Interchromosomal core duplicons drive both evolutionary instability and disease susceptibility of the Chromosome 8p23.1 region.
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.
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Kiana
K
Mohajeri
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Stuart
S
Cantsilieris
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.|Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
John
J
Huddleston
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Bradley J
BJ
Nelson
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Bradley P
BP
Coe
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Catarina D
CD
Campbell
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Carl
C
Baker
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Lana
L
Harshman
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Katherine M
KM
Munson
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Zev N
ZN
Kronenberg
The McDonnell Genome Institute at Washington University, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
Milinn
M
Kremitzki
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.|Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
Archana
A
Raja
Dipartimento di Biologia, Università degli Studi di Bari Aldo Moro, Bari 70125, Italy.
Claudia Rita
CR
Catacchio
The McDonnell Genome Institute at Washington University, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
Tina A
TA
Graves
The McDonnell Genome Institute at Washington University, Washington University School of Medicine, St. Louis, Missouri 63108, USA.
Richard K
RK
Wilson
Dipartimento di Biologia, Università degli Studi di Bari Aldo Moro, Bari 70125, Italy.
Mario
M
Ventura
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.|Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
Evan E
EE
Eichler
D000818:Animals; D056905:Chromosome Breakpoints; D002872:Chromosome Deletion; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D019143:Evolution, Molecular; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D011323:Primates / Q000235:genetics; D056916:Segmental Duplications, Genomic