title: A large and complex structural polymorphism at 16p12.1 underlies microdeletion disease risk.
abstract: 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.
authors: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors: Francesca
authors: F
authors: Antonacci
authors: Jeffrey M
authors: JM
authors: Kidd
authors: Tomas
authors: T
authors: Marques-Bonet
authors: Brian
authors: B
authors: Teague
authors: Mario
authors: M
authors: Ventura
authors: Santhosh
authors: S
authors: Girirajan
authors: Can
authors: C
authors: Alkan
authors: Catarina D
authors: CD
authors: Campbell
authors: Laura
authors: L
authors: Vives
authors: Maika
authors: M
authors: Malig
authors: Jill A
authors: JA
authors: Rosenfeld
authors: Blake C
authors: BC
authors: Ballif
authors: Lisa G
authors: LG
authors: Shaffer
authors: Tina A
authors: TA
authors: Graves
authors: Richard K
authors: RK
authors: Wilson
authors: David C
authors: DC
authors: Schwartz
authors: Evan E
authors: EE
authors: Eichler
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D002874:Chromosome Mapping / Q000592:standards; D002885:Chromosomes, Human, Pair 16 / Q000737:chemistry / Q000235:genetics; D055028:Comparative Genomic Hybridization; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006801:Humans; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D011323:Primates / Q000235:genetics; D012107:Research Design; D012306:Risk