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

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

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


There is a complex relationship between the evolution of segmental duplications and rearrangements associated with human disease. We performed a detailed analysis of one region on chromosome 16p12.1 associated with neurocognitive disease and identified one of the largest structural inconsistencies in the human reference assembly. Various genomic analyses show that all examined humans are homozygously inverted relative to the reference genome for a 1.1 -Mb region on 16p12.1. We determined that this assembly discrepancy stems from two common structural configurations with worldwide frequencies of 17.6% (S1) and 82.4% (S2). This polymorphism arose from the rapid integration of segmental duplications, precipitating two local inversions within the human lineage over the last 10 million years. The two human haplotypes differ by 333 kb of additional duplicated sequence present in S2 but not in S1. Notably, we show that the S2 configuration harbors directly oriented duplications, specifically predisposing this chromosome to disease-associated rearrangement.

Original languageEnglish (US)
Pages (from-to)745-751
Number of pages7
JournalNature Genetics
Issue number9
StatePublished - Sep 2010

All Science Journal Classification (ASJC) codes

  • Genetics


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