Fyodor A. Kondrashov
ADDRESS
Section on Ecology,
Behavior and Evolution
Division of Biological
Sciences
2218
Email:
fkondrashov@ucsd.edu
Phone: 858-822-1832
Fax: 858-534-7108
and
Engelhardt Institute of
Molecular Biology
EDUCATION
2005 – PhD program,
2003
– 2004 Master of Arts,
1996
– 2000 Bachelor of Arts in biology and
ecology, Simon's
RESEARCH EXPERIENCE
2000
- 2003 Research Scientist, NCBI, NIH,
GRANTS AND AWARDS
2005 – National Science Foundation Graduate
Fellow.
2003 Darwin Trust Fund Fellowship
(declined).
TEACHING
2005
2005
2003-4 UC Davis, TA: Genetics and Zoology.
2003
REVIEWING
Biofizika,
BMC Bioinformatics, BMC Evolutionary Biology, BMC Genomics, Gene, Genetical Research, Genome Biology, Human Molecular
Genetics, Journal of Molecular Evolution, Molecular Biology and Evolution, Molecular Phylogenetics and Evolution, Nature, Nature Genetics,
Nature Reviews Genetics, Nucleic Acid Research, PLoS
Biology, PLoS Genetics, Trends in Genetics.
GEOGRAPHY OF INVITED PRESENTATIONS:
Toronto (Canada);
Heidelberg (Germany); Moscow, Pushchino (Russia);
Taipei (Taiwan); Bath, Brighton, Cambridge, Edinburgh, London, Reading (UK);
Arlington, Bethesda, Boston, Chicago, Davis, New Haven, Los Angeles, Norfolk,
Rockville, San Diego (USA).
PRESENTATIONS AT CONFERENCES
Advances in Science of Drug Discovery. July 2005, Prediction of pathogenic mutations in
human mitochondrially encoded tRNAs.
Symposium on Theoretical Ecology and Evolutionary
Biology. February 2005, Finding pathogenic mutations in healthy organisms:
reconciling data and theory.
Poplation
Genetics Group Meeting. January
Gordon
Research Conference in Structural and Evolutionary Bioinformatics.
August 2002, Compensatory substitutions and the prevalence of
Dobzhansky-Muller incompatibilities in protein
evolution.
Second
Annual UMass Conference in Bioinformatics.
May 2002, Compensatory substitutions and the prevalence of Dobzhansky-Muller incompatibilities in protein evolution.
PUBLICATIONS
1. Kondrashov
AS and Kondrashov FA. (1999)
Interactions among quantitative traits in the course of sympatric speciation.
Nature 400, 351-354.
2.
Wolf YI, Kondrashov FA and Koonin
EV. (2000) No footprints of
primordial introns in a eukaryotic genome. Trends in Genetics 16, 333-334.
3.
Rogozin IB, Kondrashov FA
and Glazko GV. (2001) Use of mutation spectra analysis software. Hum Mutat. 17, 83-102.
4.
Wolf YI, Kondrashov FA and Koonin
EV. (2001) Footprints of primordial introns on the eukaryotic genome: still no clear traces. Trends in Genetics 17, 499-501.
5. Kondrashov
FA and
6. Rogozin
IB, Kochetov AV, Kondrashov
FA, Koonin EV and Milanesi
L. (2001) Presence of ATG triplets in 5' untranslated
regions of eukaryotic cDNAs correlates with a 'weak'
context of the start codon. Bioinformatics. 17, 890-900.
7. Kondrashov
FA and Koonin EV. (2001) Origin of
alternative splicing by tandem exon duplication.
Human Molecular Genetics 10, 2661-2669
8.
Jordan KI, Kondrashov FA, Rogozin
IB, Tatusov RL, Wolf YI and Koonin
EV. (2001) Constant relative rate
of protein evolution and detection of functional diversification among
bacterial, archaeal and eukaryotic proteins. Genome Biology 2, research0053.1-0053.9
9. Kondrashov
FA, Rogozin IB, Wolf YI and Koonin
EV. (2002) Selection in the evolution of gene duplications.
Genome Biology 3, research0008.1-0008.9
10. Perelygin AA, Kondrashov FA, Rogozin IB and Brinton MA. (2002) Evolution of the mouse polyubiquitin
C gene. Journal of Molecular
Evolution 55, 202-210.
11. Castillo-Davis C, Mekhedov SI, Hartl DL, Koonin EV and Kondrashov FA.
(2002)
Selection for shorter introns in highly expressed genes. Nature Genetics 31,
415-418.
12. Kondrashov AS, Sunyaev S and Kondrashov FA. (2002) Dobzhansky-Muller
incompatibilities in protein evolution. Proceedings of the National Academy of Sciences USA 99,
14878-14883.
