Research Program
Gene and Transcript Innovations:
The process of segmental duplication
provides a vehicle for primate gene innovation in two different
ways. First, duplications may lead to the adaptive evolution of
genes “liberated” from the selective constraint of ancestral function.
Second, the accumulation of diverse duplications at prescribed
locations in the genome juxtaposes different gene cassettes in novel
genomic texts. This has led to the formation of “chimeric” transcripts
in a process akin to “exon shuffling”. Although most random mutations
create duplicate pseudogenes, occasionally functional products may
emerge. One interesting highlight of our research has been the
discovery of both rapidly evolving genes and fusion genes specific to
the human and great-ape lineages. The latter show a bias toward
germline
expression. We plan to develop a new model of the birth-death process
for gene duplication by studying the transcripts derived from segmental
duplications. This requires the unambiguous delineation between gene
and pseudogene. Using the human as a reference, we will systematically
identify all novel gene products and compare expression profiles of
each to their progenitor genes. The goal here will be measure
qualitative differences in expression between ancestor and duplicate
gene with the hypothesis that functional adaptive shifts will be
accompanied by significant changes in expression profiles. Our
analysis will entail the construction of specialized primate tissue
resources and the development of specialized expression microarrays/
reverse-transcription PCR assays that discriminate between paralogous
copies. In parallel, functionality will be
assessed by identifying signatures of either significant positive or
purifying selection based on the comparative sequence analysis from
multiple non-human primates. Genes that show evidence of
significant positive selection
will be further analyzed for intraspecific variation as a test for
evidence of a selective sweep through specific primate populations. We
anticipate that only a small fraction of transcripts will show evidence
of functionality and/or coordinated shifts in gene expression.
This subset will serve as the basis for further functional
characterization at the protein level and cellular level. The
determination of the function of such novel genes in the absence of
model organisms represents one of the most significant challenges of
the genetics/genomic community and will remain a long-term objective of
our research program.