OK, so what's the speed of dark?
--- Steven Wright

Eichler Lab

Department of Genome Sciences,
University of Washington

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.