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1st RECESS Meeting
7.IV.2009
Mikhail Gelfand
2003
+
Institute for
Information
Transmission
Problems
(Russian
Academy of
Sciences)
Faculty of
Bioengineering
and
Bioinformatics,
Moscow State
University
=
Research and
Training Center
“Bioinformatics”
Research
• Comparative genomics of alternative splicing
• Evolution of post-transcriptional
modifications
• Evolution of bacterial regulatory systems
– Evolutionary dynamics of regulons
– Codes of protein-DNA interactions
• Functional annotation of genes and genomes
(bacteria and phages)
… via the analysis of regulation
• Metagenomics
• Comparative genomics of bacterial strains
– Yersinia and Escherichia spp.
– CRISPR systems
Alternative splicing is…
• frequent (1998, cf. P.Bork, EMBL)
• shuffling protein domains and affecting
functional sites (2001, with P.Bork, EMBL;
R.Apweiler, EBI; S.Sunyaev, Harvard)
• evolutionary flexibile (2002, cf. C.Lee,
UCLA)
• evolving under positive selection (2008)
• Qualitative analysis (2008-…)
– aging in human
– speciation in drosophilas
Regulation of transcription
in bacteria
• Alternative RNA structures
– riboswitches (1998-2002)
– T-boxes (2006-…)
• Comparative techniques =>
evolutionary flexibility of regulatory
systems (1998-…)
• Co-evolution of TFs and their binding
motifs (2006-…)
Riboswitch regulatory mechanism
Transcription attenuation
Translation attenuation
How FruR has become Cra:
“globalisation” of a local regulator
Mannose
Glucose
manXYZ
ptsHI-crr
edd
epd
eda
adhE
aceEF
Mannitol
mtlA
gapA
fbp
Fructose
pykF
mtlD
fruBA
fruK
pfkA
pgk
gpmA
icdA
ppsA
pckA
aceA
tpiA
aceB
Gamma-proteobacteria
Enterobacteriales
E. coli and Salmonella spp.
Regulation of iron
metabolism genes
in functional
subsystems
Rhizobiales
Bradyrhizobiaceae
Rhodobacteriales
The Zoo (likely
ancestral state)
Correlated pairs of TFs from the LacI family
and their binding motifs
Metagenomics
• Riboswitches
– new regulon members
• CRISPRs
– co-occurrence of CRISPR spacers and
phage protospacers in different
locations (Sorcerer II)
– evolutionary dynamics of CRISPR
cassettes
Functional annotation
• Acholeplasma laidlawii
(2007): the first genome
sequenced in Russia
• Human gut bacterial
metagenome
• Hundreds of bacterial
regulatory sites, tens of
gene functions.
Sometimes unexpected
functions:
– Ribosomes as a zinc depot
– transporters
Ribosomes as a zinc depot.
Observation: Zn-independent homologs of Zn-dependent
ribosomal proteins are regulated by zinc repressors
Sufficient Zn
ribosomes
repressor
R
Zn-depenent
enzymes
Zn starvation
R
A new type of
transporters:
a universal
energizing
component and
varying
specificitydetermining
components,
sometimes
capable of
independent
transport
Some confirmed predictions
• Regulators
– riboswitches
• Vitamins: riboflavin, thiamine, cobalamin
• Amino acids: lysin, methionine
– Transcription factors
•
•
•
•
NrdR: ribonucleotide-reductases
MtaR, CmbR: methionine and cysteins
NiaR, NrtR: NAD metabolism
NsrR, NnrA: nitrosative stress
• Regulatory interactions
– DNA regulatory motifs (>10)
– Individual TF binding sites (>20)
• Enzymes
–
–
–
–
–
ThiN and TenA (thiamine biosynthesis)
CobX, CobZ (cobalamin biosynthesis)
FadE (fatty acids metabolism)
AbnA, Xca (arabinose catabolism)
NagK, NagBII (N-acetylglucosamine
catabolism)
• Transporters
– Vitamins and cofactors
• YpaA/RibU and RibM:
riboflavin
• Bio(MN)Y: biotin
• ThiXYZ: thiamin
• NiaP: niacin
• Vng1369-71: corrinoids
– Sugars and polysaccharides
• OgtABCD: pectin
degradation products
• NagP: N-acetylglucosamine
– Amino acids
• MetD: methionine
• SteT: threonine
– Metal ions
• CbiMNQO, HoxN: cobalt
• NikMNQO: nickel
– nucleotides:
• YicE: xantin
Current collaborations
• Irena Artamonova (Institute of General Genetics,
Moscow, Russia)
• Inna Dubchak (LBNL, Berkeley, USA)
• Dmitry Frishman (TUM, Munich, Germany)
• P.Khaitovich (Partner Institute for Computational
Biology / MPG, Shanghai, China)
• Eugene Koonin (NCBI, Bethesda, USA)
• Andrei Mironov (FBB MSU, Moscow, Russia)
• Arkady Mushegian (Stowers Institute, Kansas City,
USA)
• Andrei Osterman (Burnham Institute, La Jolla, USA)
• Pavel Pevzner (UC San Diego, USA)
• Konstantin Severinov (Institute of Gene Biology,
Moscow, Russia)
Lecture courses
(with A.A.Mironov’s group)
• Comparison of genetic texts (year 1, semester 2 )
– D.Ravcheev (practicum, with A.B.Rakhmaninova)
• Functional analysis of genomic sequences (year 2, semester 3 )
– D.Ravcheev, E.Ermakova (lectures and practicum)
• Informatics and programming (year 3, semester 5 )
– E.Stavrovskaya, D.Vinogradov
(practicum for the lecture course by A.A.Mironov)
• Algorithms of bioinformatics (year 3, semester 6)
– E.Stavrovskaya, D.Vinogradov
(practicum for the lecture course by A.A.Mironov)
• Comparative genomics (year 4, semester 7)
– M.S.Gelfand (lecture course, practicum, journal club)
• Evolutionary and medical genomics (year 5, semester 8)
– G.A.Bazykin (lecture course)
Also at Moscow Physic-Technical Istitute
• Information processes in living systems (year 5, spring semester)
– M.Gelfand
Support
• Howard Hughes Medical Institute (2000-2005, 2006-2010)
• INTAS (2006-2008)
• Russian Foundation of Basic Research (7 grants in 2009)
– РФФИ-DFG
• Russian Academy of Sciences,
– Molecular and Cellular Biology
– Fundamental Sciences for Medicine
– Gene Funds and Biodiversity
Plans for RECESS
• Post-translational modification
– … and AS
– evolution
• Systems analysis
(integration of high-throughput data)
• Evolution of regulation
MCCMB-09 (4th Int. Moscow Conference
on Computational Molecular Biology)
July 20-23 (+ post-conference events)