Interchromosomal core duplicons drive both evolutionary instability and disease susceptibility of the Chromosome 8p23.1 region
Open accessAbstract
Recurrent rearrangements of Chromosome 8p23.1 are associated with congenital heart defects and developmental delay. The complexity of this region has led to inconsistencies in the current reference assembly, confounding studies of genetic variation. Using comparative sequence-based approaches, we generated a high-quality 6.3-Mbp alternate reference assembly of an inverted Chromosome 8p23.1 haplotype. Comparison with nonhuman primates reveals a 746-kbp duplicative transposition and two separate inversion events that arose in the last million years of human evolution. The breakpoints associated with these rearrangements map to an ape-specific interchromosomal core duplicon that clusters at sites of evolutionary inversion (P = 7.8 × 10−5). Refinement of microdeletion breakpoints identifies a subgroup of patients that map to the same interchromosomal core involved in the evolutionary formation of the duplication blocks. Our results define a higher-order genomic instability element that has shaped the structure of specific chromosomes during primate evolution contributing to rearrangements associated with inversion and disease.
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These contained genes known to have CNVs associated with human health, including amylase (four to ten copies), β-defensin (three to seven copies, DEFB107A) and NOTCH2NLC-NOTCH2NLB (one additional copy).
“These contained genes known to have CNVs associated with human health, including amylase61 (four to ten copies), β-defensin62 (three to seven copies, DEFB107A) and NOTCH2NLC–NOTCH2NLB63 (one additional copy).”
From A draft human pangenome reference. (2023) · cites this paper as [62]
The Abstract (page unavailable) links β-defensin copy-number variation to immune-related conditions. Results > Human sequence diversity analyses (page unavailable) reports 2–8 diploid copies for the β-defensin cluster, not the claimed three to seven, and the passages found do not identify DEFB107A specifically. The other genes have separate citations in the citing sentence and are not attributed to this source. (LLM, conf=0.86)
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A draft human pangenome reference.
Liao, W.-W., Asri, M., Ebler, J., Doerr, D., Haukness, M., Hickey, G., Lu, S., Lucas, J. K., Monlong, J., Abel, H. J., et al. (2023) · Nature · doi:10.1038/s41586-023-05896-x · Cited by 1,129 · see citing works
“These contain genes known to have CNV associated with human health including amylase (Falchi et al., 2014) (4-10 copies), beta-defensin (Mohajeri et al., 2016) (3-8 copies, DEFB107A), and NOTCH2NLC/B (Fiddes, Lodewijk, et al., 2018) (1 additional copy).”
BackgroundSelf-citation
- Authors
- Mohajeri, K., Cantsilieris, S., Huddleston, J., Nelson, B. J., Coe, B. P., Campbell, C. D., Baker, C., Harshman, L., Munson, K. M., Kronenberg, Z. N., Kremitzki, M., Raja, A., Catacchio, C. R., Graves, T. A., Wilson, R. K., Ventura, M., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Washington University in St. Louis (US)
- University of Bari Aldo Moro (IT)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2016-10-07
- Volume
- 26
- Issue
- 11
- Pages
- 1453-1467
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC5088589
- OpenAlex
- W2528840539
- Cited by
- 42
- References
- 48
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 8 · 2022: 10 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 3
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Funders
- US National Institutes of Health
- NIH (2R01HG002385, U41HG007635)
- American Asthma Foundation Senior Investigator award (10-0159)
- National Health and Medical Research Council
- CJ Martin Biomedical (1073726)
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- chromosomal inversions, evolutionary instability, congenital heart disease, developmental delay, primate evolution, genome rearrangement, disease susceptibility
- MeSH terms
- Animals, Chromosome Deletion, Chromosomes, Human, Pair 8, Humans, Primates, Evolution, Molecular, Genetic Predisposition to Disease, Genomic Instability, Chromosome Breakpoints, Segmental Duplications, Genomic
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