Neurons with complex karyotypes are rare in aged human neocortex

Megabase-scale somatic copy number variants (CNVs) lead to complex karyotypes that alter allelic diversity in a subset of human neocortical neurons. Reported frequencies of neurons with complex karyotypes range from ~5% of neurons in some individuals to greater than 30% in other individuals. Genome-wide and familial studies implicitly assume a constant brain genome when assessing the genetic risk architecture of neurological disease, thus it is critical to determine whether divergent levels of neurons with complex karyotypes (CNV neurons) reflect normal individual variation or technical differences between approaches. We developed a computational approach that measures single cell library quality based on Bayesian Information Criterion and identifies integer-like variant segments from population-level statistics. A brain CNV atlas was assembled using a new dataset (>800 neurons from 5 neurotypical individuals) and published data from 10 additional neurotypical individuals. This atlas reveals that the frequency of neocortical neurons with complex karyotypes varies widely among individuals, but that this variability is not readily accounted for by tissue quality or CNV detection approach. Rather, the age of the individual is anti-correlated with CNV neuron frequency. Fewer CNV neurons are observed in aged individuals than young individuals.