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Introduction to Bioinformatics
07/17/14 BAL HARI POUDEL CDBT KIRTIPUR

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What is Bioinformatics?

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What is Bioinformatics? - Research, development,
and application of computational tools and
approaches for expanding the use of biological,
medical, behavioral, and health data, including the
means to acquire, store, organize, archive, analyze,
or visualize such data.
What is Computational Biology? - The
development and application of analytical and
theoretical methods, mathematical modeling and
computational simulation techniques to the study of
biological, behavioral, and social data.
on molecular

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Large databases that can be accessed and analyzed with
sophisticated tools have become central to biological
research and education. The information content in the
genomes of organisms, in the molecular dynamics of
proteins, and in population dynamics, to name but a few
areas, is enormous. Biologists are increasingly finding that
the management of complex data sets is becoming a
bottleneck for scientific advances. Therefore,
bioinformatics is rapidly become a key technology in all
fields of biology.

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The present bottlenecks in bioinformatics include the education of
biologists in the use of advanced computing tools, the recruitment
of computer scientists into this evolving field, the limited
availability of developed databases of biological information, and
the need for more efficient and intelligent search engines for
complex databases.

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The present bottlenecks in bioinformatics include the education ofthe education of
biologists in the use of advanced computing toolsbiologists in the use of advanced computing tools, the recruitment
of computer scientists into this evolving field, the limited
availability of developed databases of biological information, and
the need for more efficient and intelligent search engines for
complex databases.

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Molecular Bioinformatics involves the use
of computational tools to discover new
information in complex data sets (from the
one-dimensional information of DNA through
the two-dimensional information of RNA and
the three-dimensional information of proteins,
to the four-dimensional information of
evolving living systems).

From DNA to Genome
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Watson and Crick
DNA model
Sanger sequences
insulin protein
Sanger dideoxy
DNA sequencing
PCR (Polymerase
Chain Reaction)
1955
1960
1965
1970
1975
1980
1985
ARPANET
(early Internet)
PDB (Protein
Data Bank)
Sequence
alignment
GenBank
database
Dayhoff’s Atlas

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1995
1990
2000
SWISS-PROT
database
NCBI
World Wide Web
BLAST
FASTA
EBI
Human Genome
Initiative
First human
genome draft
First bacterial
genome
Yeast genome

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The first protein sequence reported was that of
bovine insulin in 1956, consisting of 51
residues.
Origin of bioinformatics and
biological databases:
Nearly a decade later, the first nucleic acid
sequence was reported, that of yeast
tRNAalanine
with 77 bases.

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In 1965, Dayhoff gathered all the available
sequence data to create the first bioinformatic
database (Atlas of Protein Sequence and
Structure).
The Protein DataBank followed in 1972 with a
collection of ten X-ray crystallographic protein
structures. The SWISSPROT protein sequence
database began in 1987.07/17/14 BAL HARI POUDEL CDBT KIRTIPUR

Nucleotides

Complete Genomes
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1994 0
1995 1
December 2006 376
Eukaryotes 22
Bacteria 327
Archaea 27

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What can we do with sequences and other type of molecular information?

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Annotation
Open reading frames
Functional sites
Structure, function

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CCTGACAAATTCGACGTGCGGCATTGCATGCAGACGTGCATG
CGTGCAAATAATCAATGTGGACTTTTCTGCGATTATGGAAGAA
CTTTGTTACGCGTTTTTGTCATGGCTTTGGTCCCGCTTTGTTC
AGAATGCTTTTAATAAGCGGGGTTACCGGTTTGGTTAGCGAGA
AGAGCCAGTAAAAGACGCAGTGACGGAGATGTCTGATG CAA
TAT GGA CAA TTG GTT TCT TCT CTG AAT ......
.............. TGAAAAACGTA

