Posts Tagged ‘exome’

Lanosterol reverses protein aggregation in cataracts : Nature : Nature Publishing Group

Monday, August 17th, 2015

Lanosterol reverses protein aggregation in cataracts
http://www.nature.com/nature/journal/v523/n7562/full/nature14650.html A finding from rare-disease #exome sequencing cc @solvemendelian

QT:{{”
…Lanosterol is an
amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygousLSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSSprevents intracellular protein aggregation of various
cataract-causing mutant crystallins.
“}}

Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate w ith Conserved or Catalytic Residues

Thursday, August 7th, 2014

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

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…

Sunday, July 20th, 2014

#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.

Finding the lost treasures in exome sequencing data

Sunday, April 6th, 2014

Finding lost treasures in #exome sequencing data. Mining off-target, often noncoding, reads from 1000G, TCGA, ESP, &c
http://www.ncbi.nlm.nih.gov/pubmed/23972387

Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants : Nature : Nature Publishing Group

Saturday, August 31st, 2013

QT:”
We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000–10,000 years.

6,515 #exomes reveals the recent origin of most human protein-coding variants: ~75% #SNVs arose in last ~7.5K yrs
http://www.nature.com/nature/journal/v493/n7431/full/nature11690.html

An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People

Monday, August 20th, 2012

Paper with the NS/S ratio: (See Fig 2C).
http://www.sciencemag.org/content/337/6090/100.abstract
Presaging what we’ll see in exomes to come….