NEW YORK (GenomeWeb) – A new study suggests that the recurrent rearrangements and segmental duplications at the chromosome 16 locus 16p11.2 — implicated in roughly 1 percent of autism spectrum disorder (ASD) cases — appear to be a consequence of human-specific gene family expansion.
In a paper appearing online today in Nature, researchers at the University of Washington and other sites in the US, Switzerland, and Italy report their comparison and analysis of reference-quality genome sequences for half a dozen human, chimpanzee, and orangutans. By comparing the genomes to one another and to sequences from other animals, they uncovered a duplication involving the BOLA2 gene that's present in humans but not in other living primates or in sequenced archaic hominins.
"[T]he level of genetic differences between humans and chimpanzees for chromosome 16p11.2 stands in sharp contrast to the oft-quoted 99 [percent] genetic identity between the species," senior author Evan Eichler, a genome sciences researcher at the University of Washington, and his co-authors wrote. "The region has undergone extensive inversion and duplication, including a [95,000 base] segment containing BOLA2 that duplicated after our divergence with ancient hominins."
The team traced the BOLA2 gene duplication, which appears to be one of the most recent at that locus, back roughly 282,000 years in the modern human lineage. Each of us carries some duplication at this site, the group explained. And almost all of the chromosome 16p11.2 rearrangements identified in individuals with conditions such as ASD contain breakpoints that land within human-duplicated sequences.
"Remarkably, the BOLA2 duplication rapidly rose to high frequency in humans despite predisposing our species to recurrent [copy number variation] associated with disease," the researchers reported.
The team used single-molecule, real-time sequencing to sequence bacterial artificial chromosome clones for humans from three haplotypes, along with two chimps, and one orangutan. The sequences were assembled and error corrected to produce high-quality genome sequences for each. By tapping into the read depth data, the researchers were able to get copy number genotypes for humans, non-human primates, and archaic hominins using available whole-genome sequence data.
When they focused in on the chromosome 16p11.2 locus of interest, they found that the orangutan carried the ancestral configuration at this site, which was most similar the version found in mice. In contrast, the locus was almost twice as long in both humans and chimps and contained half a dozen inversions not found in the orangutan. And in humans, the team detected a block of segmental duplications neighboring the region that's rearranged in some individuals with ASD.
One of these, the BOLA2-contining duplication, appears to have arisen at roughly the same time that the modern human species emerged, according to mutation rate and divergence time estimates. While the gene is apparently duplicated and subjected to positive selection in living and ancient modern humans, the team failed to find comparable duplications in any of the archaic hominins or non-human primates.
Based on reported roles for BOLA2 in iron regulation in other vertebrate animals, the study's authors suspect the newfound expansion may contribute to iron utilization and homeostasis features in humans that are important for processes such as embryonic development. Consistent with that notion, they saw signs that BOLA2 expression is enhanced in the presence of duplications and is also expressed at higher-than-usual levels in human induced pluripotent stem cells.