Target Essentiality… Characterizes Drug Side Effects – much more so than the total number of targets for a #drug
http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.100311
Archive for the 'SciLit' Category
PLOS Computational Biology: Target Essentiality and Centrality Characterize Drug Side Effects
August 7, 2014Dissecting Disease Inheritance Modes in a Three-Dimensional Protein Network Challenges the “Guilt-by-Asso ciation” Principle
August 7, 2014Inheritance 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 the “Molecular Brake” Regions of Protein Kinases and Do Not Associate w ith Conserved or Catalytic Residues
August 7, 2014Activating 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
Is Sleep Essential?
August 3, 2014Is Sleep Essential?
http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0060216 Amusing evidence from varied animals, eg 1-hemisphere dolphin #sleep & dying sleep-deprived rats
less than 10 percent of the human genome is functional
July 30, 2014‘Kardashian index’ in science
July 30, 2014A great article discussing the major issue of hyped social media presence:
“Social media makes it very easy for people to build a seemingly impressive persona by essentially ‘shouting louder’ than others. Having an opinion on something does not make one an expert.”
In pursuit of design principles of regulatory sequences – Nat Rev Genet
July 29, 2014http://www.nature.com/nrg/journal/v15/n7/abs/nrg3684.html
In pursuit of design principles of regulatory sequences
Michal Levo & Eran Segal
Nature Reviews Genetics 15, 453–468 (2014) doi:10.1038/nrg3684
Ecker mentions: Design principles of regulatory sequences
http://www.nature.com/nrg/journal/v15/n7/abs/nrg3684.html … for schematics on how to follow up reg. variants #GSPfuture
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
July 29, 2014Lots of LOF! — Boenke mentions: LOF mutations in SLC30A8 protect against T2D http://www.nature.com/ng/journal/v46/n4/full/ng.2915.html Power of combining data for mult. variants #GSPfuture
Evolution at Two Levels: On Genes and Form
July 23, 2014Evolution at 2 Levels: Genes &
Formhttp://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0030245 Reg evol likely for genes in mult tissues, w. pleiotropic coding SNPs & mult CRMs
QT:{{”
One critical parameter that affects the relative contribution of different genetic mechanisms to anatomical variation is the pleiotropy of mutations []. In general, it is expected that mutations with greater pleiotropic effects will have more deleterious effects on organismal fitness and will be a less common source of variation in form than mutations with less widespread effects.
Over the past 30 years, several key features of gene structure, function, and regulation in multicellular organisms have emerged that govern the pleiotropy of mutations and thus shape the capacity of species to generate anatomical variation and to evolve (see ). Because of these features, mutations in different genes and different parts of genes (that is, non-coding and coding sequences) can differ
dramatically in their degree of pleiotropy. For example, a mutation in the coding region of a transcription factor that functions in multiple tissues may directly affect all of the genes the protein regulates. In contrast, a mutation in a single cis-regulatory element will affect gene expression only in the domain governed by that element.
…
The most influential single publication of this era, however, was Susumu Ohno’s book Evolution by Gene Duplication []. Ohno focused on the importance of gene redundancy in allowing “forbidden” mutations to occur that could impart new functions to proteins. His opening motto, “natural selection merely modified, while redundancy created,” reflected a view of natural selection as a largely purifying, conservative process. Ohno insisted that “allelic mutations of already existing gene loci cannot account for major changes in evolution.”
…the estimated rate of gene duplication is about once per gene per 100 million years []. This figure suggests that gene duplication can contribute to genome evolution over longer spans of evolutionary time (for example, greater than 50 million years)….
The human FOXP2 gene encodes a transcription factor, and mutations at the locus were discovered to be associated with a speech and language disorder…. While it would certainly be convenient if the two changes in the FOXP2 protein were functional, the additional hypothesis must be considered that functional regulatory changes might have occurred at theFOXP2 locus. In weighing alternative hypotheses of FOXP2 or any gene’s potential involvement in the evolution of form (or neural circuitry), we should ask the following questions. (i) Is the gene product used in multiple tissues? (ii) Are mutations in the coding sequence known or likely to be pleiotropic? (iii) Does the locus contain multiple cis-regulatory elements?
If the answers are yes to all of these questions, then regulatory sequence evolution is the more likely mode of evolution than coding sequence evolution.
…
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Myosin gene mutation correlates with anatomical changes in the human lineage : Abstract : Nature
July 23, 2014From S Caroll, “Many approaches are being taken, and a few intriguing associations of candidate genes and the evolution of particular traits have been discovered, such as the…MYH16 muscle-specific myosin pseudogene and the evolutionary reduction of the masticatory apparatus.”
QT:{{”
Powerful masticatory muscles are found in most primates, including chimpanzees and gorillas…. In contrast, masticatory muscles are considerably smaller in both modern and fossil members of Homo. …Here, we show that the gene encoding the predominant myosin heavy chain (MYH) expressed in these muscles was inactivated by a
frameshifting mutation after the lineages leading to humans and chimpanzees diverged. Loss of this protein isoform is associated with marked size reductions in individual muscle fibres and entire masticatory muscles. Using the coding sequence for the myosin rod domains as a molecular clock, we estimate that this mutation appeared approximately 2.4 million years ago.
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http://www.nature.com/nature/journal/v428/n6981/abs/nature02358.html
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