PolyDoms-Austin

1
Abstract
Additional Gene Targets from NCBI (not included in NIEHS candidate gene list) with BRCT domain Additional Gene Targets from NCBI (not included in NIEHS candidate gene list) with BRCT domain Additional Gene Targets from NCBI (not included in NIEHS candidate gene list) with BRCT domain Additional Gene Targets from NCBI (not included in NIEHS candidate gene list) with BRCT domain Additional Gene Targets from NCBI (not included in NIEHS candidate gene list) with BRCT domain
Gene Symbol No. of nsSNP In a Domain nsSNPs (NCBI-dbSNP) In a Domain Nonsense SNP Count Nonsense SNP
FLJ12847 9 Ser 7 AsnArg 76 SerAla 117 ThrIle 209 ArgHis 219 AspAsp 297 GlyThr 587 AsnAla 666 ValPro 733 Ser 0 0
ADPRTL1 6 Ser 122 AsnTyr 215 PheAla 899 ThrMet 936 ValThr 936 MetIle 1012 Val 0 0
TOPBP1 5 His 58 AsnPro 212 LeuGln 370 LysIle 550 ValSer 955 Asn 0 0
BARD1 3 Met 507 ValLeu 653 PheArg 658 Cys 0 0
CTDP1 3 Ser 282 PheThr 340 MetPro 519 His 0 0
PAXIP1L 3 Ile 124 LeuAla 882 ThrMet 979 Val 1 232 Trp
BRAP 2 Tyr 249 Asp 489 Glu 1 489 Glu
DNTT 1 Arg 112 Gly 0 0
ECT2 0 - 0 0
NIEHS Candidate Genes Prioritized List
As discoveries of genetic polymorphisms in the
human population expand, so does the opportunity
and challenge of correlating these with
disease-risk. Thus, there is a critical need to
efficiently organize large-scale polymorphism
analyses and to prioritize their further testing
through experimental and epidemiologic studies.
To approach this, we have developed a web
accessible server PolyDoms (http//polydoms.cchmc.
org/) as a resource that can serve as an initial
filter for the identification of potentially high
impact nsSNPs (nonsynonymous Single Nucleotide
Polymorphisms). In particular we have
concentrated on potentially deleterious
polymorphisms that might affect gene expression,
protein function and pathways that could lead to
increased environmental agent sensitivity and
risk of diseases associated with loss of genomic
integrity. We have now mapped all EGP
(Environmental Genome Project) cSNPs (coding
SNPs) onto the corresponding conserved and known
functional protein domains from NCBIs CDD
(Conserved Domain Database) and the 3D structures
from PDB (Protein Data Bank). PolyDoms provides
an interactive graphical visualization web
interface, is easy to update with new
polymorphisms and automatically retrieves
relevant literature references. Using an
automatic link to the Polyview server
(http//polyview.cchmc.org), polymorphisms are
also mapped to extremely high quality predictions
of protein secondary structures and relative
solvent accessibilities with polymorphic residues
highlighted. This is also available for each of
the DNA repair and cell cycle control group of
proteins. In addition, the results from nsSNP
effect-prediction servers like PolyPhen
(Polymorphism Phenotyping) and SIFT (Sorting
Intolerant from Tolerant) are also performed
automatically and made available for each of the
nsSNPs. We are now also extending the horizon of
polymorphisms studied to include insertions and
deletions of putative regulatory regionslikely
to be of much higher regulatory impact than
SNPsof environmentally responsive genes.
NIEHS Candidate Genes (not sequenced) List of genes with at least one nsSNP occurring in a domain and predicted as deleterious/damaging. NIEHS Candidate Genes (not sequenced) List of genes with at least one nsSNP occurring in a domain and predicted as deleterious/damaging. NIEHS Candidate Genes (not sequenced) List of genes with at least one nsSNP occurring in a domain and predicted as deleterious/damaging.
Gene nsSNP Frequency
BIRC1 Leu 1323 Trp 000
CAPN2 Lys 568 Gln 0
CKB Lys 267 Glu 0
CYP2A6 Leu 160 His 00.1.035.022
EPHX1 Arg 49 Cys 0.0210.00500
EPHX1 Tyr 113 His 0.38000.29.240
F13B Tyr 543 Ser .025
F3 Arg 163 Trp .025
F5 Pro 809 Ser .025
F5 Asn 817 Thr .10000
GTF2H2 Thr 199 Ile 000
HSPA6 Pro 276 Leu 000
HSPA6 Thr 297 Lys 0
IL12A Met 213 Thr 0
MMP1 Asp 252 Gly 0
NF1 Thr 354 Lys 0
PTGS1 Arg 108 Gln 0
SERPINA1 Cys 256 Trp 0
SERPINA1 Glu 288 Val .02500
SERPINA1 Gly 373 Trp 0
NIEHS Candidate Genes (not sequenced) List of genes with at least one nsSNP predicted as deleterious/damaging. NIEHS Candidate Genes (not sequenced) List of genes with at least one nsSNP predicted as deleterious/damaging. NIEHS Candidate Genes (not sequenced) List of genes with at least one nsSNP predicted as deleterious/damaging.
Gene nsSNP Frequency
CYP2D6 Arg 365 His 0
CYP2D6 Met 451 Ile 0
FGFR4 Arg 388 Gly 0
HSPB1 Val 6 Phe 0
Significant correlation reported between FGFR4
SNP (Arg 388 Gly) and prognosis in patients with
soft tissue sarcoma. This SNP might be used to
improve the prediction of clinical prognosis and
lead to new treatment strategies in patients with
soft tissue sarcomas (Morimoto et al., 2003).
