Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability

Antonacci, Francesca; Dennis, Megan Y.; Huddleston, John; Sudmant, Peter H.; Steinberg, Karyn Meltz; Rosenfeld, Jill A.; Miroballo, Mattia; Graves, Tina; Vives, Laura; Malig, Maika; Denman, Laura; Raja, Archana; Stuart, Andrew B.; Tang, Joyce; Munson, Brenton; Shaffer, Lisa G.; Amemiya, Chris T.; Wilson, Richard K.; Eichler, Evan E.

doi:10.1038/ng.3120

Cited by 104 publications

(126 citation statements)

References 62 publications

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“…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: Discussionsupporting

confidence: 77%

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

et al. 2016

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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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Section: Discussionsupporting

confidence: 77%

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

et al. 2016

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“…The palindromic nature of SDs has enabled a high degree of genome plasticity in primate evolution (Kehrer-Sawatzki and Cooper 2008) and has led to their association with disease-related instability in various human chromosomes (Antonacci et al 2014). We describe the first collection of vervet SDs; their localization will facilitate future studies focused on the evolution of OWMs or examining their phenotypic impact in vervet populations.…”

Section: Discussionmentioning

confidence: 99%

The genome of the vervet (Chlorocebus aethiops sabaeus)

et al. 2015

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We describe a genome reference of the African green monkey or vervet (Chlorocebus aethiops). This member of the Old World monkey (OWM) superfamily is uniquely valuable for genetic investigations of simian immunodeficiency virus (SIV), for which it is the most abundant natural host species, and of a wide range of health-related phenotypes assessed in Caribbean vervets (C. a. sabaeus), whose numbers have expanded dramatically since Europeans introduced small numbers of their ancestors from West Africa during the colonial era. We use the reference to characterize the genomic relationship between vervets and other primates, the intra-generic phylogeny of vervet subspecies, and genome-wide structural variations of a pedigreed C. a. sabaeus population. Through comparative analyses with human and rhesus macaque, we characterize at high resolution the unique chromosomal fission events that differentiate the vervets and their close relatives from most other catarrhine primates, in whom karyotype is highly conserved. We also provide a summary of transposable elements and contrast these with the rhesus macaque and human. Analysis of sequenced genomes representing each of the main vervet subspecies supports previously hypothesized relationships between these populations, which range across most of sub-Saharan Africa, while uncovering high levels of genetic diversity within each. Sequence-based analyses of major histocompatibility complex (MHC) polymorphisms reveal extremely low diversity in Caribbean C. a. sabaeus vervets, compared to vervets from putatively ancestral West African regions. In the C. a. sabaeus research population, we discover the first structural variations that are, in some cases, predicted to have a deleterious effect; future studies will determine the phenotypic impact of these variations.

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“…Shinawi et al [2009] assumed FAM7A1/2 to function as a breakpoint, whereas Szafranski et al [2010] suspected CHRNA7 and CHRFAM7A to be responsible for the recurrent deletion in the 15q13.3 locus. Antonacci et al [2014] suggested the gene family GOLGA8 as possible candidates. An attempt was made to validate these theories by using FISH.…”

Section: Breakpoint Analysismentioning

confidence: 99%

Clinical and Genetic Heterogeneity of the 15q13.3 Microdeletion Syndrome

et al. 2015

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The 15q13.3 microdeletion is a recurrent CNV, presumably mediated by NAHR between segmental duplications in chromosome 15. The 15q13.3 deletion and duplication are associated with a wide range of clinical manifestations, such as intellectual deficits, seizures, autism, language and developmental delay, neuropsychiatric impairments, and behavioral problems illustrating incomplete penetrance and expressivity. This study comprises an evaluation of 106 symptomatic patients carrying the heterozygous deletion, as well as of 21 patients carrying the duplication, who have been described in previous studies. The analysis shows considerable heterogeneity for the manifestation of different key symptoms and familiar occurrence. Furthermore, 8 new patients are introduced. Convoluted familiar connections give new insights into the complexity of symptomatic manifestation. In previous studies, different opinions have been expressed as to the nature and precise location of the deletion breakpoints. Here, we show that not CHRNA7 and CHRFAM7A, but rather FAM7A or GOLGA8, serve as breakpoint regions concerning our patients. The deletion is described as heterogeneous in size. However, we assume that not only different breakpoints but also the imprecision of aCGH analysis on chromosome 15 due to segmental duplications accounts for the variability in size.

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Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability

Cited by 104 publications

References 62 publications

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

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

The genome of the vervet (Chlorocebus aethiops sabaeus)

Clinical and Genetic Heterogeneity of the 15q13.3 Microdeletion Syndrome

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