| CBSE 2005 Winter Seminar Series in Bioinformatics
and Genomics
Biomolecular
Engineering 280B, Winter Quarter 2005
This nine-week series features researchers
from industry and academia covering emerging
topics in bioinformatics and genomics.
Tuesdays, 2:00–3:30pm
(February 15 will be 11:00am–12:00pm)
Baskin Engineering 156
February 15, March 1, and March 15 will be in 599 Engineering 2
coffee, tea, and cookies provided
To accommodate a disability,
please contact Sandra Walton, (831) 459-1544
or swalton@soe.ucsc.edu
Click
on the seminar name to read the abstract
January 11—Steven
Brenner (Plant and Microbial
Biology, UC Berkeley)
Regulated
unproductive splicing is a conserved mechanism
for modulating gene expression
January 18—Michael
B. Eisen (Molecular and
Cellular Biology, Lawrence Berkeley National
Lab, UC Berkeley)
Understanding
and exploiting the evolution of eukaryotic
regulatory sequences
January 25—Luciano
Brocchieri (Mathematics,
Stanford University)
Mutational
biases and selective processes in the
evolution of genes and proteins: applications
to gene finding and evolutionary trees
February 1—William
Scott (Chemistry, UC Santa
Cruz) RNA structural
genomics and RNA genomes
February 8—Teresa
Lyn Head-Gordon (Bioengineering,
UC Berkeley) Influence
of denatured and intermediate states of
folding on protein aggregation
February 15—Different time and place: 11:00 am in 599 Engineering 2
Adam
Arkin ( Physical Biosciences,
Lawrence Berkeley National Lab; Bioengineering
and Chemistry, UC Berkeley)
Design and diversity in control of cellular networks
February 22—Mark
Akeson (Biomolecular Engineering,
UC Santa Cruz)
Recent advances in the use of nanoscale pores to examine the structure and dynamics of single DNA molecules
March 1—Different place: 599 Engineering 2
Kevin Plaxco (Chemistry & Biochemistry, UC Santa Barbara)
Better living through biosensors
March 8—CANCELLED
SPECIAL SEMINAR ADDED TO SCHEDULE, NOT A PART OF BME 280B:
March 15—2:00–3:30PM; 599 Engineering 2
Eddy Rubin (Genomics, Lawrence Berkeley National Laboratory)
Comparative genomics at the extremes
 MORE…
view the schedule from last year's series
MORE… View the schedule from the 2003 series
MORE… View the schedule from the 2002 series
Abstracts
January 11—Steven
Brenner (Plant and Microbial
Biology, UC Berkeley)
Regulated unproductive splicing
is a conserved mechanism for modulating
gene expression
Abstract
Richard E. Green, Liana F. Lareau, Benjamin
P. Lewis, Marco Blanchette, R.Tyler Hillman,
Rajiv S. Bhatnagar, Don Rio, and Steven
E. Brenner
[Note:
This talk will begin with a brief introduction
to SIFTER: Statistical Inference of Function
Through Evolutionary Relationships, a
Bayesian approach to predicting protein
molecular function from sequence. Barbara
Engelhardt and Michael Jordan are co-authors
on this work.]
Nonsense-mediated mRNA decay (NMD) is
a eukaryotic RNA surveillance system that
recognizes transcripts with premature
termination codons (PTCs) and degrades
them. In addition to acting on the products
of mutated genes and mis-spliced pre-mRNAs,
NMD apparently also recognizes many natural
alternative splice forms in human cells.
We found that one-third of reliably-inferred
alternative mRNA splice forms possess
a PTC and are candidate substrates for
NMD. In many cases, the splicing that
generates prematurely-terminating isoforms
is regulated and is used to modulate protein
expression, a process we call regulated
unproductive splicing and translation
(RUST).
Further evidence of the importance of
RUST comes from its evolutionary conservation.
For example, CDC-Like Kinase 1 (CLK1)
is a high-level regulator of alternative
splicing involved in tissue differentiation.
