Abstract
We have established that human genome sequences encoding a novel protein domain, DUF1220, show a dramatically elevated copy number in the human lineage (>200 copies in humans vs. 1 in mouse/rat) and may be important to human evolutionary adaptation. Copy-number variations (CNVs) in the 1q21.1 region, where most DUF1220 sequences map, have now been implicated in numerous diseases associated with cognitive dysfunction, including autism, autism spectrum disorder, mental retardation, schizophrenia, microcephaly, and macrocephaly. We report here that these disease-related 1q21.1 CNVs either encompass or are directly flanked by DUF1220 sequences and exhibit a dosage-related correlation with human brain size. Microcephaly-producing 1q21.1 CNVs are deletions, whereas macrocephaly-producing 1q21.1 CNVs are duplications. Similarly, 1q21.1 deletions and smaller brain size are linked with schizophrenia, whereas 1q21.1 duplications and larger brain size are associated with autism. Interestingly, these two diseases are thought to be phenotypic opposites. These data suggest a model which proposes that (1) DUF1220 domain copy number may be involved in influencing human brain size and (2) the evolutionary advantage of rapidly increasing DUF1220 copy number in the human lineage has resulted in favoring retention of the high genomic instability of the 1q21.1 region, which, in turn, has precipitated a spectrum of recurrent human brain and developmental disorders.