Abstract

Complex eukaryotic genomes are now being sequenced at an accelerated pace primarily using whole-genome shotgun (WGS) sequence assembly approaches. WGS assembly was initially criticized because of its perceived inability to resolve repeat structures within genomes. Here, we quantify the effect of WGS sequence assembly on large, highly similar repeats by comparison of the segmental duplication content of two different human genome assemblies. Our analysis shows that large (> 15 kilobases) and highly identical (> 97%) duplications are not adequately resolved by WGS assembly. This leads to significant reduction in genome length and the loss of genes embedded within duplications. Comparable analyses of mouse genome assemblies confirm that strict WGS sequence assembly will oversimplify our understanding of mammalian genome structure and evolution; a hybrid strategy using a targeted clone-by-clone approach to resolve duplications is proposed.

1. Department of Genome Sciences, University of Washington School of Medicine, 1705 NE Pacific Street, Seattle, Washington 98195, USA
2. Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA
3. National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Building 38A, 8600 Rockville Pike, Bethesda, Maryland 20894, USA
4. Applied Biosystems, 45 West Gude Drive, and
5. The Center for the Advancement of Genomics, 1901 Research Boulevard, Suite 600, Rockville, Maryland 20850, USA

Correspondence to: Evan E. Eichler¹ Correspondence and requests for materials should be addressed to E.E.E. (Email: eee@gs.washington.edu).

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