13. Kondrashov FA and Koonin EV.
(2003) Evolution of alternative splicing: deletions, insertions and origin of
functional parts of proteins from intron sequences. Trends in Genetics 19, 115-119.
14. Sunyaev S, Kondrashov FA, Bork P
and Ramensky V. (2003) Impact of selection, mutation
rate and genetic drift on human genetic variation. Human Molecular Genetics 12, 3325-3330.
15. Panchenko AR, Kondrashov FA and
Bryant S. (2004) Prediction of functional sites by analysis of sequence and
structure conservation. Protein Science
13, 884-892
16. Kondrashov FA, Ogurtsov AY and
17. Castillo-Davis C, Kondrashov FA. Hartl DL and Kulathinal RJ. (2004) The functional genomic distribution of protein divergence in
two animal phyla: coevolution, genomic conflict, and
constraint. Genome Res. 14, 802-811.
18. Bazykin GA, Kondrashov FA, Sunyaev S, Ogurtsov AY and
19. Kondrashov FA and Koonin EV. (2004) A common framework for understanding the origin of genetic
dominance and evolutionary fates of gene duplications. Trends in Genetics 20, 287-290.
20. Kern AD and Kondrashov FA (2004) Mechanisms and convergence of
compensatory evolution in mammalian mitochondrial tRNAs. Nature Genetics 36, 1207-1212.
21. Kondrashov FA (2005) In search of the limits of evolution. Nature Genetics 37, 9-10 (news and views).
22. Jordan IK, Kondrashov FA, Adzhubei IA, Wolf
YI, Koonin EV, Kondrashov
AS and
Sunyaev S. (2005) A universal trend of amino acid gain and loss in
protein evolution. Nature 433, 633-638.
23. Kondrashov
FA. (2005) Analysis of monomer sequences in protein and tRNAs and the manifestation of compensated pathogenic
deviations in their evolution. Biofizika 50,
389-395. [In Russian]
24. Kondrashov
FA. (2005) Convergent evolution of secondary structure of
mitochondrial cysteine tRNA
in the nine-banded armadillo Dasypus novemcinctus. Biofizika 50, 396-403. [In Russian]
25. Kondrashov FA
(2005) Prediction of pathogenic mutations in mitochondrially
encoded human tRNAs. Human Molecular Genetics 14, 2415-2419.
28. Yampolsky LY, Kondrashov
FA and Kondrashov AS. (2005) Strength of selection against amino acid replacements in human
proteins. Human Molecular
Genetics (In press).
27. Kondrashov FA and Kondrashov AS
(2005) Causes of fixation of duplicated genes. Journal of Theoretical Biology (In press).
28. Kondrashov FA, Ogurtsov AY and
29. Babenko VN, Basul MK, Kondrashov FA, Rogozin IB, Koonin EV. (2005) Signs of positive
selection of somatic mutations in human cancers detected by EST sequence
analysis. BMC Cancer
(submitted).
In preparation:
30. Kondrashov FA and Gurbich
TA (2006). Selection and gene conversion in elongation factor Tu in gamma proteobacteria.
31. Kondrashov FA and Houle D (2006) Introns enhance the efficacy of selection in mammalian
genes.
32. Kondrashov FA, Ogurtsov AY, Shabalina SA and
33. Kondrashov FA and Andolfatto P.
(2006) Positive selection for gene dosage in Drosophila melanogaster.
34. Kondrashov FA,
Schmidt S and Sunyaev S. (2006) A
comparison of the dominance coefficients in human haploinsufficient
and haplosufficient genes.
RESEARCH INTERESTS
I am generally
interested in investigating the selective, mutational, and functional
properties of genes and genomes that influence their structure and evolution.
While this may not seem like a feasible research program I cannot characterize
my research interests any narrower. What limits the scope of my studies is the
methodology I use. At
A specific problem that I am
interested in embroidering further is the investigation of complex fitness
ridges at the macroevolutionary level. These ridges
can be thought of as a topological map (in many dimensions) that relates
genotype to fitness. Many evolutionary and functional characteristics of
organisms and molecules depend on the ruggedness of the ridges on the map.
Currently very little is known about this map and theoretical predictions have
not been rigorously defined. There are several ways to address these questions,
but perhaps the most promising will be characterization of functional overlap
in metabolic and genetic networks and probing the structural integrity of
proteins and RNA molecules through site-directed mutagenesis.
