.com/ajhg/abstract/S0002-9297(14)00176-1

vs

http://papers.gersteinlab.org/papers/vat