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CCTGACAAATTCGACGTGCGGCATTGCATGCAGACGTGCATG
CGTGCAAATAATCAATGTGGACTTTTCTGCGATTATGGAAGAA
CTTTGTTACGCGTTTTTGTCATGGCTTTGGTCCCGCTTTGTTC
AGAATGCTTTTAATAAGCGGGGTTACCGGTTTGGTTAGCGAGA
AGAGCCAGTAAAAGACGCAGTGACGGAGATGTCTGATG CAA
TAT GGA CAA TTG GTT TCT TCT CTG
AAT .................................
.............. TGAAAAACGTA
TF binding sitepromoter
Ribosome binding Site
ORF = Open Reading Frame
CDS = Coding Sequence
Transcription
StartSite

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Comparative
genomics
Comparing ORFs
Identifying orthologs
Inferences on structure
and function
Comparing functional sites
Inferences on regulatory
networks

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Similarity profiles
Researchers can learned a great deal about the structure and
function of human genes by examining their counterparts in
model organisms.07/17/14 BAL HARI POUDEL CDBT KIRTIPUR

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Xenopus MALWMQCLP-LVLVLLFSTPNTEALANQHL
Bos MALWTRLRPLLALLALWPPPPARAFVNQHL
**** : * *.*: *:..* :. *:****
Xenopus CGSHLVEALYLVCGDRGFFYYPKIKRDIEQ
Bos CGSHLVEALYLVCGERGFFYTPKARREVEG
: ** :*::*
Xenopus AQVNGPQDNELDG-MQFQPQEYQKMKRGIV
Bos PQVG---ALELAGGPGAGGLEGPPQKRGIV
.**. ** * *
Xenopus EQCCHSTCSLFQLENYCN
Bos EQCCASVCSLYQLENYCN
**** *.***:**
Alignment preproinsulin

Ultraconserved Elements in the
Human Genome
Gill Bejerano, Michael Pheasant, Igor Makunin, Stuart
Stephen, W. James Kent, John S. Mattick, & David Haussler
(Science 2004. 304:1321-1325)
There are 481 segments longer than 200 base pairs (bp) that are
absolutely conserved (100% identity with no insertions or
deletions) between orthologous regions of the human, rat, and
mouse genomes. Nearly all of these segments are also conserved
in the chicken and dog genomes, with an average of 95 and 99%
identity, respectively. Many are also significantly conserved in
fish. These ultraconserved elements of the human genome are
most often located either overlapping exons in genes involved in
RNA processing or in introns or nearby genes involved in the
regulation of transcription and development.
There are 156 intergenic, untranscribed,
ultraconserved segments

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Junk is real!
Junk:Junk:
Supporting evidenceSupporting evidence

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Functional
genomics
Genome-wide profiling of:
• mRNA levels
• Protein levels
Co-expression of genes
and/or proteins
Identifying protein-protein
interactions
Networks of interactions

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Understanding the function of genes and otherUnderstanding the function of genes and other
parts of the genomeparts of the genome

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Structural
genomics
Assign structure to all
proteins encoded in
a genome

Structural Genomics
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~300
unique folds
in PDB
~300 unique folds
CurrentlyCurrently
27761 structures

Structural Genomics
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1000-3000
unique folds
in “structure space”
EstimateEstimate

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Origin of tools
Immediately after the establishment of the
first databases, tools became available to
search them - at first in a very simple
manner, looking for keyword matches and
short sequence words and, then, in a more
sophisticated manner by using pattern
matching, alignment based methods, and
machine learning techniques.

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Despite the huge explosion in the number
and length of sequences, the tools used for
storage, retrieval, analysis, and
dissemination of data in bioinformatics are
very similar to those from 15-20 years ago.

