communications
Post on 11-May-2015
506 Views
Preview:
TRANSCRIPT
L. ARAVINDNational Center for Biotechnology Information
Apprehending Life’s complexity: Making and communicating biological discoveries
We are becoming meme and teme machines !
It is all about replicators: biological and otherwise
The good old genes Memes Temes
Summary of issues
Discovery in biologyDifferent philosophies: Natural history versus “hypothesis driven science”Evolutionary theory and computation as a bridge between the philosophical antipodes
•Example of the PAS domainA rich breeding ground for memes
Levels of organization in the living world and its complexityMicroscopic, mesoscopic and macroscopic world views need integrationSeeking gold at the end of the mazeFollowing natural order: hierarchies and networks
•Examples of classifications and hierarchies
The meme machine: transmission of discoveriesDatabases and search toolsScientific collaboration and competition Journal systems
The two philosophies in biology
Natural history: discovery of new forms, cataloguing and
classification
Hypothesis-> attempt at falsification->paradigms:
Popper’s world view
Largely a history of clash
or neglect
Building the bridge: Evolutionary theory and computation
+
...
.
•Sequence profile analysis
•Structure similarity
comparisons
•Contextual analysis
Understanding and predicting protein
(biomolecule) function
Systems biology:Ensembles of biomolecules
in functional guilds
The “omics” (regular and meta):From sequence to organismal
biology and ecology
Earlydomain universe
The protein universe shows enormous diversity but an underlying unity
•These relationships are powerful predictors of protein evolution, function and behavior
?
?
?
?
The largest assemblage of homologous domains that can unified by sequence features is formally a superfamily
Several superfamilies may share a common folding pattern and arrangement of secondary structure elements: unified to a fold
ALL LIFE FORMSBACTERIAARCHAEAEUKARYA
•The ribosome, and the associated enzymes like some RNAses (including RnaseHII), PseudoU synthases, RNA methylases, thioU synthases, Clamp loader ATPase, RecA, RNA polymerases, translation GTPases, AATRS, ABC, MinD ATPases, OSGP like chaperone/protease. PCNA, DNA ligases, rRNA and tRNAs
DNA polymerases, Holliday junction resolvases, Primases, Replicative Helicases, Origin recognition complexes
Ribozymes are well-known: so an RNA world of sorts must have existed
There was a common ancestor of all life; the main functions of this life form revolved around RNA metabolism and translation; some cellular functions related to DNA had developed but modern DNA replication “crystallized” later
So there was a RNA centered ancestral form with a possible DNA intermediate in replication
Unifying life and inferring the common ancestor
Getting behind biological clocks, photodetectors and oxygen sensors
Regulation of circadian rhythms in animals
Periodic growth and sporulation in fungi
Light regulated expression of photosynthetic pigments
Oxygen-seeking behavior in aerobic bacteria
A master regulator of the clock the period protein
(per)
WC-1 and WC-2 two light sensory
regulators of gene-expression in
Neurospora
BAT a regulator of photosynthetic
pigment expression
The aerotaxis receptor of E.coli
and other bacteria
The PAS domain
A ligand binding domain which binds diverse ligands like heme, tetrahydropyrrole and flavin nucleotides
Thus, it can sense diverse stimuli like light, redox or both
Transmits this stimulus to a diverse range of other “effector” domains
Curr Biol. 1997 Nov 1;7(11):R674-7. PAS: a multifunctional domain family comes to light. Ponting CP, Aravind L.
Curr Biol. 7(11):R674-7. PAS: a multifunctional domain family comes to light.
Ponting CP and Aravind L
PASG
ATAPAS
PAS
PASPAS
bHLH
PAS
PAS
PASC6
PASAAA+
HTH
Transcription
WC-1
SIM
PER
PAS
PAS S/T-Kinase
GAF
GAF
Adeny ly lcy clase
PAS
GAF
PASPAS
H-kina se
ERG-channels: redox sensing in
animal hearts
Phytochrome:Light sensing in
plants and bacteria
Signaling intracellular redox states
Small-molecule based regulation
of signaling enzymes
Birth of a meme…
•Detection of the PAS domain allows a definitive functional prediction
•The mechanisms of critical molecules across the entire diversity of life could be predicted
•It was a very successful meme indeed: 887 publications following up on the original characterization and function prediction of the PAS domain have emerged since – around 80-90 per year.
