Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility

Xander Nuttle, Giuliana Giannuzzi, Michael H. Duyzend, Joshua G. Schraiber, Iñigo Narvaiza, Peter H. Sudmant, Osnat Penn, Giorgia Chiatante, Maika Malig, John Huddleston, Chris Benner, Francesca Camponeschi, Simone Ciofi-Baffoni, Holly Stessman, Maria C.N. Marchetto, Laura Denman, Lana Harshman, Carl Baker, Archana Raja, Kelsi Penewit & 10 others Nicolette Janke, W. Joyce Tang, Mario Ventura, Lucia Banci, Francesca Antonacci, Joshua M. Akey, Chris T. Amemiya, Fred H. Gage, Alexandre Reymond, Evan E. Eichler

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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 16p11.2 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.

Original languageEnglish (US)
Pages (from-to)205-209
Number of pages5
JournalNature
Volume536
Issue number7615
DOIs
StatePublished - Aug 3 2016
Externally publishedYes

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Chromosomes
Genes
Hominidae
Genomic Segmental Duplications
Genome
Gene Dosage
Pan troglodytes
Human Genome
Autistic Disorder
Primates
Homeostasis
Stem Cells
Iron
History
RNA
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Nuttle, X., Giannuzzi, G., Duyzend, M. H., Schraiber, J. G., Narvaiza, I., Sudmant, P. H., ... Eichler, E. E. (2016). Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility. Nature, 536(7615), 205-209. https://doi.org/10.1038/nature19075

Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility. / Nuttle, Xander; Giannuzzi, Giuliana; Duyzend, Michael H.; Schraiber, Joshua G.; Narvaiza, Iñigo; Sudmant, Peter H.; Penn, Osnat; Chiatante, Giorgia; Malig, Maika; Huddleston, John; Benner, Chris; Camponeschi, Francesca; Ciofi-Baffoni, Simone; Stessman, Holly; Marchetto, Maria C.N.; Denman, Laura; Harshman, Lana; Baker, Carl; Raja, Archana; Penewit, Kelsi; Janke, Nicolette; Joyce Tang, W.; Ventura, Mario; Banci, Lucia; Antonacci, Francesca; Akey, Joshua M.; Amemiya, Chris T.; Gage, Fred H.; Reymond, Alexandre; Eichler, Evan E.

In: Nature, Vol. 536, No. 7615, 03.08.2016, p. 205-209.

Research output: Contribution to journalArticle

Nuttle, 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, H, Marchetto, MCN, Denman, L, Harshman, L, Baker, C, Raja, A, Penewit, K, Janke, N, Joyce Tang, W, Ventura, M, Banci, L, Antonacci, F, Akey, JM, Amemiya, CT, Gage, FH, Reymond, A & Eichler, EE 2016, 'Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility', Nature, vol. 536, no. 7615, pp. 205-209. https://doi.org/10.1038/nature19075
Nuttle X, Giannuzzi G, Duyzend MH, Schraiber JG, Narvaiza I, Sudmant PH et al. Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility. Nature. 2016 Aug 3;536(7615):205-209. https://doi.org/10.1038/nature19075
Nuttle, Xander ; Giannuzzi, Giuliana ; Duyzend, Michael H. ; Schraiber, Joshua G. ; Narvaiza, Iñigo ; Sudmant, Peter H. ; Penn, Osnat ; Chiatante, Giorgia ; Malig, Maika ; Huddleston, John ; Benner, Chris ; Camponeschi, Francesca ; Ciofi-Baffoni, Simone ; Stessman, Holly ; Marchetto, Maria C.N. ; Denman, Laura ; Harshman, Lana ; Baker, Carl ; Raja, Archana ; Penewit, Kelsi ; Janke, Nicolette ; Joyce Tang, W. ; Ventura, Mario ; Banci, Lucia ; Antonacci, Francesca ; Akey, Joshua M. ; Amemiya, Chris T. ; Gage, Fred H. ; Reymond, Alexandre ; Eichler, Evan E. / Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility. In: Nature. 2016 ; Vol. 536, No. 7615. pp. 205-209.
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AU - Nuttle, Xander

AU - Giannuzzi, Giuliana

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AU - Schraiber, Joshua G.

AU - Narvaiza, Iñigo

AU - Sudmant, Peter H.

AU - Penn, Osnat

AU - Chiatante, Giorgia

AU - Malig, Maika

AU - Huddleston, John

AU - Benner, Chris

AU - Camponeschi, Francesca

AU - Ciofi-Baffoni, Simone

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AU - Denman, Laura

AU - Harshman, Lana

AU - Baker, Carl

AU - Raja, Archana

AU - Penewit, Kelsi

AU - Janke, Nicolette

AU - Joyce Tang, W.

AU - Ventura, Mario

AU - Banci, Lucia

AU - Antonacci, Francesca

AU - Akey, Joshua M.

AU - Amemiya, Chris T.

AU - Gage, Fred H.

AU - Reymond, Alexandre

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