07/17/14 31BAL HARI POUDEL CDBT KIRTIPUR

Database or databank?
Initially
Databank (in UK)
Database (in the USA)
Solution
The abbreviation db

What is a database?A collection of data
structured
searchable (index) -> table of contents
updated periodically (release) -> new edition
cross-referenced (hyperlinks) -> links with other db
Includes also associated tools (software) necessary for
access, updating, information insertion, information
deletion….
Data storage management: flat files, relational
databases…

Database: a « flat file » example
Accession number: 1
First Name: Amos
Last Name: Bairoch
Course: Pottery 2000; Pottery 2001;
//
Accession number: 2
First Name: Dan
Last name: Graur
Course: Pottery 2000, Pottery 2001; Ballet 2001, Ballet 2002
//
Accession number 3:
First Name: John
Last name: Travolta
Course: Ballet 2001; Ballet 2002;
//
Easy to manage: all the entries are visible at the same time !
Flat-file database (« flat file, 3 entries »):

Database: a « relational » example
Course Year Involved
teachers
Advanced
Pottery
2000; 2001 1; 2
Ballet for Fat
People
2001; 2002 2; 3
Teacher Accession
number
Education
Amos 1 Biochemistry
Dan 2 Genetics
John 3 Scientology
Relational database (« table file »):

Why biological databases?Exponential growth in biological data.
Data (genomic sequences, 3D structures, 2D gel
analysis, MS analysis, Microarrays….) are no longer
published in a conventional manner, but directly
submitted to databases.
Essential tools for biological research.

Distribution of sequences
Books, articles 1968 -> 1985
Computer tapes 1982 -> 1992
Floppy disks 1984 -> 1990
CD-ROM 1989 ->
FTP 1989 ->
On-line services 1982 -> 1994
WWW 1993 ->
DVD 2001 ->

Some statistics
More than 1000 different ‘biological’ databases
Variable size: <100Kb to >20Gb
 DNA: > 20 Gb
 Protein: 1 Gb
 3D structure: 5 Gb
 Other: smaller
Update frequency: daily to annually to seldom to forget about
it.
Usually accessible through the web (some free, some not)

Some databases in the field of molecular biology…
AATDB, AceDb, ACUTS, ADB, AFDB, AGIS, AMSdb,
ARR, AsDb, BBDB, BCGD, Beanref, Biolmage,
BioMagResBank, BIOMDB, BLOCKS, BovGBASE,
BOVMAP, BSORF, BTKbase, CANSITE, CarbBank,
CARBHYD, CATH, CAZY, CCDC, CD4OLbase, CGAP,
ChickGBASE, Colibri, COPE, CottonDB, CSNDB, CUTG,
CyanoBase, dbCFC, dbEST, dbSTS, DDBJ, DGP, DictyDb,
Picty_cDB, DIP, DOGS, DOMO, DPD, DPlnteract, ECDC,
ECGC, EC02DBASE, EcoCyc, EcoGene, EMBL, EMD db,
ENZYME, EPD, EpoDB, ESTHER, FlyBase, FlyView,
GCRDB, GDB, GENATLAS, Genbank, GeneCards,
Genline, GenLink, GENOTK, GenProtEC, GIFTS,
GPCRDB, GRAP, GRBase, gRNAsdb, GRR, GSDB,
HAEMB, HAMSTERS, HEART-2DPAGE, HEXAdb, HGMD,
HIDB, HIDC, HlVdb, HotMolecBase, HOVERGEN, HPDB,
HSC-2DPAGE, ICN, ICTVDB, IL2RGbase, IMGT, Kabat,
KDNA, KEGG, Klotho, LGIC, MAD, MaizeDb, MDB,
Medline, Mendel, MEROPS, MGDB, MGI, MHCPEP5
Micado, MitoDat, MITOMAP, MJDB, MmtDB, Mol-R-Us,
MPDB, MRR, MutBase, MycDB, NDB, NRSub, 0-lycBase,
OMIA, OMIM, OPD, ORDB, OWL, PAHdb, PatBase, PDB,
PDD, Pfam, PhosphoBase, PigBASE, PIR, PKR, PMD,
PPDB, PRESAGE, PRINTS, ProDom, Prolysis, PROSITE,
PROTOMAP, RatMAP, RDP, REBASE, RGP, SBASE,
SCOP, SeqAnaiRef, SGD, SGP, SheepMap, Soybase,
SPAD, SRNA db, SRPDB, STACK, StyGene,Sub2D,
SubtiList, SWISS-2DPAGE, SWISS-3DIMAGE, SWISS-
MODEL Repository, SWISS-PROT, TelDB, TGN, tmRDB,
TOPS, TRANSFAC, TRR, UniGene, URNADB, V BASE,
VDRR, VectorDB, WDCM, WIT, WormPep, YEPD, YPD,
YPM, etc .................. !!!!

