Clustering disease connections

revealed by DMDM:
Domain Mapping of Disease Mutations

Nathan L. Nehrt, MS1, Thomas A. Peterson1,

Asa O. Adadey1, Maricel G. Kann, PhD1
1University of Maryland, Baltimore County, Baltimore, MD
Protein Domains
 Protein domains are highly conserved structural and
functional subunits of the protein
 Domains fold and function independently, and
frequently mediate interactions with other proteins

Human CFTR
Different Ways to View Mutation
 Traditional gene-centric view
 Relate the mutation to the entire gene

 New domain-centric view

 Relate the mutation to a specific domain
Domain View vs. Gene View

 Domain view gives the functional context of

the mutation
Same Protein:
Different Domains, Different Diseases

Gene Disease Domain

 Zhong & Vidal et al. Molecular Systems Biology (2009)

Same Protein:
Different Domains, Different Diseases
SPTB
Spectrin beta chain, erythrocytic

Spherocytosis mutation Elliptocytosis mutations

actin binding domains helix forming domains

Domain View vs. Gene View

 Domain view gives the functional context of

the mutation

 Domain view reduces the space of inquiry

Reduces the space of inquiry
 ≈22,000 human genes
 ≈34,500 human RefSeq proteins
 Over 550,000 human proteins from all
databases listed in NCBI

 Fewer than 4,500 human protein domains

Domain View vs. Gene View

 Domain view gives the functional context of

the mutation

 Domain view reduces the space of inquiry

 Majority of disease mutations in coding

regions occur inside domains
Majority of Disease Mutations are
Inside Domains

Swiss-Prot Swiss-Prot
Polymorphisms Disease Mutations

Outside
Outside Inside 18%
48% 52% Inside

82%
 DMDM Search Page

http://bioinf.umbc.edu/DMDM/
 Data
 Proteins: RefSeq and SwissProt human proteins
 Domains: CDD, Pfam, SMART, COG
 Variants: non-synonymous coding variants from
OMIM, Swiss-Prot, dbSNP

 Method
 Created HMMs from domain alignments (HMMER)
 Aligned domain models to proteins (HMMER)
 Mapped variants to protein and domain positions
 HMMER: http//hmmer.wustl.edu/
 Shared Domain
Disease A
Protein 1

Disease B
Protein 2

Disease A Disease C
Protein 3

DMDM Domain View

A B A,C Disease Mutation

Non-Disease SNP
284
Disease Connections
Shared Domain
Disease A
Protein 1

Disease B
Protein 2

Disease A Disease C
Protein 3

DMDM Domain View

A B A,C Disease Connection
Disease Connections
MAP4K2
p.Met210Lys
Maturity Onset
Diabetes of the
Young, Type 2

RET
p.Thr946Met
Multiple Endocrine
Neoplasia,
Type 2B

STKc_MAPK - Position 284

Disease Connections:
Same Domain Position, Dissimilar Proteins
Discovery of non-obvious
molecular similarities of diseases Connections found:

Different Disease Categories  Maturity Onset Diabetes

of the Young
& Multiple Endocrine Neoplasia

Same Disease Category

 Colon & Lung Cancer

Different Types of  Bardet-Biedl Sydrome

Related Diseases
Type 6 & Type 10

Same  46 XY Disorder of Sex Dev.

Disease & 46XY Gonadal Dysgenesis*

* filtered out when searching only

for dissimilar proteins
Noise in our dataset
Translational Impact
Transfer of information
between connected diseases

Transfer of information can help us to:

 Better understand the molecular basis of the
connected diseases
 Improve the prediction of deleteriousness of newly
discovered mutations
 Apply existing drugs to the treatment of
different diseases
 Identify new drug targets from domain hotspots
Challenges
 Disease clustering and categorization

 How do we distinguish between different diseases?

 Semantic similarity

 How do we assign disease categories?

 Phenotypic similarity - based on the Disease
Ontology or Human Phenotype Ontology
Challenges
 Evaluation of disease connections
 How do we determine when a connection is novel,
significant, translatable?
 Literature search (PubMed articles where both
disease titles present)
 Identification of existing drugs (DrugBank)

 Working on statistical methods for determining

significance of connections (Yue et al., created
scoring method for domain hotspots)
 Experimental validation of molecular similarity
of diseases

 Yue et al. Human Mutation (2010)

Challenges
 We need your help!
Thank You

 DMDM Authors:
 Tom Peterson, Asa Adadey, Ivette Santana-Cruz,
Yanan Sun, Andrew Winder, and Dr. Maricel Kann

 Additional members of the Kann Lab:

 Guisong Wang, Emily Doughty, Olumide Omobo
References
Peterson, T.A., Adadey, A.O., Santana-Cruz, I., Sun,
Y., Winder, A., Kann, M.G. (2010) DMDM: domain
mapping of disease mutations. Bioinformatics, 26,
2458-2459.

Yue, P. et al. (2010) Inferring the Functional Effects of

Mutation through Clusters of Mutations in
Homologous Proteins. Human Mutation, 31, 264-
271.

Zhong, Q. et al. (2009) Edgetic perturbation models of

human inherited disorders. Molecular Systems
Biology, 5:321