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

作者：Antonacci Francesca; Kidd Jeffrey M; Marques Bonet Tomas; 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 A; Wilson Richard K; Schwartz David C; Eichler Evan E^*

来源：Nature Genetics, 2010, 42(9): 745-U29.

DOI：10.1038/ng.643

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.

• 出版日期2010-9