Integrating Genotype and Phenotype
The first complete genome of
an organism was published in 1995. Today
the genomes of over 500 organisms have been sequenced; and the rate of growth is accelerating. Now, the focus is changing from seeking DNA
sequence information to seeking to understand how it works. The challenge
for life science research that this cluster-hiring initiative aims to further
is integration of newly emerging fields of science that seek to elucidate the
genetic architecture of life.
The
incredible wealth of genomic information has thrown an outstanding problem of
modern biology into sharp relief: the
gap in our knowledge of the relationship between the genetic material and the
phenotype (observable traits) of an organism.
We have had long practice at characterizing phenotypes: an organism’s
physical structure, its behavior, physiology, development, etc. We know what whole organisms are like. With whole genome sequencing, our ability to
characterize the DNA has suddenly become complete. However, our knowledge of the way in which
different component parts of the genome are sequentially deployed to construct
an organism is still rudimentary. For example, a recent
study suggests that 62% of the mouse genome is transcribed into RNA, contrary
to previous assumptions of less than 10% FANTOM Consortium 2005)<. More importantly,
the parts of these RNA transcripts that lie outside of protein-coding regions
have just recently been shown to have important regulatory consequences. Inferring which parts of the mammalian genome
are functionally important requires that we determine which portions have
phenotypic consequences.
Understanding
the relationship between genotype and phenotype is the unstated mission of much
of modern biology; this cluster will make this focus explicit. Our aim is to connect two traditions for the
study of genotype-phenotype relationships: the whole-organism perspective of
evolutionary biology, and the molecular approach of modern genetics. Each is well represented at FSU. We propose to hire scientists whose work
directly bridges these traditions, thereby building an interactive group that
creates synergies with faculty already at FSU.
Intellectual Benefits
Understanding
the relationship between genotype and phenotype is the central challenge
implicit in all of biology. A complete
understanding of the genotype phenotype map yields an understanding of the
architecture of life, an understanding of the way organisms function, the way
they have evolved and their potential for further change. The current structure of biology is largely
one where scientists choose a level of organization as their life’s work – geneticists
work on DNA, cellular biologist work on cells, physiologist work at the level
of organ systems, etc. Historically,
functional molecular genetics and evolutionary biology lie at opposite ends of
the life-sciences spectrum. These are
two frames of reference that tend to see the genotype-to-phenotype gap in
different contexts and do different types of experiments. Indeed, at many peer institutions these
traditions are embodied in distinct academic departments, with names like
Genetics or Ecology and Evolution. It is
clear that progress now depends on the integration of these different levels of
knowledge across research traditions.
To
take a concrete example, developmental geneticists have worked to describe all
the genes which when mutated have developmental effects. In Drosophila one of these many genes was
given the name bric-a-brac because of the garbled appearance of the ovarian
follicles in animals mutant for the gene.
On the organismal side of biology, biologists noted that the pattern of
stripes and spots on the abdomens of flies varies among species, and have
speculated about the significance of these differences. In 2001 these two bits of knowledge were
unexpectedly united when evolutionary developmental biologists demonstrated
that differences in the bric-a-brac gene are responsible for many of the
changes in color among species (Kopp et al. 2000). This
demonstration then allows us to study directly a key difference between
species, and so begin to unravel the evolutionary forces acting on the
gene. For this gene, we can now study
the entirety of its normal function, and not just what happens when the
function of the gene is disrupted.
We
seek to hire a group of faculty whose research interests span molecular
genetics to evolutionary biology. This
will entail simultaneously hiring two somewhat distinct groups of faculty. First, we will seek colleagues in the
emerging fields that consider the genotype-phenotype relationship from an
explicitly evolutionary perspective.
These include fields such as comparative genomics, evolution of
development, ecological genetics and molecular evolution. Second we will build a critical mass in molecular
genetics of regulatory systems. One
promising area within this is epigenetics, in particular the nascent fields of
RNA interactions and chromatin remodeling.
This combination will empower FSU faculty and students to investigate
the entire network of gene expression, regulation and function, so that the
phenotypic consequences of variation and genetic basis of phenotypes can
simultaneously be unraveled.
The salient feature that
unites the evolutionary end of our cluster is the use of comparative
techniques, that is, comparing aspects of biology between species. This extremely powerful methodology can be
applied to all levels of organisation.
At the genomic level, regions of genomes that do
not vary among species are likely to be functionally important and variation in
them a potential cause of disease; less conserved regions may be the key to
evolutionary transformations and true novelty.
At the phenotype level, the rate of change in a trait suggests which
traits are selected to preserve their form, and which are subject to different
selection in different circumstances.
FSU is a world leader in phylogenetic methods, the reconstruction of
evolutionary history, which is the basis for all comparative studies.
