CANDID: A candidate gene identification tool

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CANDIDA candidate gene identification tool

• Janna Hutz
• jehutz_at_artsci.wustl.edu
• March 19, 2007

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Candidate genes

• Positional
• Linkage evidence
• Deletion syndrome
• Loss of heterozygosity
• Disease-related amplification
• Association
• Biological
• Pathways
• Phenotypic characteristics

ACTA/GGGA
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A case study acd
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A case study acd
0 cM
acd
31 cM
Os
Es-1
82 cM
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A case study acd
3/145
0/145
0/145
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Which gene is acd?
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Prioritization tools

• Endocrinologist/Geneticist
• Ensembl
• RT-PCR
• Sequencing

BINGO!
two years later.
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How can we improve this?
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Improve our tools

• Clinician
• Has memorized information about many disorders
  can name some relevant genes
• Gets his/her information from

PubMed
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PubMed

• How do we use PubMed to analyze our candidates?
• Enter our phenotypic keywords into PubMed. Read
  the papers that come up in the results. Make a
  list of genes.
• Do PubMed searches for all the candidates. Read
  the papers that come up in the results. Rate the
  candidates.

Better Dont do it yourself
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PubMed

• Each publication has a PubMed ID
• Each gene has a Gene ID
• Wouldnt it be nice if we could link Gene IDs and
  PubMed IDs?

• ftp//ftp.ncbi.nlm.nih.gov/gene/DATA
• gene2pubmed.gz
• TaxonomyID GeneID PubMedID

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Who makes that file? (1)

• From http//www.ncbi.nlm.nih.gov/entrez/query/stat
  ic/entrezlinks.html
• Links between Gene and PubMed are the result of
  the following
• 1. Manual curation within NCBI. Part of the
  process of generating a REVIEWED RefSeq is an
  analysis of the current literature. Papers that
  are seminal in defining the gene, its sequence,
  and its function are added to the record at that
  time. Alert users point out gaps or errors in
  papers associated with a Gene record. These
  messages are reviewed and implemented as required.

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Who makes that file? (2)

• 2. Integration of information from other public
  databases. Gene integrates gene-citation from
  resources external to NCBI such as model
  organism-specific databases, Gene Ontology (GO),
  groups curating interactions, and sequence
  databases. The assumption in using these source
  is that they report citations specific to a gene
  in a known species. Gene does not process
  citations from OMIM automatically, because many
  of citations in OMIM refer to studies of genes in
  species other than human.

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Example 1
pancreatic cancer
sequence candidates

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Help Sally.

• Use CANDIDs literature criterion
• http//dsgweb.wustl.edu/llfs/secure_html/hutz/inde
  x.html
• User workshop Password perl031907

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Help Sally.

• Look for genes that are involved with pancreatic
  cancer.
• What are some keywords we can use?

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A measure of relevancy

• Find relevant publications
• Is Gene X linked to these publications?
• How many publications match?
• What percent of Gene Xs publications match?

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By the numbers

• Literature scores run from 0 to 1.

• The score is

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Matching

• Every publication has a Text Words field that
  includes, when available,
• Title
• Abstract
• Other abstract
• MeSH terms
• MeSH subheadings
• Publication types
• Substance names
• Personal name as subject
• MEDLINE secondary source
• Other terms

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Summary
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Results
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Exporting to Excel

• Output file is a comma-separated file
• Download it, and change the .output to .csv.
• If Excel doesnt open it automatically when you
  click on it, paste the data into a new sheet and
  use the Text Import Wizard to separate the
  columns.

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Drawbacks

• What if a gene isnt associated with any
  publications?
• Its not important
• Its not yet characterized

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What about those genes?
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Analyzing the other genes

• We dont have literature data.
• We dont have expression data.
• All we have is a sequence.

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Fun with sequences

• DNA
• Cross-species conservation
• RNA (cDNA)
• Cross-species conservation
• Protein sequence prediction
• Protein conservation
• Protein domain prediction

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Protein domains

• InterPro
• Conserved Domain Database (NCBI)
• Wouldnt it be nice if we could link Gene IDs and
  protein domains?

Interpro
ftp//ftp.ncbi.nlm.nih.gov/gene/DATA
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Who makes those links?

• From http//www.ncbi.nlm.nih.gov/entrez/query/stat
  ic/entrezlinks.html
• Links between Entrez Gene and Conserved Domain
  Database (CDD) are calculated from the domains
  annotated by the CDD group on Reference Sequence
  proteins.

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How can we use this?

• The CDD domains have descriptions.
• These descriptions can be searched

just like when we searched PubMed!

1. CANDID finds domains containing our keywords.
2. If a gene has one of those domains, it gets a
   score of 1.

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How far back does our gene go?

• Is our gene in mammals?
• Fish?
• Bacteria?

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More sequence fun

• Many measures of conservation
• Nucleotide similarity (percentage, pairwise)
• Amino acid similarity (percentage, pairwise)
• etc., etc.

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HomoloGene

• Gets sequences
• Uses amino acid AND nucleotide similarity
  measures
• Plus lots more math, equals
• A label that answers our question

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Labels used in CANDID

• Homo sapiens
• Primates (chimp, gorilla)
• Rodents (rat, mouse)
• Eutherian mammals (dog, cow, cat)
• Amniota (chicken)
• Insects (mosquito, bee)
• Bilateria (C. elegans)
• Fungi
• Eukaryotes

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Example 2
Known and unknown genes
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Array candidates

• Lets increase the number of CANDID results we
  got in Example 1

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Weighting system

• Prioritize genes of known or unknown function
• Modify weights for each category
• Well-characterized genes higher literature
  weight
• Uncharacterized genes higher domains,
  conservation weights

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Example 3

• Make up your own example!
• Use literature, domains, and/or conservation
  criteria.

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Next week

• Expression data
• Linkage data
• Association data
• CANDIDs efficiency
• Anything else?

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