Characterizing the Major Structural Variant Alleles of the Human Genome

Peter A. Audano; Arvis Sulovari; Tina A. Graves-Lindsay; Stuart Cantsilieris; Melanie Sorensen; Anne Marie E. Welch; Max L. Dougherty; Bradley J. Nelson; Ankeeta Shah; Susan K. Dutcher; Wesley C. Warren; Vincent Magrini; Sean D. McGrath; Yang I. Li; Richard K. Wilson; Evan E. Eichler

doi:10.1016/j.cell.2018.12.019

Characterizing the Major Structural Variant Alleles of the Human Genome

Peter A. Audano, Arvis Sulovari, Tina A. Graves-Lindsay, Stuart Cantsilieris, Melanie Sorensen, Anne Marie E. Welch, Max L. Dougherty, Bradley J. Nelson, Ankeeta Shah, Susan K. Dutcher, Wesley C. Warren, Vincent Magrini, Sean D. McGrath, Yang I. Li, Richard K. Wilson, Evan E. Eichler

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311 Scopus citations

Abstract

In order to provide a comprehensive resource for human structural variants (SVs), we generated long-read sequence data and analyzed SVs for fifteen human genomes. We sequence resolved 99,604 insertions, deletions, and inversions including 2,238 (1.6 Mbp) that are shared among all discovery genomes with an additional 13,053 (6.9 Mbp) present in the majority, indicating minor alleles or errors in the reference. Genotyping in 440 additional genomes confirms the most common SVs in unique euchromatin are now sequence resolved. We report a ninefold SV bias toward the last 5 Mbp of human chromosomes with nearly 55% of all VNTRs (variable number of tandem repeats) mapping to this portion of the genome. We identify SVs affecting coding and noncoding regulatory loci improving annotation and interpretation of functional variation. These data provide the framework to construct a canonical human reference and a resource for developing advanced representations capable of capturing allelic diversity.

Original language	English
Pages (from-to)	663-675.e19
Journal	Cell
Volume	176
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2018.12.019
State	Published - Jan 24 2019

Keywords

gap closure
human reference genome
major allele
real-time (SMRT) sequencing
single-molecule
structural variation
whole-genome sequence and assembly

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10.1016/j.cell.2018.12.019

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Audano, P. A., Sulovari, A., Graves-Lindsay, T. A., Cantsilieris, S., Sorensen, M., Welch, A. M. E., Dougherty, M. L., Nelson, B. J., Shah, A., Dutcher, S. K., Warren, W. C., Magrini, V., McGrath, S. D., Li, Y. I., Wilson, R. K., & Eichler, E. E. (2019). Characterizing the Major Structural Variant Alleles of the Human Genome. Cell, 176(3), 663-675.e19. https://doi.org/10.1016/j.cell.2018.12.019

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abstract = "In order to provide a comprehensive resource for human structural variants (SVs), we generated long-read sequence data and analyzed SVs for fifteen human genomes. We sequence resolved 99,604 insertions, deletions, and inversions including 2,238 (1.6 Mbp) that are shared among all discovery genomes with an additional 13,053 (6.9 Mbp) present in the majority, indicating minor alleles or errors in the reference. Genotyping in 440 additional genomes confirms the most common SVs in unique euchromatin are now sequence resolved. We report a ninefold SV bias toward the last 5 Mbp of human chromosomes with nearly 55% of all VNTRs (variable number of tandem repeats) mapping to this portion of the genome. We identify SVs affecting coding and noncoding regulatory loci improving annotation and interpretation of functional variation. These data provide the framework to construct a canonical human reference and a resource for developing advanced representations capable of capturing allelic diversity.",

keywords = "gap closure, human reference genome, major allele, real-time (SMRT) sequencing, single-molecule, structural variation, whole-genome sequence and assembly",

author = "Audano, {Peter A.} and Arvis Sulovari and Graves-Lindsay, {Tina A.} and Stuart Cantsilieris and Melanie Sorensen and Welch, {Anne Marie E.} and Dougherty, {Max L.} and Nelson, {Bradley J.} and Ankeeta Shah and Dutcher, {Susan K.} and Warren, {Wesley C.} and Vincent Magrini and McGrath, {Sean D.} and Li, {Yang I.} and Wilson, {Richard K.} and Eichler, {Evan E.}",

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AU - Welch, Anne Marie E.

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AU - Nelson, Bradley J.

AU - Shah, Ankeeta

AU - Dutcher, Susan K.

AU - Warren, Wesley C.

AU - Magrini, Vincent

AU - McGrath, Sean D.

AU - Li, Yang I.

AU - Wilson, Richard K.

AU - Eichler, Evan E.

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N2 - In order to provide a comprehensive resource for human structural variants (SVs), we generated long-read sequence data and analyzed SVs for fifteen human genomes. We sequence resolved 99,604 insertions, deletions, and inversions including 2,238 (1.6 Mbp) that are shared among all discovery genomes with an additional 13,053 (6.9 Mbp) present in the majority, indicating minor alleles or errors in the reference. Genotyping in 440 additional genomes confirms the most common SVs in unique euchromatin are now sequence resolved. We report a ninefold SV bias toward the last 5 Mbp of human chromosomes with nearly 55% of all VNTRs (variable number of tandem repeats) mapping to this portion of the genome. We identify SVs affecting coding and noncoding regulatory loci improving annotation and interpretation of functional variation. These data provide the framework to construct a canonical human reference and a resource for developing advanced representations capable of capturing allelic diversity.

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Characterizing the Major Structural Variant Alleles of the Human Genome

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Keywords

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