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 primates1, including more recently the genomes of archaic hominins2,3. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for ~1% of autism cases4,5 and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. We reconstructed the evolutionary history of the locus and identified BOLA2 (bolA family member 2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95 kbp segment containing BOLA2 duplicated across the critical region ~282 thousand years ago (kya), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carry 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 showed that >96% of breakpoints occur within the Homo sapiens-specific duplication. In summary, the duplicative transposition of BOLA2 at the root of the Homo sapiens lineage ~282 kya simultaneously increased copy number of a gene associated with iron homeostasis and predisposed our species to recurrent rearrangements associated with disease.

High-resolution comparative analysis of great ape genomes

“…In particular, we are still missing many larger, more complex events, including inversions and SDs that have differentially evolved between the lineages. For example, we recovered only one of five ape inversions identified by comparative BAC-based sequencing of a 2 Mbp region of chromosome 16p11.2 (64), although optical mapping techniques did identify four of the events. In this case, all inversions are flanked by large blocks of SDs (>200 kbp) that cannot be currently assembled by long-read WGS.…”

“…We predict that such large, multi-megabase-pair inversions represent a common uncharacterized source of human–ape genetic variation that has been underestimated. Long-range sequencing and mapping technologies, such as Strand-seq (49), BAC-based sequencing (64), optical mapping (Table S12) and longer-read sequencing (65) will be necessary to sequence-resolve such large, more complex SVs.…”

How well do we understand the basis of classic selective sweeps in humans?

“…Although there are examples of sweeps that have reached fixation (e.g. on iron homeostasis influenced by a BOLA2 duplication ~ 280 000 years ago ) or near‐fixation (e.g. increased resistance to severe sepsis due to CASP12 inactivation beginning > 100 000 years ), the examples we discuss below all show high population differentiation.…”

Evolution of the Human Nervous System Function, Structure, and Development

“…BOLA2 is contained in a modern-human-specific segmental duplication in a complex region of chromosome 16, showing 2–5 copies in almost all present-day humans analyzed (Prüfer et al, 2014; Sudmant et al, 2013; Nuttle et al, 2016), which is an instance of a quick fixation after a duplication event. The DUF1220 protein domain, extensively studied by Sikela and colleagues, shows the largest expansion of protein-coding sequence in the human genome, with an estimated addition of 28 copies every million years since the split with chimpanzees, resulting in ~270 copies in humans compared to the 90–125 copies in great apes (Fortna et al, 2004; O’Bleness et al, 2012a; O’Bleness et al, 2012b; Popesco et al, 2006).…”