Categories of databases for Life Sciences
Sequences (DNA, protein)
Genomics
Mutation/polymorphism
Protein domain/family
Proteomics (2D gel, Mass Spectrometry)
3D structure
Metabolism
Bibliography
Expression (Microarrays,…)
Specialized

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NCBI (National Center for Biotechnology Information) is a
resource for molecular biology information. NCBI creates and
maintains public databases, conducts research in computational
biology, develops software tools for analyzing genome data, and
disseminates biomedical information. The NCBI site is constantly
being updated and some of the changes include new databases
and tools for data mining.
NCBI offers several searchable literature, molecular and
genomic databases and many bioinformatic tools. An up-to-date
list of databases and tools can be found on the NCBI Sitemap.
Resources

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Bookshelf: A collection of searchable biomedical books linked to
PubMed.
PubMed: Allows searching by author names, journal titles, and a
new Preview/Index option. PubMed database provides access to
over 12 million MEDLINE citations back to the mid-1960's. It
includes History and Clipboard options which may enhance your
search session.
PubMed Central: The U.S. National Library of Medicine digital
archive of life science journal literature.
OMIM: Online Mendelian Inheritance in Man is a database of
human genes and genetic disorders (also OMIA).
Literature Databases:

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GenBank:
http://www.ncbi.nlm.nih.gov/Genbank/
EBI:
http://www.ebi.ac.uk/
DDBJ:
http://www.ddbj.nig.ac.jp/

Type in a Query term
Enter your search words in the
query box and hit the “Go” button
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http://www.ncbi.nlm.nih.gov/entrez/query/static/help/helpdoc.html#Searching

The Syntax …
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1. Boolean operators: AND, OR, NOT must be entered in
UPPERCASE (e.g., promoters OR response elements). The default
is AND.
2. Entrez processes all Boolean operators in a left-to-right sequence.
The order in which Entrez processes a search statement can be
changed by enclosing individual concepts in parentheses. The terms
inside the parentheses are processed first. For example, the search
statement: g1p3 OR (response AND element AND promoter).
3. Quotation marks: The term inside the quotation marks is read as one
phrase (e.g. “public health” is different than public health, which will
also include articles on public latrines and their effect on health
workers).
4. Asterisk: Extends the search to all terms that start with the letters
before the asterisk. For example, dia* will include such terms as
diaphragm, dial, and diameter.07/17/14 BAL HARI POUDEL CDBT KIRTIPUR

Refine the Query
Often a search finds too many (or too few) sequences, so you
can go back and try again with more (or fewer) keywords in
your query
The “History” feature allows you to combine any of your past
queries.
The “Limits” feature allows you to limit a query to specific
organisms, sequences submitted during a specific period of
time, etc.
[Many other features are designed to search for literature in
MEDLINE]

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You can search for a text term in sequence annotations or in
MEDLINE abstracts, and find all articles, DNA, and protein
sequences that mention that term.
Then from any article or sequence, you can move to "related
articles" or "related sequences".
•Relationships between sequences are computed with BLAST
•Relationships between articles are computed with "MESH" terms
(shared keywords)
•Relationships between DNA and protein sequences rely on accession
numbers
•Relationships between sequences and MEDLINE articles rely on
both shared keywords and the mention of accession numbers in the
articles.
Related Items

Database Search Strategies
General search principles - not limited to
sequence (or to biology).
Start with broad keywords and narrow the search
using more specific terms.
Try variants of spelling, numbers, etc.
Search many databases.
Be persistent!!

