A large and complex structural polymorphism at 16p12.1 underlies microdeletion disease risk

Antonacci, Francesca; Kidd, Jeffrey M.; Marquès‐Bonet, Tomàs; Teague, Brian; Ventura, Mario; Girirajan, Santhosh; Alkan, Can; Campbell, Catarina D.; Vives, Laura; Malig, Maika; Rosenfeld, Jill A.; Ballif, Blake C.; Shaffer, Lisa G.; Graves, Tina; Wilson, Richard K.; Schwartz, David C.; Eichler, Evan E.

doi:10.1038/ng.643

Cited by 90 publications

(93 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…comparative sequencing studies of human genomic disorder breakpoint regions have reported increasing complexity in the human lineage as a predisposing factor to rearrangement associated with disease (Rochette et al 2001;Antonacci et al 2010;Boettger et al 2012). Our results show that loci of increasing complexity are present in other great ape lineages creating speciesspecific hotspots prone to deletion and disease.…”

Section: Discussionmentioning

confidence: 56%

Evolution and diversity of copy number variation in the great ape lineage

et al. 2013

Self Cite

View full text Add to dashboard Cite

Copy number variation (CNV) contributes to disease and has restructured the genomes of great apes. The diversity and rate of this process, however, have not been extensively explored among great ape lineages. We analyzed 97 deeply sequenced great ape and human genomes and estimate 16% (469 Mb) of the hominid genome has been affected by recent CNV. We identify a comprehensive set of fixed gene deletions (n = 340) and duplications (n = 405) as well as >13.5 Mb of sequence that has been specifically lost on the human lineage. We compared the diversity and rates of copy number and single nucleotide variation across the hominid phylogeny. We find that CNV diversity partially correlates with single nucleotide diversity (r 2 = 0.5) and recapitulates the phylogeny of apes with few exceptions. Duplications significantly outpace deletions (2.8-fold). The load of segregating duplications remains significantly higher in bonobos, Western chimpanzees, and Sumatran orangutans-populations that have experienced recent genetic bottlenecks (P = 0.0014, 0.02, and 0.0088, respectively). The rate of fixed deletion has been more clocklike with the exception of the chimpanzee lineage, where we observe a twofold increase in the chimpanzee-bonobo ancestor (P = 4.79 3 10 -9 ) and increased deletion load among Western chimpanzees (P = 0.002). The latter includes the first genomic disorder in a chimpanzee with features resembling Smith-Magenis syndrome mediated by a chimpanzee-specific increase in segmental duplication complexity. We hypothesize that demographic effects, such as bottlenecks, have contributed to larger and more gene-rich segments being deleted in the chimpanzee lineage and that this effect, more generally, may account for episodic bursts in CNV during hominid evolution.

show abstract

Section: Discussionmentioning

confidence: 56%

Evolution and diversity of copy number variation in the great ape lineage

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…11). In total, the data are compelling that this particular interchromosomal core represents a preferential site of genomic instability, a property we have previously observed for core duplicons identified on 16p.12.1, 17q21.31, and 15q13.3 (LCR16a, LRRC37, GOLGA) (Zody et al 2008;Antonacci et al 2010Antonacci et al , 2014.…”

Section: Discussionmentioning

confidence: 74%

Interchromosomal core duplicons drive both evolutionary instability and disease susceptibility of the Chromosome 8p23.1 region

et al. 2016

Self Cite

View full text Add to dashboard Cite

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

show abstract

“…2005), while the 16p11.2-12.2 region has seen a rapid integration of segmental duplications in the last 15 million years of hominoid evolution that contributed to a profound modification of these chromosomal bands (Johnson et al 2001;Antonacci et al 2010), putting them at risk for recurrent pathogenic rearrangements ( Fig. 1; Girirajan et al 2010;Walters et al 2010;Jacquemont et al 2011).…”

Section: Resultsmentioning

confidence: 99%

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures

2014

View full text Add to dashboard Cite

Human and chimpanzee genomes are 98.8% identical within comparable sequences. However, they differ structurally in nine pericentric inversions, one fusion that originated human chromosome 2, and content and localization of heterochromatin and lineage-specific segmental duplications. The possible functional consequences of these cytogenetic and structural differences are not fully understood and their possible involvement in speciation remains unclear. We show that subtelomeric regions-regions that have a species-specific organization, are more divergent in sequence, and are enriched in genes and recombination hotspots-are significantly enriched for species-specific histone modifications that decorate transcription start sites in different tissues in both human and chimpanzee. The human lineage-specific chromosome 2 fusion point and ancestral centromere locus as well as chromosome 1 and 18 pericentric inversion breakpoints showed enrichment of human-specific H3K4me3 peaks in the prefrontal cortex. Our results reveal an association between plastic regions and potential novel regulatory elements.

show abstract

A large and complex structural polymorphism at 16p12.1 underlies microdeletion disease risk

Cited by 90 publications

References 52 publications

Evolution and diversity of copy number variation in the great ape lineage

Evolution and diversity of copy number variation in the great ape lineage

Interchromosomal core duplicons drive both evolutionary instability and disease susceptibility of the Chromosome 8p23.1 region

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures

Contact Info

Product

Resources

About