Mutation@A Glance
ヒト遺伝子バリアント統合可視化ツール
土方敦司、白井 剛＠長浜バイオ大学

http://harrier.nagahama-i-bio.ac.jp/mutation/
BackgroundNGS enabled to identify novel genes/
mutations responsible for diseases

But the MECHANISM of the mutation
for the disease in Black-box？？？

Mutation

Diseasehttps://jp.illumina.com/

Healthy!
individuals

GenomePatients

Variants/Mutations

Increasing success identiﬁcations
Published articles!

GWAS

300!
250!
200!
150!
100!
50!
0!
2008!

2009!

2010!

2011!

2012!

2013!

2014!

2015!

Genome DNA Sequences
Amino acid Sequences
Protein 3D Structures
Supramolecular Structures

Mutation@A Glance!
Integrative analytical platform!
!
3D!
Decoding disease-causing mechanisms
4Dand variants unknown significance

1DYearUsage
Step 1. Search for genes/diseases of interest
Home

Results (Genes)

Search①② Click to Go

Results (Diseases)② Click to GoQueries:üüGene symbol/names!
Sequence accessions!
(RefSeq/Ensembl/UniProt)!
ü Disease names/OMIM#!
ü dbSNP reference ID (rsID)!

Query form

If two or more candidates hit by the query, the candidate are listed as shown above. If only one
gene matched by the query, it jumps to the gene page directly. Click the “GO” button or Genesymbol to jump the gene page manually.!

Step 2. Visualize variants/mutations along with the sequences/structures@Genome3D/Supramolecular structures@Protein

Filter variants

Click
Click

Click

At genome level, the genetic
variants are mapped on theschematic diagram (above)
and also nucleotide sequences(in this case, the sequences
are separated by exons).
Mappability for NGS data also
displayed.!

@

If a residue of either
nucleotide or amino acid in“Variant Map” or “Sequence”
is clicked, detail of theresidue variants is appearedwith a window.!

Step 3. Analyze the disease mutations (Case of STAT1)
Mutation locations
Mechanismon supramolecules

Disease nameInheritanceComplete STAT1
deficiency (ARSTAT1)

ARLFInterior of STAT1
molecule

Eﬀect of mutations
Destabilize subunit structure

AD STAT1 deficiency

ADDN

Interface of subunit/
DNA molecules in
active form

Inhibit forming active form

Chronic
mucocutaneous
candidiasis (CMC)AD

GF

Interface of subunit in
Destabilize inactive form/
inactive form/Interface
Stable active form
between CC and DBD

@SH2

DBD
CCDNA

At protein level, the genetic
variants are visualized on
the “Variant Map” (above),multiple sequencealignment among thehomologous sequences(below). The target aminoacid sequence is also
displayed solely. !

If the structure data are available
for the target proteins, the 3D list
is displayed by clicking thelightblue bar in the “VariantMap”. By clicking the “View”
button, 3D structure data isdisplayed. The NGL molecular
viewer is implemented.!
The molecule can be colored byvarious types of features:!

Databases
Genetic variations in humans!
dbSNP (www.ncbi.nlm.nih.gov/projects/SNP/)!
ExAC(exac.broadinstitute.org)!
COSMIC (cancer.sanger.ac.uk/cosmic)!
ClinVar (www.ncbi.nlm.nih.gov/clinvar/)!
KGP(www.internationalgenome.org/)!
2KJPN (igvd.megabank.tohoku.ac.jp)

Human Genome/Gene/Protein Sequences!
NCBI Gene (www.ncbi.nlm.nih.gov/gene)!
MapView (www.ncbi.nlm.nih.gov/mapview/)!
RefSeq(www.ncbi.nlm.nih.gov/refseq/)!
Ensembl (www.ensembl.org/)!
UniProt(www.uniprot.org)
Protein Structure!
PDB(pdbj.org/)

AD-STAT1: DN mutations
AR-STAT1: AR mutations

CCSH2

DBD

AD-CMC: GF mutations

References
Hijikata, A., Tsuji, T., Shionyu, M., Shirai, T. Sci. Rep. (2017)!
Hijikata, A., Raju, R., Keerthikumar, S., Ramabadran, S., Balakrishnan, L., Ramadoss, S. K.,
Pandey, A., Mohan, S., Ohara, O. DNA Res. (2010)

Acknowledgements
Licensed under a Creative Commons表示4.0国際ライセンス!
©2017 土方 敦司 (長浜バイオ大学)