http://nature-wonder.livejournal.com/192600.html

1
????, ?????????? ????

• ???????? 2010-2020

http//nature-wonder.livejournal.com/192600.html
2
???? ??????? Global HIV Vaccine Enterprise (???)

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3
??????? ?????National Center for Biotechnology
Information (NCBI) (???)

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• ??????????? ????????? ?????? ???????, ??????? ??
  ?????? ?????? ???????? ????? (gene transfer
  agents, GTAs). ? ???? ???????? ?????????
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  ??????????????? ?? GTAs. ??????????? ????????
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4
??????? ?????National Center for Biotechnology
Information (NCBI) (???)

• GTAs ? ???????? ?????????????????? ???????
  ??????????????? ???????? ??????? ?????????
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• ?? ??????????????? ??????? ??????? ??????????????
  ??????? ? ?????? ????????? ????????? ??????????
  ???????? ?????? - CRISPR/Cas ???????. ????
  ???????? ?????????? ?????? ??????????? ??????????
  ??? ? CRISPR ??????. ?? ? ??? ????????? ????
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  ???????????? ?????????????? CRISPR/Cas ???????, ?
  ?? ?????? ? ?? ?????, ????????, ????? ?????????
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5
?RISPR/Cas ???????
The CRISPR System Protects Microbes against
Phages, Plasmids
Palindromic DNA repeat sequences immunize
microorganisms against phages and plasmids, while
also directing their evolution. Rodolphe
Barrangou and Philippe Horvath
????????? ???????????? ??????? ? ????????? ????
???????? ? ????????? ??????????????? ????????
?????????? ???????? ??? ????????? ?? ??????????
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?????.
6
??????? ??????The Leibniz Institute of Plant
Genetics and Crop Plant Research (????????)

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7
??????? ??????The Leibniz Institute of Plant
Genetics and Crop Plant Research (????????)

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8
??????? ??????The Leibniz Institute of Plant
Genetics and Crop Plant Research (????????)

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9
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10
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1. ?.?. ??????, ?.?. ??????, ?.?. ????????.
?????????? ? ?????????? ????????????
???????? ??????? ?????, 2007, ??? 11, ? 2 2. ?.?.
C?????, ?.?. ????????. ???????????? ???????? ?
???????????? ???????????? ???????. ??????? ?????,
2009, ??? 13, ? 2
11
???????? ???????????????????? ?-? ???

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12
???????? ???????????????????? ?-? ???

• 3. ????? ???????? ???? ??????????????? ?????? ?
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• .

13

• ?????????????? ??? ?????? ?????????? ?????????,
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• ?????? ????. ??? ???????? ? ?????? ???????.
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  ??????? ?? ?????? ????? ??????.
• ?.????????.

14

• ?????? ?????? ??????????????, ? ???? ?????
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  ????????????. ?????????? ????? ????????? ?? ??,
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  ???????? - ????? ????? ??????, ? ????????????
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  ?????? ??? ????????????? ???????????? ???????,
  ???? ????? ?????. ??? ????? ?????????, ?????
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  ????????. ??????????, ??-????????, ?????
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  ????????????? ????????? ? ?????????????
  ???????????????. ?????? ??? ?????????? ? ????
  ???????.
• ?.????????.

15
Bio-Informatics Tools Laboratory Bio-Informatics
(overview).
16
Bioinformatics - A New Discipline
Large scale analysis and interpretation of
genomics data.
Math Stats
Computing
Life sciences
Physical sciences
Taken from D. Gilberts C. Tan,
2002 http//www.brc.dcs.gla.ac.uk/drg/courses/bio
informatics_city/slides/slides1/sld018.htm
17
From Chromosomes to Sequence Data
Large scale DNA sequencing
CGCCAGCTGGACGGGCACACCATGAGGCTGCTGACCCTCCTGGGCCTTCT
GTGTGGCTCGGTGGCCACCCCCTTAGGCCCGAAGTGGCCTGAACCTGTGT
TCGGGCGCCTGGCATCCCCCGGCTTTCCAGGGGAGTATGCCAATGACCAG
GAGCGGCGCTGGACCCTGACTGCACCCCCCGGCTACCGCCTGCGCCTCTA
CTTCACCCACTTCGACCTGGAGCTCTCCCACCTCTGCGAGTACGACTTCG
TCAAG
http//www.ornl.gov/hgmis/graphics/slides/images/0
1-0085.tif
18
Different Eukaryotic Cell Types
Different genes are activated in different cells,
creating the specific proteins that give a
particular cell type its character.
http//www.accessexcellence.org/AE/AEPC/NIH/gene03
.html
19
DNA
Eukaryotic Genome
Structure
4 Nucleotides (bases) Adenine (A) Cytosine
(C) Guanine (G) Thymine (T)
20 amino acids (A, L, V, S etc.)
triplet codons genetic code
Sequence data Strings of letters
20
Translation in Eukaryotes
http//www1.imim.es/courses/Lisboa01/slide1.6_tran
slation.html
Animation http//cbms.st-and.ac.uk/academics/ryan
/Teaching/medsci/Medsci6.htm
21
Proteins Determines Cell Structure and Function