It is known to be autoregulated via the
production of two mRNA isoforms: long
and short. The long mRNA produces protein
and indirectly promotes splicing to yield
the short isoform, whose skipping exon
4 leads to a frameshift and a PTC and
is preferentially stabilized by the NMD
inhibitor cycloheximide. The short mRNA,
presumably by not producing protein, promotes
splicing to yield the long isoform. The
CLK2 and CLK3 paralogs undergo precisely
the same splicing events seen in CLK1,
to produce either the long mRNA isoform,
or the short form with a PTC. Remarkably,
orthologs of all three genes in mouse
also show the same alternative gene structures
and splicing events. Even the Ciona
intestinalis ortholog, whose gene
structure has changed considerably in
the 3' region, shows the same PTC-generation
by skipping exon 4, which is flanked by
introns with comparatively high levels
of conservation.
Many other genes also have conserved alternative
splicing patterns that produce mRNAs with
PTCs. For example, human splicing factor
SC35 autoregulates its expression using
the coupling of alternative splicing and
NMD. Its C. elegans ortholog, Srp30b,
also has a PTC isoform that is down-regulated
by NMD. Similarly, both human and C.
elegans orthologs of ribosomal protein
genes RP3, RP10a, and PR12 have isoforms
with PTCs. Regulation of expression via
RUST is also observed in yeast ribosomal
proteins, including RPL30.
References
Hillman RT, Green RE, Brenner SE.
An unappreciated role for RNA surveillance.
Genome Biology 2004;5:R8.1-R8.16.
Lewis BP, Green RE, Brenner SE. Evidence
for the widespread coupling of alternative
splicing and nonsense-mediated mRNA decay
in humans. Proceedings of the National
Academy of Sciences of the United States
of America 2003; 100:189-192.
January
18—Michael
B. Eisen (Molecular and Cellular
Biology, Lawrence Berkeley National Lab,
UC Berkeley)
Understanding and exploiting the
evolution of eukaryotic regulatory sequences
Abstract
Identifying and understanding sequences
involved in regulating gene expression
is critical to elucidating the relationship
between genome sequence and organismal
form and function. Unfortunately, for
most animal species, these sequences have
remained largely elusive, as there exist
neither experimental nor computational
methods that can identify them en masse.
A major rationale for comparative sequencing
underway in primates, vertebrates, insects,
and other taxa is the expectation that
these comparative data will allow us to
identify functional elements—especially
regulatory sequences—that have previously
escaped detection. While this approach
has yielded some successes, I will argue
that the successful exploitation of comparative
sequence data requires a better understanding
of evolution of regulatory sequences.
I will present several examples from my
lab's work where we have characterized
the evolution of different types of regulatory
sequences and have used models of regulatory
evolution to identify and begin to dissect
the function of regulatory sequences in
fungi and flies.
January
25—Luciano
Brocchieri (Mathematics,
Stanford University)
Mutational biases and selective
processes in the evolution of genes and
proteins: applications to gene finding
and evolutionary trees
Abstract
I will describe size and compositional
biases of genes from eukaryotic and prokaryotic
genomes in relation to different life-styles
and levels of expression and an application
to gene prediction in highly biased Herpesvirus
genomes. I will also discuss the relevance
of mutational biases and selective processes
for the reconstruction of phylogenetic
trees.
February
1—William
Scott (Chemistry and Biochemistry,
UC Santa Cruz)
RNA structural genomics and RNA
genomes
Abstract
Viral genomes, unlike those of other life
forms, are sometimes composed of RNA rather
than DNA. Like DNA genomes, viral RNA
genomes often contain non-coding regions
whose sequences are highly conserved.
Unlike those found in genomic DNA, these
highly conserved RNA sequences typically
form higher-ordered or tertiary structures
whose function is critical to the life-cycle
of the virus. Two such examples are a
self-cleaving (or catalytic) RNA found
in various small plant viruses and virus-like
genomes, and the stem-loop 2 motif (or
s2m) RNA found in the SARS virus and the
related astroviruses and coronaviruses.
