Caution, Blind Man Driving.

Eichler Lab

Department of Genome Sciences,
University of Washington

Research Program


Our research program has focused on understanding the functional and structural impacts of segmental duplications on the human genome.  Using computational and experimental approaches, we have investigated duplications at a genomic rather than strictly at the genic level.  Our research has challenged the field of vertebrate genome evolution which largely held that “most of nature’s experiments with duplication must have been done at the stages of fish and amphibians”.  Within the genetics and evolutionary community, this has led to a resurgence of interest in genomic duplications and series of unanswered questions:  How did this complex architecture of duplications evolve in humans?  What is the underlying mechanism?  How variable are these regions within the human population and to what extent do they contribute to disease and phenotypic differences?  How does the human structure compare to that of great apes and other mammals?  Have new genes evolved by this mechanism which are important for human/great ape adaptation?  Our research program is committed to addressing these questions.  We summarize below some of our major contributions to this field.
  • Human genome duplication architecture:  We provided the first global view of segmental duplications within the human genome and showed that they account for ~5% of the genome. We developed a computational pipeline that utilizes whole-genome shotgun sequences as a means to detect duplications independently from a whole-genome assembly.  We used this information to develop a road-map of likely sites of recurrent chromosomal structural rearrangement and rapid evolutionary change.  The relationship of these regions with human disease is an active area of investigation.

  • Pericentromeric Model: We developed a donor-acceptor model for the origin and spread of segmental duplications based on detailed study of a subset of hotspot regions near the pericentromeric regions of human chromosomes. The data indicate that euchromatic genomic segments ranging in length from 5-150 Kb have been preferentially integrated near pericentromeric DNA, that specific low complexity repeat sequences serve as preferred sites for integration and that these segments transposed to these regions very recently (1-15 Mya) through a complex series of events.

  • Genome assembly quality and validation. We developed experimental and computational approaches to resolve these problematic regions of the genome and applied these tools to improving single nucleotide polymorphism assignment and genome assembly in these regions. These same approaches are now being applied to other mammalian genomes to understand their genomic duplication properties in spite of assembly issues.

  • Comparative Primate Genomics and Adaptive Evolution. We have documented some of the first quantitative and qualitative differences in the distribution of segmental duplication among the genomes of humans and the great-apes. We have discovered some of the most rapidly evolving gene families within these duplications and demonstrate that ~12% of all expression differences between human and chimpanzee brains occur within segmental duplications.

  • Alu- mediated duplicative Transposition: We systemically examined the sequence features at duplication junctions and showed an enrichment of Alu short interspersed repeat sequences near the edges. We propose that the primate-specific burst of Alu retroposition activity (which occurred ~40 million years ago) sensitized the ancestral human genome for Alu-Alu-mediated recombination events, which, in turn, initiated the expansion of gene-rich segmental duplications.

  • Non-random Chromosomal Rearrangement. A comparison between sites of segmental duplication and breakpoints in regions with conserved synteny between man and mouse showed that ~30% of all synteny breaks mapped to clusters of segmental duplication. We noted a similar association when human and primate genomes were compared. These data suggest hotspots or fragile sites of chromosomal breakage and challenge the Nadeau-Taylor random breakage model of chromosomal evolution.