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 Homo neaderthalensis and Homo denisoviensis. Not all regions of the genome, however, are equally amenable to such studies.
A specific recurrent copy-number variation (CNV) at chromosome 16p11.2 accounts for ~1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. In the attached report, authors reconstruct the evolutionary history of this locus and identify BOLA family member-2 (BOLA2) as a gene that has been duplicated exclusively in Homo sapiens. Authors estimated that a 95-kilobase-pair (kbp) segment (~95,000 DNA bases) containing BOLA2 duplicated across this critical region ~282,000 years ago (282 ka), which represents 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 almost completely “became fixed” early in the human lineage—a pattern unlikely to have arisen so rapidly in the absence of “selection” (P <0.0097), i.e. an unknown type of genomic DNA adaptation to an enironmental stressor. Authors showed that the duplication of BOLA2 has resulted in a novel, human-specific in-frame fusion transcript, and that the BOLA2 copy number correlates with both RNA expression [r = 0.36, which is NOT a very robust correlation] and protein level (r = 0.65)—with the greatest expression difference between human and chimpanzee (as determined in experimentally-derived stem cells).
Analyses of 152 autistic patients carrying the chromosome 16p11.2 rearrangement showed that more than 96% of breakpoints have occurred within the H. sapiens-specific duplication. In summary, the duplicative transposition of BOLA2, at the root of the H. sapiens lineage, which apparently occurred ~282 ka ago, simultaneously increased the copy number of a gene that is associated with iron homeostasis and predisposition of humans to recurrent rearrangements that are sometimes associated with a complex disease such as some cases of autism.
Nuttle et al., Nature 11 Aug 2o16; 536: 205–209