Researching SNPs (PKU)

Mutants walk the earth.

There are mutants on your block. There's a mutant right next door. There's one in your shoes.

We are, face it, all mutants. Humanity amounts to a string of mutations millennia-old, tweaks that gave us an edge over the next brute down the line. Upright posture; opposable thumb; prefrontal lobes.

The all-time specifically human thing is language. Familiar yet mysterious, language is the angelic part of us angel/beasts. It is spiritual, evanescent, fugitive - even gorgeous words like those have an unearthly shimmer. - from philly.com

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Short Task Description

In this weeks task, we will research SNPs in the PAH gene that cause or do not cause a different phenotype of the phenylalanine hydroxylase. The chosen databases are: The public release of the Human Gene Mutation Database (HGMD), dbSNP, SNPdbe, OMIM and SNPedia. You may find a detailed task description here. A very dense journal, which offers only a small overview over the things we did can be found here.

Databases

Overview

<figtable id="tab:modelling_scores"> Key Values of the different SNP databases

Database	Last Update	Number of Entries	Number of Entries concerning PAH	Type of information	Sources	Curation/Verification	Comment
HGMD	public after 3 years (quarterly updated)	50,129 (only mis-/nonsense)	397 (only mis-/nonsense)	all types of mutations	current literature	manual and computerised search in current literature	too much advertising
dbSNP	Oct 2011	292,031,791	2590	SNPs, short in/dels, polymorphisms, others	submitted by registered sources (labs, institutes,.. )	clustering of identical submissions by NCBI
SNPdbe	Mar 2012	1,691,464	328	nonsyn. SNPs	Swissprot, dbSNP, PMD, OMIM, 1000 genomes	cf. sources	Predictions of functional effect, experimental evidence if available in source
OMIM	June 2012	21,257 (Summary entries)	1 (64 selected SNPs)	catalog of human genes and genetic disorders and traits	current literature	manually curated
SNPedia	continuous, Wiki-style	29,058	53	SNPs	publicly edited	publicly edited	get genotyped and predicted

</figtable>

Distribution of Mutations

<figtable id="tab:mutation_distri"> Distribution of SNPs from different databases on the PAH gene.

Distribution of SNPs from HGMD on the PAH gene.

Distribution of SNPs from SNPdbe on the PAH gene.

Distribution of SNPs from dbSNP on the PAH gene.

Distribution of missense SNPs from dbSNP on the PAH gene.

Distribution of silent SNPs from dbSNP on the PAH gene.

</figtable>

HGMD

http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PAH

dpSNP

http://www.ncbi.nlm.nih.gov/snp/?term=PAH

29 synonymous SNPs

OMIM

http://omim.org/entry/612349

use to annotate common variants/interesting SNPs (e.g. .0002)

SNPdbe

http://www.rostlab.org/services/snpdbe/dosearch.php?id=name&val=PAH&organism2=human&organism1=

Following the task description, we looked at the conservation score, to determine quickly, whether a mutation found here is disease causing or not. Our reasoning can be found at this subpage.

SNPedia

http://www.snpedia.com/index.php/PAH

The SNPs concerning PAH in SNPedia all appear in dbSNP and there is no additional information attached so we do not investigate them in any separate way.

Mapping

<figure id="fig:SNPMapping">

Mapping of SNP entries found in the different databases. The bar on the left symbolizes the sequence of the PAH-gene. Every horizontal line refers to at least one entry from any of the databases. The numbers on the left of the bar refer to their amino acid position. Colorcoding in the middle section which contains the different mutations:
red: disease causing according to HGMD
orange: missense, but no entry in HGMD
green: silent mutation
Colorcoding in the last column of the picture is for better overview and is according to the meaning of the effect from SNPdbe:
red: probably disease causing
green: probably not disease causing

</figure>