Our
proposed emphasis on epigenetic (RNA and histone-based) interactions
complements an evolutionary emphasis by furnishing FSU with a critical mass in
genome-based molecular genetics. In the
past five years, our knowledge of epigenetic mechanisms has expanded from a few
peculiar examples, to recognition that such interactions are ubiquitous. The regulatory networks that control gene
expression are far more complex than previously imagined, with multiple
feedbacks between DNA, RNA and proteins.
A few examples will illustrate the scope and profound importance of
epigenetic processes. Non-protein coding
RNAs have been shown to play well-defined functional roles. When RNA folds up to form double-stranded
molecules (dsRNA), unlike the usual protein-coding RNAs that remain
single-stranded, it can target the destruction of protein-coding RNA that
matches its sequence. This phenomenon is
already being exploited to manipulate gene expression, and may prove useful for
gene therapies. A large number of short
dsRNAs, for example micro RNAs (miRNA), have been shown to be a normal part of
gene regulation in plants and animals.
A very different epigenetic process is the ‘histone code.’ Histones are proteins that package DNA to either
enhance or retard the ability of genes to be expressed. A key step in the modulation of gene activity
is accomplished by discrete chemical modifications to the ends of one type of
histone. Many of the "writers"
and "readers" of the histone code have been discovered in the last
few years. We are only just beginning to learn many of the basic players and
epigenetic elements involved in gene regulation, making this a perfect time to
establish a leadership role in this exciting new sub-field that promises to revolutionize
modern biology.
Most regulatory networks that lead from genotype to
phenotype contain epigenetic links
Therefore we can anticipate that, for example, a biologist interested in
the evolution of development might well end up working an epigenetic process as
a central component of their research.
Such integration of molecular and evolutionary biology is key to
advancing the life sciences. A recent
paper provides an excellent example of the sort of synergism likely from our
cluster hiring. Farh et al. (2005) studied the expression of genes in relation to a few
specific regulatory micro RNAs. They
showed that the specific sequences targeted by miRNAs to reduce expression of
some genes are also selected against in other genes expressed in the same
tissues, an evolutionary consequence not previously suspected. Other outstanding examples of
genotype-phenotype studies make clear the interdisciplinary nature of the
field. Sunyaev et al. (2001) combined data on nucleotide polymorphism within and between species with structural
data and population genetic principles to predict which amino acid
substitutions would lead to deleterious health consequences in humans. Lynch and Conery (2003) built an intriguing case that growth in genome size due to
non-selective factors is the cause of the evolutionary complexity of organisms,
rather than the other way around. All of
these projects combined traditional genome-level information from sequencing
projects with expertise from evolutionary biology.
In
2002, the prestigious journal Science declared that the “Breakthrough of the
Year” had been the discovery of the biological role of small RNAs. Since that time, the study of this neglected
level of regulation has exploded in importance.
In 2005, Science declared the study of Evolution in Action the
Breakthrough of the Year, based largely on the vast increase in our knowledge
of genomes. This hiring initiative exploits
the natural intellectual relationship between these dynamic areas to capitalize
on both.
Why FSU?
FSU
is well positioned for growth in this area.
This proposal builds on a very strong group in ecology and evolution, which
was the highest ranked group in the entire University in the last NRC
survey. In particular, FSU is a world
leader in phylogenetic methods. The
Biology Department also has a young group of faculty members with expertise and
rapidly growing reputations in molecular
genetics, as well as a distinguished groups in cell structure and motility,
structural biology and sensory neurobiology. The genotype-phenotype initiative seeks to
hire in precisely the areas that bridge the evolutionary groups noted above and
the reductionist and functional orientation of the rest of Biological Science
Department.
A key to this cluster is
that it spans both evolutionary and functional aspects of the problem, forming
a genuine bridge between these different aspects of biology. Inter-disciplinary initiatives often fail to
achieve the synergism desired because of the mundane problems of administrative
balkanization and physical separation.
The conceptual grouping of molecular genetics and evolutionary biology
will coincide with the administrative and physical grouping of many of the
foundational faculty in the new Life Sciences Research Complex, thus quickly
capitalizing on FSU’s investments in research infrastructure. The cluster is further enhanced by expertise in
other departments at FSU in the area of RNA structure (H. Li, Chemistry),
computational modeling of protein polymers and interactions, (H-X. Zhou,
References
FANTOM
Consortium, et al. 2005. The transcriptional landscape of the mammalian genome.
Science 309: 1559-1563.
Farh, K. K.-H., et al. 2005. The widespread impact of
mammalian microRNAs on mRNA repression and evolution. Science: 1121158.
Kopp, A., I. Duncan and S. B. Carroll 2000. Genetic
control and evolution of sexually dimorphic characters in Drosophila. Nature
408: 553-559.
Lynch, M. and J. S. Conery 2003. The origins of
genome complexity. Science 302: 1401-1404.
Sunyaev, S., et al. 2001. Prediction of deleterious
human alleles. Hum. Mol. Genet. 10: 591-597.