• Unique protein expression
• by each cell type.
• Proteins are 60 of
• dry mass of living cell.
• Proteins determine function.

http//www.library.csi.cuny.edu/davis/Bioinfo_326
/lectures/centralDogmaProteins/centralDogma.html
22
The Central Dogma
DNA RNA
Protein
Symptomes
(Phenotype)
Cells express different subset of the genes in
different tissues and under different conditions.
23
The BIG Goal

• The greatest challenge, however, is analytical.
  Deeper biological insight is likely to emerge
  from examining datasets with scores of samples.
• Eric
  Lander, array of hope Nat. Gen.
• volume 21
  supplement pp 3 - 4, 1999.

Bio-informatics Provide methodologies for
elucidating biological knowledge from biological
data.
24
What is Bio-Informatics ?
Computational methods for global
understanding of biological data.
Better biological and medical understanding.
Data produced by bio-labs and stored in
database.
Bio-Informatics Algorithms and Tools
Goal Enable the discovery of new biological
insights and create a global perspective for
life sciences.
25
Computer Science Tools are Crucial

• New bio-technologies create huge amounts of data.
• It is impossible to analyze data
• by manual inspection.
• Novel mathematical, statistical,
• algorithmic and computational
• tools are necessary !
• An emerging interdisciplinary
• research area, bringing together
• experimental and computational
• approaches to biology and bio-
• medicine.
• Deals with the computational management
• and analysis of biological information
• genes, genomes, proteins, cells,
  clinical information.

http//www.library.csi.cuny.edu/davis/Bioinfo_326
/lectures/lect14/lect_14.html
26
Bio-Informatics working definition (NIH National
Institute of Health, USA)

• Bioinformatics
• Research, development, or application of
  computational tools and
• approaches for expanding the use of biological,
  medical, behavioral
• or health data, including those to acquire,
  store, organize, archive,
• analyze, or visualize such data.
• Computational biology
• The development and application of
  data-analytical and theoretical
• methods, mathematical modeling and computational
  simulation
• techniques to the study of biological,behavioral,
  and social systems.

27
Important Bio-Info. Topics

• Sequence comparison and alignment.
• Gene finding analysis.
• Finding regulatory motifs.
• Structural biology 3D protein structure,
• correlated to function.
• Constructing phylogeny trees from sequences.

28
Why Use Bio-Informatics ?

• A more global view of experimental design.
• (from one scientist one gene/protein/
• disease paradigm to whole organism
• consideration).
• Data mining - functional/structural
• information is important for studying
• the molecular basis of diseases,
• diagnostics, developing drugs
• (personal medicine), evolutionary
• patterns, etc.

http//www.sanger.ac.uk/PostGenomics/S_pombe/prese
ntations/EMBOCopenhagenWebsite.pdf
29
The Next Step Locate all the genes and describe
their function.
This will probably take another 15-20 years !
Future of Bio-Informatics
30
The Job of Biologists is Changing

• One can efficiently find information
• E-mail.
• Web - information and software.

How likely are you to use a free bio-informatics
library of accessible software ?
http//www.cryst.bbk.ac.uk/classlib/BBSRC_poster/p
otential.html
31
Primary (Raw) Databases
Types of Data (Databases)
?ibbons
Publications
Cylinders
Secondary (analyzed) Databases
32
NCBI
ENTREZ PubMed
33
The Globin Story
Bio-informatics Tour Highlights
34
Red Blood Cells

• Carry oxygen from the lungs.
• Carry carbon dioxide back to the lungs.
• Contain hemoglobin.
• Made from iron, folic acid and
• vitamin B12, in the bone marrow.

