NeuroGem, a knowledgebase of genetic modifiers in neurodegenerative diseases

Dokyun Na, Mushfiqur Rouf, Cahir O'Kane, David C Rubinsztein and Jrg Sponer

Presented byAnjani K DhrangadhariyaJunior Student, MS Life Science InformaticsBonn Aachan International Institute of Information TechnologyUniversitt Bonn

Terms

Knowledge base: a special kind of database for knowledge management. A knowledge base provides a means for information to be collected, organized, shared, searched and utilized.

Genetic modifiers: genes that have small quantitative effects on the level of expression of another gene.

Neurodegenerative disease: Progressive loss of neurons in human brain

http://www.ndsu.edu/pubweb/~mcclean/plsc431/mendel/mendel7.htm

http://helpdeskhelps.com/education/what-is-a-knowledge-base/

PubMed: NeuroGem

Unabridged data

Majority of neurodegenerative diseases are sporadic.

However, strong genetic components linked to ND's identified.

Recent times show significant efforts not only in identification of disease causing genes but also the ND modifying genes.

So you have lots of experimental data which identifies numerous genetic modifiers in different organisms in different NDs. What will you probably do if you want to find new knowledge from all these experiments?

Building the bridge

But till date there exists no compedium that lists or crosslinks genetic modifiers of different ND's

First knowledgebase providing integrated information on genetic modifiers of 9 different NDs.

Improve the approaches to discover what is common to and distinct for different proteinopathies

Characteristics of NeuroGem

Detailed information on experimental condition

Protein-protein interaction sub-network around modifier

Search and display tool

Search for orthologs of human and mouse genes

Includes both high throughput and low throughput data

Users can submit their data on request

Construction and content

Data Collection3 model organisms

9 disease models

Modifiers from variety of diseases

Total experimental records = 87,864

Modifiers = 3,618

Non-modifiers = 84,246

Contents of NeuroGem

Content description

Modifier gene information taken from

Has link for PubMed entry of original study

Protein interaction data from

Facilitate searching genes with same function or if they were involved in same process by incorporating data from

Searching homologs of human and mouse

Gene information, GO annotations, interaction data

DB implementation

Implemented with interface compatible with common web browsers.

Data is stored in RDBMS (MySQL 5.0.59 server)

Improvement of search functions: Javascript and Ajax

HTML generation for displaying information using PHP 5.3.3

Protein-protein interaction network: cytoscape

Current database running on Redhat Linux 5.6

Utility and discussion

Data from NeuroGem can be accessed in 3 different wayA categorical search (category-wise)

Keyword-based search (specific genes)

Ontology based search (For related genes)

Genetic modifier information

At the end of any search, users are directed to genetic modifier information page.

Search for orthologs of Human and Mouse genes

Does not contain any information on genetic modifiers of human and mouse.

However researchers are obviously interested in homologous modifier genes in higher organisms

Broad applicability

To demonstrate broad applicability of NeuroGem and how it provided with new understanding, a variety of meta analysis were performed.

Identify biological processes that are enriched with certain modifiers

Pathways enriched with certain genetic modifiers. Protein folding, cell cycle and splicing.

Researchers can focus on this pathways

HD, generic polyQ, SCA1, SCA3, SCA7 share genetic modifiers not seen in AD

SCA3 = Protein folding and splicing

AD (abeta) = protein synthesis

Identify genes that modify toxicity of several neurodegenerative disorders

Cross disease comparisions can reveal generic modifiers

These generic modifiers can then be tested for in other disease models in other organisms.

Dnaj-1 and BIRC3(thread) shown o reduce neuronal death when upregulated

Atx2 associated with increased risk of ALS

Identification of unique modifiers

Although they are all caused by agrregates

Each ND has different pathophysiology

Example, modifiers confined to AD(Tau) in D. melanogastor are sgg and par-1.

New insights into mechanism of disease modulation

HD: D. MelanogastorAnalysed modifiers and classified according to GO

Aggregate enriched: Protein folding and splicing

Toxicity enriched: Cell cycle, cytoskeleton and protein folding

PD: C. elegansAggregate enriched: Proteolysis

Toxicity enriched: Protein folding, Signaliing

Hence, aggregation modifiers support the formation of aggregates & toxicity modifiers regulate cell tolerance.

Interesting finding!

From HD modifiers, 20 genes enriched in both categories were taken taken and it was identified that the groups include Dnaj-1, thread and Atx2.

Not only these are generic but are also most enriched.

Conclusion

First compedium that catalogous and cross-links genetic modifiers.

Can be utilized for searching and retrieving modifiers, predicting roles of a modifier, visualize surrounding network of modifier, analyse homologous genes from human and mice.

Allows users to evaluate their hypothesis and develop new research directions.

Data in NeuroGem is in downloadable form so other meta analysis can be conducted

Seriously! I need a constructive feedback

Was I too loud?

Was it too fast?

Anything that I can improve...

Thank You