Segmental duplications: organization and impact within the current human genome project assembly.

By J. Bailey, Amy M. Yavor, H. Massa, B. Trask, Evan E. Eichler. Genome Research, 2001

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Segmental duplications play fundamental roles in both genomic disease and gene evolution. To understand their organization within the human genome, we have developed the computational tools and methods necessary to detect identity between long stretches of genomic sequence despite the presence of high copy repeats and large insertion-deletions. Here we present our analysis of the most recent genome assembly (January 2001) in which we focus on the global organization of these segments and the role they play in the whole-genome assembly process. Initially, we considered only large recent duplication events that fell well-below levels of draft sequencing error (alignments 90%-98% similar and > or =1 kb in length). Duplications (90%-98%; > or =1 kb) comprise 3.6% of all human sequence. These duplications show clustering and up to 10-fold enrichment within pericentromeric and subtelomeric regions. In terms of assembly, duplicated sequences were found to be over-represented in unordered and unassigned contigs indicating that duplicated sequences are difficult to assign to their proper position. To assess coverage of these regions within the genome, we selected BACs containing interchromosomal duplications and characterized their duplication pattern by FISH. Only 47% (106/224) of chromosomes positive by FISH had a corresponding chromosomal position by comparison. We present data that indicate that this is attributable to misassembly, misassignment, and/or decreased sequencing coverage within duplicated regions. Surprisingly, if we consider putative duplications >98% identity, we identify 10.6% (286 Mb) of the current assembly as paralogous. The majority of these alignments, we believe, represent unmerged overlaps within unique regions. Taken together the above data indicate that segmental duplications represent a significant impediment to accurate human genome assembly, requiring the development of specialized techniques to finish these exceptional regions of the genome. The identification and characterization of these highly duplicated regions represents an important step in the complete sequencing of a human reference genome.

Subfields: Genetics, Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/7802ab52364c4fcfc518c4bcf552f6c8ee77c09c

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Citations in the corpus

Distinguishing protein-coding and noncoding genes in the human genome (2007, background): “Genes with low RFC scores are also enriched for segmental duplications with 31% of low RFC RefSeq genes overlapping regions of segmental duplication (Bailey et al. 2001), com- pared to only 9% of the high RFC scoring genes being in segmental duplications.”
Long-read human genome sequencing and its applications (2020, neutral): “These inaccessible parts of the genome include centromeres, telomeres and acrocentric genomic regions, where massive arrays of tandem repeats predominate, as well as the 5% of our genome (and associated genes) mapping to large segmental duplications 11 .”
Human and chimpanzee Luteinizing hormone/ Chorionic Gonadotropin beta (LHB/CGB) gene clusters: diversity and divergence of young duplicated genes (2009, background): “Segmental duplications that have >90% DNA sequence identity and range from one to several hundred kilobases, cover 5.2% of human genome (Bailey et al. 2001).”
Reconstructing contiguous regions of an ancestral genome. (2006, background): “72%) in human-specific breakpoint regions is in human segmental duplications (Bailey et al. 2001).”
wANNOVAR: annotating genetic variants for personal genomes via the web (2012, methodology): “25 Compared with the manually compiled RefSeq gene de ﬁ nitions, ENSEMBL genes and UCSC genes are supplemented with computational predictions of transcripts and genes.”
Evaluation of GRCh38 and de novo haploid genome assemblies demonstrates the enduring quality of the reference assembly (2016, background): “While a subset of missing sequences are associated with gaps deemed recalcitrant to cloning, segmental duplications or other complex genomic architectures are implicated in most remaining gaps or mis-assemblies (Chaisson et al. 2015a; Sharp et al. 2005; Bailey et al. 2001).”
Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes (2005, background): “]. However, the involvement of segmental duplications, perhaps by an LCR/NAHR mechanism, is yet to be determined. Segmental duplications account for some 5%–10% of the human genome [”
PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. (2007, methodology): “We retrieved segmental duplication regions from the UCSC Genome Browser (Kuhn et al. 2007) and consolidated them into a list of 8546 non-overlapping regions encompassing 154 Mb (Bailey et al. 2001).”
The UCSC Genome Browser Database: update 2006 (2005, background): “The Segmental Dups track, contributed by the Eichler lab at the University of Washington, shows putative genomic duplications in the human genome (48).”
The genome of melon (Cucumis melo L.) (2012, methodology): “The whole-genome assembly comparison (WGAC) strategy (42), based on selfcomparison of the whole genome using BLAST pairwise genome analysis, identified 4.”
The consensus coding sequence (CCDS) project: Identifying a common protein-coding gene set for the human and mouse genomes. (2009, background): “Genes with low RFC scores are also enriched for segmental duplications with 31% of low RFC RefSeq genes overlapping regions of segmental duplication (Bailey et al. 2001), compared to only 9% of the high RFC scoring genes being in segmental duplications.”