35
Similarity / Analogy
Examples If looks like an elephant, and smells
like an elephant its an elephant. If walks
like a duck, and quacks like a duck its a
duck.
http//cbms.st-and.ac.uk/academics/ryan/Teaching/m
olbiol/Bioinf_files/v3_document.htm
36
Similarity Search in Databanks
Pairwise alignment
Find similar sequences to a working draft. As
databanks grow, homologies get harder, and
quality is reduced. Alignment Tools BLAST
FASTA (time saving heuristics- approximations).
37
The Globin Family Multiple Sequence Alignment
(MSA)
Multiple alignment find protein families and
functional domains.
All globin molecules have a similar 3D structure,
despite large sequence differences. Globins amino
acid sequence identities range from 99 (very
similar) to 16 (very different).
38
The Structural Prediction Problem
Given a protein sequence, compute its structure.
GCTCCTCACTGTCTGTGTTTATTCTTTTAGCTTCTTCAGATCTTTTAGTC
TGAGGAAGCCTGGCATGTGCAAATGAAGTTAACCTAA...

• Possible in principle.
• Astronomical, highly under-constrained search
  space.
• Biophysics complex and incomplete.
• Next to impossible in practice.

39
Structure - Function Relationships
structure
sequence
function
40
3D Structure of Globins
Yellow Lupine Leghemoglobin
Human a-Globin
Whale Myoglobin
41
Phylogeny
Evolution - a process in which small changes
occur within species over time. These changes
could be monitored today using molecular
techniques.

• The Tree of Life
• A classical, basic
• science problem,
• since Darwins 1859
• Origin of Species.

42
How Did the Globin Gene Family Evolve ?
43
Searching Protein Sequence Databases - How far
can we see back ?
Tree of Life
Mammalian radiation
Invertebrates/ vertebrates
Plant/ animals
Prokaryotes/ eukaryotes
First self replicating systems
Formation of the solar system
Origin of the universe ?
44
What is a Gene ?
Un-coded region
Transcribed region
Un-coded region
exon
exon
exon
promotor
intron
intron
Start codon
Terminal codon

• DNA contains various recognition sites
• Promoter signals.
• Transcription start signals.
• Start codon.
• Exon, intron boundaries.
• Transcription termination signal.

45
Gene Finding

• Only 2 of the human genome encodes for
• functional genes.
• Genes are found along large non-coding
• DNA regions.
• Repeats, pseudo-genes, introns, contamination
  
• of vectors, are confusing.

46
Gene Finding
Existing programs for locating genes within
genomic sequences utilize a number of
statistical signals and employ statistical models
such as hidden Markov models (HMMs). The
problem is not solved yet !
47
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48
Genomic Mapping
A map - graphic representation that provides
information about the location of sites and the
spacing between them. Maps for the genome
provide the relative order of items (markers)
along the chromosome.

• Two Major Types of
• Genomic Maps
• Genetic maps.
• Physical maps.

49
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50
Microarrays (DNA Chips)
Leading edge, future technologies (since 1988)
In a single experiment, measure expression level
of thousands of genes.

• Find informative genes that may
• have predictive power for
• medical diagnosis.
• Potential for personalized
• medicine, e.g. kits for identifying
• cancer types and prescribe
• personal treatment.

51
Microarray (DNA Chip) Analysis
Discover meaningful relationships among genes

• Clustering algorithms
• Identify
• Biological function.
• Similar regulation.

52
Pharmaco-genomics

• Use DNA information to measure and predict
• the reaction to drugs.
• Personalized medicine.
• Faster clinical trials selected populations.
• Less drug side-effects.

53
Putting it all together Bio-Informatics
ORTHOLOG GENES (Taxonomy)
SEQUENCE ALIGNMENT
CODING REGIONS
CONSERVED DOMAINS
SEQUENCES LITERATURE
3-D STRUCTURE
GENE FAMILIES
SIGNAL PEPTIDE
MUTATIONS POLYMORPHISM
GENOME MAPS
CELLULAR LOCATION
54
Putting it all together Bio-Informatics
ORTHOLOG GENES (Taxonomy)
SEQUENCE ALIGNMENT
CODING REGIONS
CONSERVED DOMAINS
GENE EXPRESSION, GENES FUNCTION, DRUG PERSONAL
THERAPY
3-D STRUCTURE
GENE FAMILIES
SIGNAL PEPTIDE
MUTATIONS POLYMORPHISM
GENOME MAPS
CELLULAR LOCATION