Stephen W. Schaeffer talks
with ScienceWatch.com and answers a few questions
about this month's Fast Moving Front in the field of
Molecular Biology & Genetics.
The Richards et al. (2005) article is highly cited because of the
value of the Drosophila pseudoobscura genome sequence data and
also because the paper contributed to our understanding of genomic
evolution at the level of genes, of gene regulation, and also of
chromosomes. Researchers have used the comparison of the D.
pseudoobscura and D. melanogaster genomes to verify gene
models and to identify regions of DNA that turn genes on and off.
This information has provided value to molecular geneticists who locate
important genes that are involved in vital cellular, metabolic, and
developmental processes. The comparison of these two genomes also provided
an opportunity to examine protein evolution at a genomic scale.
"We predicted that
the gene order comparison of
the two extant species would
map the breakpoints of one of
the D. pseudoobscura genome
rearrangements. Molecular
biological approaches
verified the mapped location
of the rearrangement
breakpoints."
Patterns of conservation in proteins can identify important peptide domains
that can be tested for functional significance. In addition, evolutionary
biologists have used this information to understand how often natural
selection has shaped genetic variation in the genome.
Finally, the paper presented a comprehensive analysis of how gene order
changes on chromosomes. The analysis of gene order has recently emerged as
an area of interest as complete genome sequences are obtained. This study
showed that short DNA repeats may drive the reorganization of genes along
the chromosome via genome rearrangements.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
Data described by Richards et al. (2005) were of particular value
for the Drosophila research community. The comparison of sequences
between the two Drosophila species verified gene models and
provided clues about sequences used to turn genes on and off.
This paper confirmed observations about chromosomal organization that were
proposed in the 1930s and '40s. Alfred Sturtevant and H. J. Muller,
students and collaborators of Thomas Hunt Morgan, proposed that genes were
conserved in location on the same chromosomal arms among different species
of Drosophila. This hypothesis was developed through the
comparison of genetic maps of eye, wing, and bristle mutations in the
different species. Although the genes were found on the same chromosome
arms, the gene orders varied among species.
This paper confirmed the observations of Sturtevant and Muller at the DNA
level, although a small fraction of genes mapped to different chromosomal
arms than predicted. The genome sequence revealed clues about how the
genome rearranges. A small, highly repetitive DNA motif associated with
sites of chromosomal breakage suggested a potential DNA-based mechanism for
genome rearrangement.
Another interesting finding was that proteins that are expressed
specifically in males, such as testis-specific genes, tended to change more
rapidly than other types of genes in the genome. In some cases,
male-specific proteins were completely absent. The rapid evolution of
testis-specific genes may play a role in the formation of new species by
generating incompatibilities in hybrid males.
The laboratory of William Gelbart at Harvard University developed
computational approaches for the identification of genes based on gene
order data. These methods helped to assemble the basic units of genomic
sequence assemblies into larger units called super scaffolds and,
ultimately, chromosomes.
Would you summarize the significance of your paper
in layman's terms?
Genomes are composed of nucleotide sequences for proteins—sequences
that regulate how genes are turned on and off—and sequences that
ensure the proper transmission of chromosomes during cell division. It is
difficult to decode the information from the genome sequence from just a
single species, but comparison of genomes of closely related species
provides an opportunity to determine the functional importance of sequences
in the genome. Sequences that are important for function of cellular and
developmental processes tend to change less than those that are unnecessary
for survival and reproduction.
Drosophila melanogaster has been an important model system for the
study of genetics and development for nearly a century. A short generation
time, the ability to make mutants and the ability to make controlled
genetic crosses, explains the longevity of this species as a model. Humans,
on the other hand, do not have these same properties, thus making it more
difficult to experimentally manipulate interesting proteins that cause
disease.
As it turns out, D. melanogaster and its close relatives share
many genes with humans that can be manipulated in a controlled laboratory
environment. The comparative genome analyses described in Richards et
al. (2005) was designed to define the important genes and the genetic
elements that turn genes on and off. This could be done because the
evolutionary process of mutation tended to occur in sequences of the genome
that were not as important for function, while leaving the footprint of
genes plus their on/off switches. With the full cache of molecular genetic
tools of Drosophila, biologists will now be able to attack
problems in human disease genetics by studying genes in the D.
melanogaster genome.
How did you become involved in this research and
were there any particular problems encountered along the way?
I was invited to collaborate on the comparative genome analysis of D.
melanogaster and D. pseudoobscura because I have worked on
the population genetics of D. pseudoobscura since I was a graduate
student at the University of Georgia.
Baylor College of Medicine received a contract from the NIH to complete the
D. pseudoobscura genome sequence and the principal investigators
there, Stephen Richards, George Weinstock, and Richard Gibbs, assembled a
diverse group of molecular and evolutionary biologists to help map,
annotate, and analyze the sequences. I was eager to participate because of
my interests in the process of genome rearrangement in populations of
D. pseudoobscura.
"This paper
confirmed observations about
chromosomal organization that
were proposed in the 1930s
and '40s."
D. pseudoobscura has had a long research history as a model for
evolutionary genetics from the moment when Alfred Sturtevant and Theodosius
Dobzhansky first documented a rich polymorphism for chromosome inversions
in natural populations. The genome project represented an ideal opportunity
to marry classical evolutionary genetics with new age comparative genomics.
There were minimal problems during the effort. The folks at Baylor were
extremely inclusive. Any researcher who wished to work on the project was
invited to participate. This collaborative process allowed a diverse group
of biologists to bring meaning to the genome data.
I was able explore the data in any way that I wished, but weekly conference
calls allowed the cross-fertilization of ideas. My laboratory was able to
identify a pair of rearrangement breakpoints from the comparative analysis.
In addition, we completed a comprehensive analysis of rearrangement
breakpoints between the two species.
Where do you see your research leading in the
future?
The availability of the D. pseudoobscura sequence will allow
further development of this species as a model system for studies of genome
rearrangement in natural populations. An open question is what evolutionary
forces are responsible for the origin and maintenance of genome
rearrangements.
It is not clear what sequences within the inverted chromosomal segments are
responsible for the increase or decrease of chromosomal frequencies in
natural populations. Next-generation sequencing technologies open the door
to re-sequencing projects that use the first D. pseudoobscura
sequence as the backbone for assembly of other gene arrangement sequences
in D. pseudoobscura.
The computational methodologies for analyzing genome rearrangements that
were developed in the comparison of D. melanogaster and D.
pseudoobscura have been extended to the analysis of 10 other diverse
Drosophila genome sequences. These methods suggest that new genome
projects should include multiple closely related species to aid in the
assembly of small DNA sequences into larger chromosomal length segments.
Do you foresee any social or political implications
for your research?
The social and political implications of this research are minor by a
biologist's standards. The mapping of the breakpoints of the genome
rearrangement relied on the implicit evolutionary assumption that D.
melanogaster and D. pseudoobscura shared a common ancestor.
We predicted that the gene order comparison of the two extant species would
map the breakpoints of one of the D. pseudoobscura genome
rearrangements. Molecular biological approaches verified the mapped
location of the rearrangement breakpoints. Given that evolutionary biology
is constantly under challenge, the data in this study provided yet another
verification of how the framework of modern biology relies on an
evolutionary model.
Stephen W. Schaeffer, Ph.D.
Associate Professor of Biology
Institute of Molecular Evolutionary Genetics
The Pennsylvania State University
University Park, PA, USA