Posts Tagged ‘lof’

PLOS Computational Biology: Analysis of Stop-Gain and Frameshift Variants in Human Innate Immunity Genes

October 24, 2014

Methods for Detecting Associations with Rare Variants for Common Diseases: Application to Analysis of Sequence Data

October 24, 2014 #ASHG14

Dissecting Disease Inheritance Modes in a Three-Dimensional Protein Network Challenges the “Guilt-by-Asso ciation” Principle

August 7, 2014

Inheritance Modes in… #Network Challenges… Guilt-by-Association #Diseases of recessive interface SNVs predictable

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

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

July 29, 2014

Lots of LOF! — Boenke mentions: LOF mutations in SLC30A8 protect against T2D Power of combining data for mult. variants #GSPfuture

mRNA surveillance mitigates genetic dominance … Mol Gen Genet. 1998 – PubMed – NCBI

July 19, 2014

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 what’s our ruler? #ismb

## REF

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

mRNA surveillance mitigates genetic dominance in Caenorhabditis elegans.

Cali BM, Anderson P.

Genetics: A gene of rare effect : Nature News & Comment

September 10, 2013

Nature: A gene of rare effect. Interesting discussion of #PCSK9 as a poster child for #LOF mutations #genetics

The woman who had this LOF mutation was identified in the large Dallas cholesterol study based on her family history.

How did the gene exert such profound effects on LDL cholesterol levels? As researchers went on to determine, the PCSK9 protein normally circulates in the bloodstream and binds to the LDL receptor, a protein on the surface of liver cells that captures LDL cholesterol and removes it from the blood. After binding with the receptor, PCSK9 escorts it into the interior of the cell, where it is eventually degraded. When there is a lot of PCSK9 (as in the French families), there are fewer LDL receptors remaining to trap and remove bad cholesterol from the blood. When there is little or no PCSK9 (as in the black people with mutations), there are more free LDL receptors, which in turn remove more LDL cholesterol.

Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

April 9, 2013

Many denovo mutations in autism but few recurrant ones.

“Here they examined over 2000 probands and found only a handful of recurrent mutations…. Also In this article they mention a beta catenin-chromatin remodelling network that seems to encompass a majority of these genes”

Exome sequencing and the genetic basis of complex traits

September 30, 2012

Figure 1 in a recent Nature Genetics paper useful for LOF — saturation of LoF, essentially something that describes how many LoF variants we see as we keep adding more samples :

Basically, LoF variants are so enriched for ultra-rare variants that they show no sign of saturation, and the catalogue will continue to grow as more and more exomes are sequenced.