Lots 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 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.
…
“}}
From 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.
“}}
http://www.nature.com/nature/journal/v428/n6981/abs/nature02358.html
#Exome sequencing & #genetic basis of complex traits
http://www.nature.com/ng/journal/v44/n6/full/ng.2303.html Key pt: amt of rare variants exceeds that from neutral model
Kiezun A, Garimella K, Do R, Stitziel NO, Neale BM, McLaren PJ, Gupta N, Sklar P, Sullivan PF, Moran JL, Hultman CM, Lichtenstein P, Magnusson P, Lehner T, Shugart YY, Price AL, de Bakker PI, Purcell SM, Sunyaev SR. Exome sequencing and the genetic basis of complex traits. Nature Genetics (2012) 44: 623-630
SUMMARY
This article serves as part review, and part research article, focusing on using exome sequencing to detect associations between variants and complex traits.
An important fact they point out, with a wide range of implications for studying disease, is that the number of rare variants exceeds the number predicted by the neutral model. Figure 1 illustrates nicely this excess of rare variants.
I agree with their statement that the majority of these mutations are not “neutral”. They attribute this excess to population expansion or purifying selection, but a plausible explanation that explains this excess, which is found in all organisms regardless of demographic history, is linked selection.
The authors compare statistics derived before and after filtering exome sequencing data of 438 individuals (HIV and Scizophrenia data-sets), illustrating the importance of filtering in obtaining high quality calls. WGS (CGI data on 37 individuals) was used as a benchmark for the number of called SNP counts of different categories (silent, missense, nonsense).
They then proceed to analyze the affect of population stratification on significance values by combining different ratios of individuals from the European-American HIV cohort and the Swedish schizophrenia cohort. (Theory predicts that older populations should have more rare variants because recombination has had more time to break up linkage blocks, and because newer populations have most likely gone through homogenizing bottlenecks.) They find that calculating p-values using a permutation test provides fewer type I errors (false positives), and that this technique can competently deal with population
stratification when conducting association studies.
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.
Linial: ClanTox (www.clantox.cs.huji.ac.il) to classify short peptides as toxins. #ismb #kn1
TOLIPS relevant to brain, neuropeptides
Linial mentions NeuroPID: a predictor for identifying neuropeptide precursors from metazoan proteomes
http://bioinformatics.oxfordjournals.org/content/early/2014/03/05/bioinformatics.btt725.abstract #ismb #kn1
survHD Bioconductor package: Synthesis of high-dimensional survival analysis.
Consistent Force Field for Calculations of Conformations, Vibrational Spectra, and Enthalpies of Cycloalkane and n‐Alkane Molecules http://scitation.aip.org/content/aip/journal/jcp/49/11/10.1063/1.1670007
Lifson & Warshel
CFF
Theoretical Studies of Enzymic Reactions :
Dielectric, Electrostatic and Steric Stabilization of
Reaction of Lysozyme
the Carbonium Ion in the
A. WARSHEL AND M. LEVITT
http://csb.stanford.edu/levitt/Warshel_JMB76_Enzymic_reactions.pdf