Summary Somatic mutations occur during brain development and are increasingly implicated as a cause of neurogenetic disease. However, the patterns in which somatic mutations distribute in the human brain are unknown. We used high-coverage whole-genome sequencing of single neurons from a normal individual to identify spontaneous somatic mutations as clonal marks to track cell lineages in human brain. Somatic mutation analyses in >30 locations throughout the nervous system identified multiple lineages and sub-lineages of cells marked by different LINE-1 (L1) retrotransposition events and subsequent mutation of poly-A microsatellites within L1. One clone contained thousands of cells limited to the left middle frontal gyrus, whereas a second distinct clone contained millions of cells distributed over the entire left hemisphere. These patterns mirror known somatic mutation disorders of brain development, and suggest that focally distributed mutations are also prevalent in normal brains. Single-cell analysis of somatic mutation enables tracing of cell lineage clones in human brain.

The 2 major types of neurodegeneration with brain iron accumulation (NBIA) are the pantothenate kinase type 2 (PANK2)-associated neurodegeneration (PKAN) and NBIA2 or infantile neuroaxonal dystrophy (INAD) due to mutations in the phospholipase A2, group VI (PLA2G6) gene. We have recently demonstrated clinical heterogeneity in patients with mutations in the PLA2G6 gene by identifying a poorly defined subgroup of patients who present late with dystonia and parkinsonism. We report the clinical and genetic features of 7 cases with PLA2G6 mutations. Brain was available in 5 cases with an age of death ranging from 8 to 36 years and showed widespread alpha-synuclein-positive Lewy pathology, which was particularly severe in the neocortex, indicating that the Lewy pathology spread corresponded to Braak stage 6 and was that of the “diffuse neocortical type”. In 3 cases there was hyperphosphorylated tau accumulation in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles. Later onset cases tended to have less tau involvement but still severe alpha-synuclein pathology. The clinical and neuropathological features clearly represent a link between PLA2G6 and parkinsonian disorders.

Gene expression profiles from the anterior cingulate cortex (ACC) of human, chimpanzee, gorilla, and macaque samples provide clues about genetic regulatory changes in human and other catarrhine primate brains. The ACC, a cerebral neocortical region, has humanspecific histological features. Physiologically, an individual's ACC displays increased activity during that individual's performance of cognitive tasks. Of Ϸ45,000 probe sets on microarray chips representing transcripts of all or most human genes, Ϸ16,000 were commonly detected in human ACC samples and comparable numbers, 14,000 -15,000, in gorilla and chimpanzee ACC samples. Phylogenetic results obtained from gene expression profiles contradict the traditional expectation that the non-human African apes (i.e., chimpanzee and gorilla) should be more like each other than either should be like humans. Instead, the chimpanzee ACC profiles are more like the human than like the gorilla; these profiles demonstrate that chimpanzees are the sister group of humans. Moreover, for those unambiguous expression changes mapping to important biological processes and molecular functions that statistically are significantly represented in the data, the chimpanzee clade shows at least as much apparent regulatory evolution as does the human clade. Among important changes in the ancestry of both humans and chimpanzees, but to a greater extent in humans, are the up-regulated expression profiles of aerobic energy metabolism genes and neuronal functionrelated genes, suggesting that increased neuronal activity required increased supplies of energy. T raditionally, humans are presumed to have superior cognitive abilities and, thereby, to be very different from other animals. This presumed superiority lies in the supposed uniqueness of such human abilities as producing cultural artifacts and engaging in language and symbolic thought. Recent work, however, shows that chimpanzees, who are the sister group of humans (1-6), engage in culture (7), use tools (8-10), and display rudimentary forms of language (11-13). Moreover, with regard to DNA changes that alter proteins and are favored by natural selection, chimpanzees diverge about as much from the most recent common human-chimpanzee ancestor as do humans (1,14). Here, by estimating the relative abundance of transcribed messages of different expressed genes, we examine in humans and several other catarrhine primates gene expression profiles in an important cerebral region involved in cognition, the anterior cingulate cortex (ACC).The ACC is typically viewed as a bridge between paleocortex and neocortex but is actually part of the neocortex (15). Histologically, the ACC shows human-specific features. For example, clusters of spindle cell pyramidal neurons occur in the ACC of humans, lesser numbers in bonobo and common chimpanzees, lesser yet in gorillas, least in orangutans, and not at all in other primates and other mammals. Moreover, the spindle cells in humans are more than twice as large as in common and bonobo chimpanzees and three...

Inspired by the evolutionary conjecture that sexually selected traits function as indicators of pathogen resistance in animals and humans, we examined the notion that human facial attractiveness provides evidence of health. Using photos of 164 males and 169 females in late adolescence and health data on these individuals in adolescence, middle adulthood, and later adulthood, we found that adolescent facial attractiveness was unrelated to adolescent health for either males or females, and was not predictive of health at the later times. We also asked raters to guess the health of each stimulus person from his or her photo. Relatively attractive stimulus persons were mistakenly rated as healthier than their peers. The correlation between perceived health and medically assessed health increased when attractiveness was statistically controlled, which implies that attractiveness suppressed the accurate recognition of health. These findings may have important implications for evolutionary models.