Brain mutations, young and old: Most neurons that make up the human brain are postmitotic, living and functioning for a very long time without renewal (see the Perspective by Lee). Baeet al.examined the genomes of single neurons from the prenatal developing human brain. Both the type of mutation and the rates of accumulation changed between gastrulation and neurogenesis. These early mutations could be generating useful neuronal diversity or could predispose individuals to later dysfunction. Lodatoet al.also found that neurons take on somatic mutations as they age by sequencing single neurons from subjects aged 4 months to 82 years. Somatic mutations accumulated with increasing age and accumulated faster in individuals affected by inborn errors in DNA repair. Postmitotic mutations might only affect one neuron, but the accumulated divergence of genomes across the brain could affect function.Science, this issue p.550, p.555; see also p.521

Significance: Neocortical beta is one of the most prominent signatures of neural activity measured noninvasively in humans. Beta expression is a strong predictor of healthy and pathological perceptual and motor performance. However, there is considerable debate as to whether beta itself is causally important in information and disease processes. Key to resolving this debate is understanding the neural mechanisms inducing beta. Here, building on prior work, we combined human magnetoencephalography, computational modeling, and laminar recordings in mice and monkeys to establish and test a new theory explaining the emergence of spontaneous transient neocortical beta events in somatosensory and frontal cortex. Our results enable a principled understanding of neocortical beta and can help guide studies seeking to understand its relation to function.

Neuropsychiatric disorders have a complex genetic architecture. Human genetic population-based studies have identified numerous heritable sequence and structural genomic variants associated with susceptibility to neuropsychiatric disease. However, these germline variants do not fully account for disease risk. During brain development, progenitor cells undergo billions of cell divisions to generate the ~80 billion neurons in the brain. The failure to accurately repair DNA damage arising during replication, transcription, and cellular metabolism amid this dramatic cellular expansion can lead to somatic mutations. Somatic mutations that alter subsets of neuronal transcriptomes and proteomes can, in turn, affect cell proliferation and survival and lead to neurodevelopmental disorders. The long life span of individual neurons and the direct relationship between neural circuits and behavior suggest that somatic mutations in small populations of neurons can significantly affect individual neurodevelopment. The Brain Somatic Mosaicism Network has been founded to study somatic mosaicism both in neurotypical human brains and in the context of complex neuropsychiatric disorders.

Repeats associated with phenotype: The degree to which repeated sequences within a genome affect human phenotypes has been difficult to establish. Mukamel et al . examined thousands of genomes in the UK Biobank and found that some of the largest effects of common genetic variants on human phenotypes, including those with clinical relevance, arise from protein-coding repeat polymorphisms (see the Perspective by Gymrek and Goren). Mapping the effects of the size and copy number of these repeated protein domains links genetic variation to human phenotypes, including lipoprotein(a) concentration, height, and male pattern balding. Furthermore, the alleles and frequencies of these repeated sequences differ between individuals of African and European descent, resulting in differences between the populations with clinical relevance for traits including lipoprotein(a) levels, a risk factor for coronary artery disease. —LMZ