PubMed
MEDLINE publication database
Over 17,000 journals
Some other citations
Papers from 1960 and on
Over 12,000,000 entries
Alerting services
http://www.pubcrawler.ie/
http://www.biomail.org/

Searching PubMed
Structureless searches
Automatic term mapping
Structured searches
Tags, e.g. [au], [ta], [dp], [ti]
Boolean operators, e.g. AND, OR, NOT, ()
Additional features
Subsets, limits
Clipboard, history

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Start working:
Search PubMed
1. cuban cigars
2. cuban OR cigars
3. “cuban cigars”
4. cuba* cigar*
5. (cuba* cigar*) NOT smok*
6. Fidel Castro
7. “fidel castro”
8. #6 NOT #7

The OMIM (Online Mendelian
Inheritance in Man)
Genes and genetic disorders
Edited by team at Johns Hopkins
Updated daily

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MIM Number Prefixes
* gene with known sequence
+ gene with known sequence and
phenotype
# phenotype description, molecular
basis known
% mendelian phenotype or locus,
molecular basis unknown
no prefix other, mainly phenotypes with
suspected mendelian basis

Searching OMIM
Search Fields
Name of trait, e.g., hypertension
Cytogenetic location, e.g., 1p31.6
Inheritance, e.g., autosomal dominant
Gene, e.g., coagulation factor VIII

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OMIM search tags
All Fields [ALL]
Allelic Variant [AV] or [VAR]
Chromosome [CH] or [CHR]
Clinical Synopsis [CS] or [CLIN]
Gene Map [GM] or [MAP]
Gene Name [GN] or [GENE]
Reference [RE] or [REF]

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Start working:
Search OMIM
How many types of hemophilia are there?
For how many is the affected gene known?
What are the genes involved in hemophilia A?
What are the mutations in hemophilia A?

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Online Literature databases
1. How to use the UH online Library?
2. Online glossaries
3. Google Scholar
4. Google Books
5. Web of Science

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How to use the online UH Library?
http://info.lib.uh.edu/07/17/14 BAL HARI POUDEL CDBT KIRTIPUR

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Online Glossaries
Bioinformatics :
http://www.geocities.com/bioinformaticsweb/glossary.html
http://big.mcw.edu/
Genomics:
http://www.geocities.com/bioinformaticsweb/genomicglossary.html
Molecular Evolution:
http://workshop.molecularevolution.org/resources/glossary/
Biology dictionary:
http://www.biology-online.org/dictionary/satellite_cells
Other glossaries, e.g., the list of phobias:
http://www.phobialist.com/class.html

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4. Google Scholar
http://www.scholar.google.com/

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Enables you to search specifically for scholarly
literature, including peer-reviewed papers,
theses, books, preprints, abstracts and technical
reports from all broad areas of research.
What is Google Scholar?

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Use Google Scholar to find articles from a
wide variety of academic publishers,
professional societies, preprint repositories
and universities, as well as scholarly articles
available across the web.

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Google Scholar
orders your
search results by
how relevant they
are to your query,
so the most
useful references
should appear at
the top of the
page
This relevance
ranking takes into
account the: full
text of each article.
the article's author,
the publication in
which the article
appeared and how
often it has been
cited in scholarly
literature.07/17/14 BAL HARI POUDEL CDBT KIRTIPUR

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What other DATA can we retrieve from the record?

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5. Google Book Search

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Start working:
Search Google Books
How many times is the tail of the giraffe
mentioned in On the Origin of Species by Mr.
Darwin?

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6. Web of science
http://portal01.isiknowledge.com.ezproxy.lib.uh.edu/portal.cgi?DestApp=WOS&Func=Frame

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Editor's Notes