PREVIOUS RESEARCH
Theory
Early in my career, I
have worked on two theoretical problems: sympatric speciation and modeling of
complex epistatic interactions. Using the hypergeometric model, we have modeled the process of
sympatric speciation under different assumptions about the genetic architecture
of the phenotypes involved. The paper that described this model demonstrated
that sympatric speciation is theoretically possible under a broad range of
parameter values. For my undergraduate thesis I investigated a general model of
complex, or multidimensional, epistasis.
Multidimensional epistasis arises when fitness cannot
be described as a function of a simple additive variable. The general concept
behind this work was that epistasis could be modeled
by looking at differences in the order of accumulation of mutations because the
additive model describes the case when the order of accumulation of mutations
does not matter and leads to the same fitness values in the course of
evolution. We investigated the advantages and disadvantages of sex on different
types of multidimensional fitness surfaces. However, this general model is also
applicable to the study of metabolic and genetic networks, genetic dominance,
gene duplications and speciation.
Genomics and Molecular Evolution
More recently, I
investigated several aspects of genome evolution and organization. In
particular, I am interested in understanding to what extent different evolutionary
mechanisms have shaped various aspects of genome structure and evolution.
1)
Evolution and selection of intronic sequences
Although introns have been discovered over 25 years ago, very little
is known about their origin, function, and selective constraints they are
subject to in nature. It is unclear how often and by what mechanisms introns originate, disappear, or relocate within or between
eukaryotic genes. Over the past 3 years, we have managed to answer two
important questions regarding the evolution of introns.
Firstly, we demonstrated the ability of introns to
appear in initially intronless sequences by studying
the distribution and density of introns in C. elegans
genes that have been recently horizontally transferred from bacteria and archaea. More recently, we have shown that selection limits
the length of introns, at least in highly expressed
genes. The reason for such selection is probably the energetic expense and time
constraint of transcription and/or splicing of long introns.
2)
Alternative splicing
Alternative splicing
is ubiquitous in higher eukaryotes and is thought to have played a pivotal role
in the evolution of animal complexity. However, its origins and evolution are
not well understood. We have looked at the possibility that tandem exon duplications lead to the origin of alternatively used
tandem exons. We found that at the very least 10% of
alternatively used tandem exons have originated
through a duplication event. The similarity among the duplicated exons also allowed us to date the duplication events and
therefore the origin of alternative splicing. We found evidence that the
alternative splicing that originated through tandem exon
duplication usually preceded the mammalian radiation, and in some cases
predates the evolution of chordates. We looked at the length difference
alternative splicing, in which the short isoform is a
subset of the longer one. We inferred the ancestral state of the alternative
splicing events, and have concluded that in approximately 1/3 of the cases the
shorter isoform corresponds to the ancestral state
and have evolved through the insertion of unrelated DNA into the ancestral
gene. The origin of the insertions in some cases was demonstrated to have come
from intronic sequences, showing that functionally
novel sequences may originate from random nonfunctional DNA.
3)
Gene duplications
Gene duplications are
generally thought to evolve neutrally, at least immediately after duplication.
We have carried a genome-wide study of duplicated genes showing that there is a
relaxation of selection on both products of the duplications. We also performed
a functional analysis of the duplicated genes, and since a large proportion of
them were genes that interacted with the environment, we proposed that gene
duplications are generally fixed in populations because they are beneficial
from the very moment of duplication.
Functional and Medical Genomics
I
work on two subjects which have evident implications to medicine.
1)
Compensated pathogenic deviations
I spent a considerable
time studying compensatory substitutions in RNAs and
proteins. We found that some mutations that cause diseases in humans are fixed
even in closely related species such as chimps. We detailed the theory behind
this phenomenon and described the molecular basis of this phenomenon. It turns
out that for many of such instances (which we call Compensated Pathogenic
Deviations or CPDs) the mechanisms of compensation
for the damaging effect of a pathogenic mutation are different sorts of
intra-molecular interactions. We demonstrated such instances vividly in
mammalian mitochondrial tRNAs.
2)
Identifying disease-causing loci
We compared two sets
of genes; genes that are known to cause disease and genes that are unknown to
be a “disease-causing” gene. We found that a number of properties differ
substantially between the two sets. Genes that were known to cause disease are
longer, more evolutionary conserved, have more introns
and have a different amino-acid composition among other interested factors.
While we do not know the reason for many of these differences we were able to
train a neural network to recognize potential disease-causing genes from among
the genes that were not previously known to cause disease. We are hoping that
this study will aid in faster identification of genes responsible for human
diseases. Instead of randomly testing candidate genes from a location on a
chromosome obtained through an association study, researchers should start with
genes that we identify as disease-causing. We estimate that using such an
approach may half the time and resources that are currently wasted at the final
stage of identification of disease-causing genes.