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Finished sequence and assembly of the DUF1220-rich 1q21 region using a haploid human genome

BACKGROUND: Although the reference human genome sequence was declared finished in 2003, some regions of the genome remain incomplete due to their complex architecture. One such region, 1q21.1-q21.2, is of increasing interest due to its relevance to human disease and evolution. Elucidation of the exa...

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Autores principales: O’Bleness, Majesta, Searles, Veronica B, Dickens, C Michael, Astling, David, Albracht, Derek, Mak, Angel C Y, Lai, Yvonne Y Y, Lin, Chin, Chu, Catherine, Graves, Tina, Kwok, Pui-Yan, Wilson, Richard K, Sikela, James M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053653/
https://www.ncbi.nlm.nih.gov/pubmed/24885025
http://dx.doi.org/10.1186/1471-2164-15-387
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author O’Bleness, Majesta
Searles, Veronica B
Dickens, C Michael
Astling, David
Albracht, Derek
Mak, Angel C Y
Lai, Yvonne Y Y
Lin, Chin
Chu, Catherine
Graves, Tina
Kwok, Pui-Yan
Wilson, Richard K
Sikela, James M
author_facet O’Bleness, Majesta
Searles, Veronica B
Dickens, C Michael
Astling, David
Albracht, Derek
Mak, Angel C Y
Lai, Yvonne Y Y
Lin, Chin
Chu, Catherine
Graves, Tina
Kwok, Pui-Yan
Wilson, Richard K
Sikela, James M
author_sort O’Bleness, Majesta
collection PubMed
description BACKGROUND: Although the reference human genome sequence was declared finished in 2003, some regions of the genome remain incomplete due to their complex architecture. One such region, 1q21.1-q21.2, is of increasing interest due to its relevance to human disease and evolution. Elucidation of the exact variants behind these associations has been hampered by the repetitive nature of the region and its incomplete assembly. This region also contains 238 of the 270 human DUF1220 protein domains, which are implicated in human brain evolution and neurodevelopment. Additionally, examinations of this protein domain have been challenging due to the incomplete 1q21 build. To address these problems, a single-haplotype hydatidiform mole BAC library (CHORI-17) was used to produce the first complete sequence of the 1q21.1-q21.2 region. RESULTS: We found and addressed several inaccuracies in the GRCh37sequence of the 1q21 region on large and small scales, including genomic rearrangements and inversions, and incorrect gene copy number estimates and assemblies. The DUF1220-encoding NBPF genes required the most corrections, with 3 genes removed, 2 genes reassigned to the 1p11.2 region, 8 genes requiring assembly corrections for DUF1220 domains (~91 DUF1220 domains were misassigned), and multiple instances of nucleotide changes that reassigned the domain to a different DUF1220 subtype. These corrections resulted in an overall increase in DUF1220 copy number, yielding a haploid total of 289 copies. Approximately 20 of these new DUF1220 copies were the result of a segmental duplication from 1q21.2 to 1p11.2 that included two NBPF genes. Interestingly, this duplication may have been the catalyst for the evolutionarily important human lineage-specific chromosome 1 pericentric inversion. CONCLUSIONS: Through the hydatidiform mole genome sequencing effort, the 1q21.1-q21.2 region is complete and misassemblies involving inter- and intra-region duplications have been resolved. The availability of this single haploid sequence path will aid in the investigation of many genetic diseases linked to 1q21, including several associated with DUF1220 copy number variations. Finally, the corrected sequence identified a recent segmental duplication that added 20 additional DUF1220 copies to the human genome, and may have facilitated the chromosome 1 pericentric inversion that is among the most notable human-specific genomic landmarks.
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spelling pubmed-40536532014-06-17 Finished sequence and assembly of the DUF1220-rich 1q21 region using a haploid human genome O’Bleness, Majesta Searles, Veronica B Dickens, C Michael Astling, David Albracht, Derek Mak, Angel C Y Lai, Yvonne Y Y Lin, Chin Chu, Catherine Graves, Tina Kwok, Pui-Yan Wilson, Richard K Sikela, James M BMC Genomics Research Article BACKGROUND: Although the reference human genome sequence was declared finished in 2003, some regions of the genome remain incomplete due to their complex architecture. One such region, 1q21.1-q21.2, is of increasing interest due to its relevance to human disease and evolution. Elucidation of the exact variants behind these associations has been hampered by the repetitive nature of the region and its incomplete assembly. This region also contains 238 of the 270 human DUF1220 protein domains, which are implicated in human brain evolution and neurodevelopment. Additionally, examinations of this protein domain have been challenging due to the incomplete 1q21 build. To address these problems, a single-haplotype hydatidiform mole BAC library (CHORI-17) was used to produce the first complete sequence of the 1q21.1-q21.2 region. RESULTS: We found and addressed several inaccuracies in the GRCh37sequence of the 1q21 region on large and small scales, including genomic rearrangements and inversions, and incorrect gene copy number estimates and assemblies. The DUF1220-encoding NBPF genes required the most corrections, with 3 genes removed, 2 genes reassigned to the 1p11.2 region, 8 genes requiring assembly corrections for DUF1220 domains (~91 DUF1220 domains were misassigned), and multiple instances of nucleotide changes that reassigned the domain to a different DUF1220 subtype. These corrections resulted in an overall increase in DUF1220 copy number, yielding a haploid total of 289 copies. Approximately 20 of these new DUF1220 copies were the result of a segmental duplication from 1q21.2 to 1p11.2 that included two NBPF genes. Interestingly, this duplication may have been the catalyst for the evolutionarily important human lineage-specific chromosome 1 pericentric inversion. CONCLUSIONS: Through the hydatidiform mole genome sequencing effort, the 1q21.1-q21.2 region is complete and misassemblies involving inter- and intra-region duplications have been resolved. The availability of this single haploid sequence path will aid in the investigation of many genetic diseases linked to 1q21, including several associated with DUF1220 copy number variations. Finally, the corrected sequence identified a recent segmental duplication that added 20 additional DUF1220 copies to the human genome, and may have facilitated the chromosome 1 pericentric inversion that is among the most notable human-specific genomic landmarks. BioMed Central 2014-05-20 /pmc/articles/PMC4053653/ /pubmed/24885025 http://dx.doi.org/10.1186/1471-2164-15-387 Text en © O’Bleness et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
O’Bleness, Majesta
Searles, Veronica B
Dickens, C Michael
Astling, David
Albracht, Derek
Mak, Angel C Y
Lai, Yvonne Y Y
Lin, Chin
Chu, Catherine
Graves, Tina
Kwok, Pui-Yan
Wilson, Richard K
Sikela, James M
Finished sequence and assembly of the DUF1220-rich 1q21 region using a haploid human genome
title Finished sequence and assembly of the DUF1220-rich 1q21 region using a haploid human genome
title_full Finished sequence and assembly of the DUF1220-rich 1q21 region using a haploid human genome
title_fullStr Finished sequence and assembly of the DUF1220-rich 1q21 region using a haploid human genome
title_full_unstemmed Finished sequence and assembly of the DUF1220-rich 1q21 region using a haploid human genome
title_short Finished sequence and assembly of the DUF1220-rich 1q21 region using a haploid human genome
title_sort finished sequence and assembly of the duf1220-rich 1q21 region using a haploid human genome
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053653/
https://www.ncbi.nlm.nih.gov/pubmed/24885025
http://dx.doi.org/10.1186/1471-2164-15-387
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