Using both static and time-resolved crystallography,
we have investigated the relationship
between the three-dimensional structures
of these RNAs and their biological functions.
February
8—Teresa
Lyn Head-Gordon (Bioengineering,
UC Berkeley)
Influence of denatured and intermediate
states of folding on protein aggregation
Abstract
We simulate the aggregation thermodynamics
and kinetics of multiple chains of two
different alpha/beta proteins, proteins
L and G, each of which self-assembles
through distinctly different folding mechanisms.
The differences in aggregation kinetics
between the two proteins are clearly correlated
with the amount and distribution of intra-chain
contacts formed in the denatured state
ensemble (DSE), or an intermediate state
ensemble (ISE) if it exists, as well as
the folding timescales of the two proteins.
Protein G aggregates more slowly than
protein L due to its rapidly formed folding
intermediate, which exhibits native intra-chain
contacts spread across the protein. Protein
L shows more localized native structure
in the DSE, with timescales of folding
that are commensurate with the aggregation
timescale, leaving it vulnerable to domain
swapping or non-native interactions with
other chains that increase the aggregation
rate. We suggest that experiments that
can characterize the structural signatures
of the DSE, ISE, or transition state ensemble
(TSE), under non-aggregating conditions
of low concentration, should show that
proteins having localized structure in
the DSE will be more aggregation-prone
than proteins with more diffuse elements
of stable structure. Because the intermediate
state of protein G is found to correlate
with its slower aggregation rate, we suggest
that early intermediates in folding may
be evolutionarily selected for their protective
role against unwanted aggregation. Finally,
given that proteins L and G can both form
amyloid fibrils under certain solution
conditions, this work also provides mechanistic
and structural insight into the formation
of the earliest prefibrillar species.
February
15—Different time and place: 11:00 am in 599 Engineering 2
Adam
Arkin ( Physical Biosciences, Lawrence
Berkeley National Lab; Bioengineering
and Chemistry, UC Berkeley)
Design and diversity in control of cellular networks
Abstract
Not available
February
22—Mark
Akeson (Biomolecular Engineering,
UC Santa Cruz)
Recent advances in the use of nanoscale pores to examine the structure and dynamics of single DNA molecules
Abstract
UC Santa Cruz has played a leading role in the development of nanoscale pores for the examination of individual DNA molecules. At its core, this technology is fairly straightforward: a voltage bias is applied between two salt solutions across a single pore embedded in a thin non-conducting support, such as a lipid bilayer or silicon nitride. The pore diameter is approximately the same as the cross section of DNA (2 nm). When the charged DNA molecule is captured in the pore, it is driven across in sequential, single-file order. As this occurs, current is impeded in a manner characteristic of the DNA strand. In this seminar, I will briefly summarize the history of this emerging technology, and then describe recent advances that permit single base resolution on individual molecules and real-time measurements at sub-angstrom precision. This technology has immediate applications in dynamic force spectroscopy applied to DNA–enzyme interactions and in DNA structural dynamics, such as flexing of HIV dsDNA during Integrase processing. It is also a core technology supported by NHGRI aimed at achieving 6X coverage of a human genome equivalent for approximately $1,000 within ten years.
March 1—Different place: 599 Engineering 2
Kevin Plaxco (Chemistry & Biochemistry, UC Santa Barbara)
Better living through biosensors
Abstract
Not available
March
8—CANCELLED
SPECIAL SEMINAR ADDED TO SCHEDULE, NOT A PART OF BME 280B:
March 15—2:00–3:30PM; 599 Engineering 2
Eddy Rubin (Genomics, Lawrence Berkeley National Laboratory)
Comparative genomics at the extremes
Abstract
Two areas exploiting comparative genomic data will be discussed: 1) the
analysis in transgenic mice of a complete chromosomal set of enhancers
identified through human fish sequence comparisons, and 2) the genomic
sequencing and analysis of DNA isolated from 40,000-year-old cave bear
bones.
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