TitleEmergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility.
Publication TypeJournal Article
Year of Publication2016
AuthorsNuttle, X, Giannuzzi, G, Duyzend, MH, Schraiber, JG, Narvaiza, I, Sudmant, PH, Penn, O, Chiatante, G, Malig, M, Huddleston, J, Benner, C, Camponeschi, F, Ciofi-Baffoni, S, Stessman, HAF, Marchetto, MCN, Denman, L, Harshman, L, Baker, C, Raja, A, Penewit, K, Janke, N, W Tang, J, Ventura, M, Banci, L, Antonacci, F, Akey, JM, Amemiya, CT, Gage, FH, Reymond, A, Eichler, EE
Date Published2016 08 11
KeywordsAnimals, Autistic Disorder, Chromosome Breakage, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Evolution, Molecular, Gene Duplication, Genetic Predisposition to Disease, Homeostasis, Humans, Iron, Pan troglodytes, Pongo, Proteins, Recombination, Genetic, Species Specificity, Time Factors

Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. Here we reconstruct the evolutionary history of the locus and identify bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95-kilobase-pair segment containing BOLA2 duplicated across the critical region approximately 282 thousand years ago (ka), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carried one or more copies of the duplication, which nearly fixed early in the human lineage--a pattern unlikely to have arisen so rapidly in the absence of selection (P < 0.0097). We show that the duplication of BOLA2 led to a novel, human-specific in-frame fusion transcript and that BOLA2 copy number correlates with both RNA expression (r = 0.36) and protein level (r = 0.65), with the greatest expression difference between human and chimpanzee in experimentally derived stem cells. Analyses of 152 patients carrying a chromosome 16p11. rearrangement show that more than 96% of breakpoints occur within the H. sapiens-specific duplication. In summary, the duplicative transposition of BOLA2 at the root of the H. sapiens lineage about 282 ka simultaneously increased copy number of a gene associated with iron homeostasis and predisposed our species to recurrent rearrangements associated with disease.

Alternate JournalNature
PubMed ID27487209
PubMed Central IDPMC4988886
Grant ListR01 MH095741 / MH / NIMH NIH HHS / United States
1F30MH105055-01 / MH / NIMH NIH HHS / United States
F30 MH105055 / MH / NIMH NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
T32 GM007266 / GM / NIGMS NIH HHS / United States
2R01HG002385 / HG / NHGRI NIH HHS / United States
R01 HG002385 / HG / NHGRI NIH HHS / United States
TR01 MH095741 / MH / NIMH NIH HHS / United States
P30 CA014195 / CA / NCI NIH HHS / United States