PolyDoms Database Statistics NCBI RefSeq NIEHS Candidates NIEHS Candidates NIEHS Candidates
PolyDoms Database Statistics NCBI RefSeq Total DNA Repair Cell Cycle
Total number 22637 583 97 135
With at least 1 nsSNP 14137 460 85 94
With at least 1 nsSNP in a functional domain 8335 380 77 77
With at least 1 nonsense SNP 778 0 0 0
With a known PDB structure 4202 346 38 83
With a Pfam functional domain defined 16306 542 90 127
CYP2A61 (wild type) is responsible for the
7-hydroxylation of coumarin. The point mutation
(T to A) in codon 160 leads to a single amino
acid substitution (Leu to His) and the resulting
protein, CYP2A2 is unable to 7-hydroxylate
coumarin (Cok et al., 2001).
Of the 127 NIEHS Cell Cycle candidate proteins
with a known functional domain, 9 of them had a
transcription factor E2F/dimerization domain.
EPHX1 (microsomal epoxide hydrolase) codon 113
Tyr/Tyr variant is associated with oropharyngeal
carcinogenesis (Amador et al., 2002).
PolyView (http//polyview.cchmc.org)
PolyDoms http//polydoms.cchmc.org
Schematic representation of secondary structures,
relative solvent accessibilities, highlighting
polymorphic residues. The RSA reflects the degree
of the residues exposure to the surrounding
solvent in the protein structure. The relative
probability of disease-causing mutations is
highest in the protein interior.
Gene nsSNP Frequency
CDKN1B Arg 15 Trp .0055560.0056
DDC Pro 210 Leu 0.0111
ERBB2 Ala 1170 Pro 0.4861.48235300.48240
FANCC Gly 139 Glu .005556.0056
MCM3 Asp 280 Val 0
MGMT Gly 160 Arg 0
MLH1 His 718 Tyr 000
MPG Pro 64 Leu 0.0056
NBS1 Arg 169 Gly 0
ORC3L Arg 588 Cys 0
PGR Arg 625 Ile 0
POLG Arg 1146 Cys 0.007937.0079
PTGS2 Glu 488 Gly .0500000
STAT2 Gln 66 His 0
STAT2 Leu 220 Pro 0
STAT2 Thr 448 Met 0.0169
STAT2 Ser 501 Ile 0
XRCC1 Arg 560 Trp 0.0135
XRCC1 Trp 194 Arg .119300.1034480
NIEHS-EGP sequenced genes that have at least one
nsSNP occurring in a protein functional domain
and predicted as probably damaging or deleterious
by PolyPhen and SIFT algorithms respectively.
There are no reports of any disease implications
of Ala1170Pro nsSNP of ERBB2A though its
predicted as deleterious and is occurring in a
functional protein domain. However, there are
conflicting reports about another nsSNP
Ile655Val. It has been associated with an
increased risk of breast cancer, particularly
among younger women. However, this SNP has
variable frequency in different ethnic groups
(Ameyaw et al., 2002). SIFT and PolyPhen
predicted it as benign or tolerated.
A RefSeq protein database search for additional
protein targets that have E2F/dimerization domain
resulted in 4 other proteins (3 hypothetical and
an E2F7). E2F7 has a nsSNP (Ala324Asp) occurring
in the E2F domain of the protein.
Twenty-three of the NIEHS candidate genes have at
least one nsSNP occurring in a known protein
functional domain and predicted as deleterious or
damaging by SIFT and PolyPhen servers
respectively.
6 DNA repair genes with at least one nsSNP occurring in a conserved domain and predicted as damaging/deleterious 6 DNA repair genes with at least one nsSNP occurring in a conserved domain and predicted as damaging/deleterious 6 DNA repair genes with at least one nsSNP occurring in a conserved domain and predicted as damaging/deleterious
Gene No. of nsSNPs nsSNPs
XRCC1 2 Trp 194 Arg Arg 560 Trp
MPG 1 Pro 64 Leu
MGMT 1 Gly 160 Arg
POLG 1 Arg 1146 Cys
MLH1 1 His 718 Tyr
FANCC 1 Gly 139 Glu
6 cell cycle genes with at least one nsSNP occurring in a conserved domain and predicted as damaging/deleterious 6 cell cycle genes with at least one nsSNP occurring in a conserved domain and predicted as damaging/deleterious 6 cell cycle genes with at least one nsSNP occurring in a conserved domain and predicted as damaging/deleterious
Gene No. of nsSNPs nsSNPs
ORC3L 1 Arg 588 Cys
NBS1 1 Arg 169 Gly
DDC 1 Pro 210 Leu
MCM3 1 Asp 280 Val
ERBB2 1 Ala 1170 Pro
CDKN1B 1 Arg 15 Trp
References

1. PolyDoms http//polydoms.cchmc.org
2. PolyView http//polyview.cchmc.org
3. SIFT http//blocks.fhcrc.org/sift/SIFT.html
4. PolyPhen http//www.bork.embl-heidelberg.de/PolyP
   hen/
5. GeneSNPs http//www.genome.utah.edu/genesnps/
6. NCBI RefSeq ftp//ftp.ncbi.nih.gov/refseq/
7. NCBI-CDD http//www.ncbi.nlm.nih.gov/Structure/cd
   d/cdd.shtml

• Mutations at Arg residues account for almost 15
  of disease mutations.
• A random mutation at a Trp or Cys residue has
  highest probability of causing disease.
• Mutations at Gly which is frequently present at
  the turns of alpha-helices, might have a negative
  impact on protein structural stability (Vitkup et
  al., 2003).
• 48 of 135 cell cycle proteins had at least one
  nsSNP affecting an Arg residue 11-Trp 15-Cys
  and 30 proteins with at least one nsSNP at a
  glycine residue.

Support
NIEHS U01 ES11038 Mouse Centers Genomics
Consortium