title: Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility.
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. 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.
authors.forename: Xander
authors.initials: X
authors.lastname: Nuttle
authors.forename: Giuliana
authors.initials: G
authors.lastname: Giannuzzi
authors.forename: Michael H
authors.initials: MH
authors.lastname: Duyzend
authors.forename: Joshua G
authors.initials: JG
authors.lastname: Schraiber
authors.forename: Iñigo
authors.initials: I
authors.lastname: Narvaiza
authors.forename: Peter H
authors.initials: PH
authors.lastname: Sudmant
authors.forename: Osnat
authors.initials: O
authors.lastname: Penn
authors.forename: Giorgia
authors.initials: G
authors.lastname: Chiatante
authors.forename: Maika
authors.initials: M
authors.lastname: Malig
authors.forename: John
authors.initials: J
authors.lastname: Huddleston
authors.forename: Chris
authors.initials: C
authors.lastname: Benner
authors.forename: Francesca
authors.initials: F
authors.lastname: Camponeschi
authors.forename: Simone
authors.initials: S
authors.lastname: Ciofi-Baffoni
authors.forename: Holly A F
authors.initials: HA
authors.lastname: Stessman
authors.forename: Maria C N
authors.initials: MC
authors.lastname: Marchetto
authors.forename: Laura
authors.initials: L
authors.lastname: Denman
authors.forename: Lana
authors.initials: L
authors.lastname: Harshman
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.forename: Archana
authors.initials: A
authors.lastname: Raja
authors.forename: Kelsi
authors.initials: K
authors.lastname: Penewit
authors.forename: Nicolette
authors.initials: N
authors.lastname: Janke
authors.forename: W Joyce
authors.initials: WJ
authors.lastname: Tang
authors.forename: Mario
authors.initials: M
authors.lastname: Ventura
authors.forename: Lucia
authors.initials: L
authors.lastname: Banci
authors.forename: Francesca
authors.initials: F
authors.lastname: Antonacci
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
authors.forename: Chris T
authors.initials: CT
authors.lastname: Amemiya
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reymond
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics; D019457:Chromosome Breakage; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D019143:Evolution, Molecular; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism; D002679:Pan troglodytes / Q000235:genetics; D057079:Pongo / Q000235:genetics; D011506:Proteins / Q000032:analysis / Q000235:genetics*; D011995:Recombination, Genetic; D013045:Species Specificity; D013997:Time Factors
chemical_list: C533596:BOLA2 protein, human; D011506:Proteins; D007501:Iron