DUF1220-Domain Copy Number Implicated in Human Brain-Size Pathology and Evolution

Abstract

DUF1220 domains show the largest human-lineage-specific increase in copy number of any protein-coding region in the human genome and map primarily to 1q21, where deletions and reciprocal duplications have been associated with microcephaly and macrocephaly, respectively. Given these findings and the high correlation between DUF1220 copy number and brain size across primate lineages (R(2) = 0.98; p = 1.8 × 10(-6)), DUF1220 sequences represent plausible candidates for underlying 1q21-associated brain-size pathologies. To investigate this possibility, we used specialized bioinformatics tools developed for scoring highly duplicated DUF1220 sequences to implement targeted 1q21 array comparative genomic hybridization on individuals (n = 42) with 1q21-associated microcephaly and macrocephaly. We show that of all the 1q21 genes examined (n = 53), DUF1220 copy number shows the strongest association with brain size among individuals with 1q21-associated microcephaly, particularly with respect to the three evolutionarily conserved DUF1220 clades CON1(p = 0.0079), CON2 (p = 0.0134), and CON3 (p = 0.0116). Interestingly, all 1q21 DUF1220-encoding genes belonging to the NBPF family show significant correlations with frontal-occipital-circumference Z scores in the deletion group. In a similar survey of a nondisease population, we show that DUF1220 copy number exhibits the strongest correlation with brain gray-matter volume (CON1, p = 0.0246; and CON2, p = 0.0334). Notably, only DUF1220 sequences are consistently significant in both disease and nondisease populations. Taken together, these data strongly implicate the loss of DUF1220 copy number in the etiology of 1q21-associated microcephaly and support the view that DUF1220 domains function as general effectors of evolutionary, pathological, and normal variation in brain size.

Characterizing polymorphic inversions in human genomes by single-cell sequencing

“…Accurately annotating these regions in the human reference has immediate applications for genetic association studies. For instance, the 1.7-Mb misoriented fragment identified on Chr 1q21 encompasses several neuroblastoma-associated genes, which may have implications for which NBPF paralogs are associated with the disease and can be used as appropriate biomarkers (Vandepoele et al 2005;Dumas et al 2012;Andries et al 2015). We also identified 46 AWC regions that likely point to repetitive sequences present in the genome that have not yet been placed in the reference assembly.…”

“…Finally, the largest misoriented fragment (ROIno.1.13) fell on Chr 1q21, overlapped 19 inversions in the DGV, and encompassed 27 unique genes. This fragment was misoriented in 93% of the population we sampled, and the breakpoints disrupted several NBPF paralogs of a tumor-suppressor gene family associated (Vandepoele et al 2005;Dumas et al 2012;Andries et al 2015). This shows that errors in genome assemblies can appear as structural variants using conventional techniques but are more accurately annotated using our Strand-seq approach.…”

No relative expansion of the number of prefrontal neurons in primate and human evolution

“…Although a number of genetic changes specific to the human brain have been found (38)(39)(40)(41)(42)(43) and certainly play some role in human cognition, we propose that this larger absolute number of neurons in human prefrontal, associative cortical regions is the main factor underlying the complexity of our cognitive abilities in comparison with other primates, and possibly all other mammals. As for nonassociative regions (37), the ensuing increase in number of cortical prefrontal areas expected with an increased absolute number of neurons and absolute cortical size would be an additional factor to contribute to increased complexity of associative processing in humans compared with other primate species.…”

Are there alternative adaptive strategies to human pro-sociality? The role of collaborative morality in the emergence of personality variation and autistic traits

“…Genes associated with autism have been argued to appear in apes (Dumas et al 2012), as they are also implicated in both ape and human brain expansion (Marques-Bonet and Eichler 2009). Autistic-like behaviours apparent across populations and with a genetic component have been recorded in macaques and in chimpanzees (K. Yoshida et al 2016;Marrus et al 2011;Faughn et al 2015).…”