The predictions:
Overview of biological complexity
Mesoscopic
Characterization of biological functional systems
Function prediction & classification
Microscopic Discovery and classification of domains
Computational analysis of whole biological systems or networks
Reconstructing organismal biology and whole ecosystemsMacroscopic
Evolutionary trajectories: Genomes to Biology
Eukaryotic signaling proteins show non-linear scaling with proteome size…
However, major superfamilies of signaling proteins show largely linear trends: invention of many lineage-specific systems independent of the large superfamiliesDeviations point to important functional adaptations: convergent evolution of LRR+kinase architectures
(Prolyl hydroxylases)
RsPbcv1
Dm
Arabidopsis
Drosophila
Lineage specific expansion of a domain family
Definition: The increase in numbers of a domain in particular lineage with respect to its number in sister reference lineage
Hom
o
Section of the contextual network for the Ub pathway
LFLFWLMUB WLMPUGWLMUB LFLFWLM WLM
PNGaseThioredoxin PAW PNGase PAWPUGUBAPUGPPPDEPUL DOMAINThioredoxinPPPDE
UBOTU-DUBUB
C2H2OTU-DUB
UB Asp Protease UBA
ThioredoxinX UBXUBXThioredoxin ZZ fingerUBA PUL DOMAINWD40
LFLFLFLFLF Calpain
A20 ZnF
UB/UBX
UBCH
LF
C2H2-U
An1 ZnF
OTU-DUB
PNGase
RAB-GEF
PUL DOMAIN
Thioredoxin
PPPDE
Asp Protease
PAW
ZZ finger
WLM (metallopeptidase)
Yif1
TM TM TM TM TM//
RAB
WD40
Calpain
E2//
UBA
*
* Predicted DUB
**
** *
Domain architectural “complexity” of eukaryotic signaling proteins
•Complexity can vary drastically even between sister lineages: parasitism causes a general fall in complexity
•The complexity in free-living forms is high in the chromalveolate+crown group clade.
•Multicellularity and cellular complexity resulted in increases in domain architectural complexity but clearly the increase was greatest in the animal lineage alone.
•Fungi as a whole show a reduction of complexity concomitant with their gene loss with respect to the ancestor of the crown group lineage.
Biology of Networks
Nodes
Links
Interaction
A
B
Network
Proteins
Physical Interaction
Protein-Protein
A
B
Protein Interaction
Metabolites
Enzymatic conversion
Protein-Metabolite
A
B
Metabolic
Transcription factorTarget genes
TranscriptionalInteraction
Protein-DNA
A
B
Transcriptional
112 TFs
711 TGs
1295 Interactions
E. coli transcriptional regulatory network
Small-scale biochemical experimentsLarge-scale ChIP-chip experiments
and genetic deletion and over-expression data
157 TFs
4410TGs
12873 Interactions
Datasets
Yeast transcriptional regulatory network
N (k) k
1
Scale-free structure
Presence of few nodes with many links and many
nodes with few links
Transcriptional networks are scale-free
Scale free structure provides robustness to the system
Albert & Barabasi, Rev Mod Phys (2002)
Crp
NarL
Crp
NarL
E. coli H. influenzae B. pertussis
NarL
Crp
Regulatory hubs which are condition specific can beeither lost or replaced
The same protein in organisms living in different lifestyles may conferdifferent adaptive value. Hence it may emerge as a regulatory
hub in the organism to which it confers high adaptive value and not in the others
Different proteins should emerge as hubs in organismswith different lifestyle
Apprehending the diversity of eukaryotes“c
row
n gr
oup”
Mos
t stu
died
“mic
robi
al e
ukar
yote
s”M
ost d
iver
se a
nd p
reva
lent
animalsfungiSlime molds
plants
Chlorophytesrhodophytes
diatoms
Heteroloboseans
parbasalidsDiplomonads
Euglenozoa
ciliates Apicomplexans
Some notable associations that might favor inter-eukaryotic gene flow
Primary endosymbiosiswith cyanobacterium
Secondary endosymbiosiswith different plant lineages
Plant lineages
Karyoklepty (e.g. ciliates)
Endosymbiosis
Engulfment
Parasitic nucleus
Nuclear invasion
Karyoparasitism (e.g. Rhodophytes)Endoparasitism (e.g. apicomplexa)
Composite selves: bacterial origins for Vitamin B12 receptors
• We discovered a novel domain that forms the common denominator for Vitamin B12 binding and recognition in both bacteria and animals. This helped us understand how B12 is taken up by animal guts
•Domain architectures and unusual phyletic distribution of this domain strongly suggested a bacterial origin for the primary animal Vitamin B12 receptor
The medium for biological discovery
The Dali Database
•BLAST•PSI-BLAST
•HMMER•HHPRED
•DALI•MUSTANG
•KALIGN•MUSCLE
….
Labs (including “Omics” centers)
Primary archival databases
Search methods and strategies
Secondary databasesJournals
Lost in the blackhole
Sociology of the process: Complexity, competition and currency
Complexity•Dispersion of efforts•Lack of integration
Gold rush for the “hot” issues
Publications seen as currency in scientific
community
•Intense competition•Secrecy and strife
Transmission of discoveries is
hampered
Can we / should we intercede?
Increased Collaboration
Genes: Natural selection; scientific memes: peer review?
Does the axe peer review, as it stands, hamper effective scientific
transmission?
•Great science was done without modern-style peer review•Long delays in publishing - damaging in a competitive scientific environment•Inane reviews with hardly any constructive value•Nitpicking – surely a primate instinct, but does is help in science?•Obstructionists: peer review as an tool against competitors •Closed one-sided process
•Crackpot science : What do we do about it•Enormous volume of scientific production: strain on referees and journal editors•Constructive criticism helps!
•Open peer review system: A viable compromise?•A test case for the model: Biology Direct at BMC journals
Conclusions
Given the “special” interests:1)Journals and publishers2)Evaluation of scientists by host institutions3)Triaging scientific publications4)Allocating Funds for Biological research5) Need to bar crackpots
Given the competition:1)Blogs2)Wikis3)Open access, open peer-review etc.4)The ubiquity of the internet5) The drive from the memes and temes!
Will out of the box thinking help?
top related