Trygve E. Bakken

The complete genome sequence of a Neanderthal from the Altai Mountains

We present a high-quality genome sequence of a Neanderthal woman from Siberia. We show that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neanderthal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neanderthals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high-quality Neanderthal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans.

Disruptive CHD8 mutations define a subtype of autism early in development.

Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.

Convergent transcriptional specializations in the brains of humans and song-learning birds.

INTRODUCTION Vocal learning, the ability to imitate sounds, is a trait that has undergone convergent evolution in several lineages of birds and mammals, including song-learning birds and humans. This behavior requires cortical and striatal vocal brain regions, which form unique connections in vocal-learning species. These regions have been found to have specialized gene expression within some species, but the patterns of specialization across vocal-learning bird and mammal species have not been systematically explored. Identifying molecular brain similarities across species. Brain region gene expression specializations were hierarchically organized into specialization trees of each species (blue lines), including for circuits that control learned vocalizations (highlighted green, purple, and orange regions). A set of comparative genomic algorithms found the most similarly specialized regions between songbird and human (orange lines), some of which are convergently evolved. RATIONALE The sequencing of genomes representing all major vocal-learning and vocal-nonlearning avian lineages has allowed us to develop the genomic tools to measure anatomical gene expression across species. Here, we asked whether behavioral and anatomical convergence is associated with gene expression convergence in the brains of vocal-learning birds and humans. RESULTS We developed a computational approach that discovers homologous and convergent specialized anatomical gene expression profiles. This includes generating hierarchically organized gene expression specialization trees for each species and a dynamic programming algorithm that finds the optimal alignment between species brain trees. We applied this approach to brain region gene expression databases of thousands of samples and genes that we and others generated from multiple species, including humans and song-learning birds (songbird, parrot, and hummingbird) as well as vocal-nonlearning nonhuman primates (macaque) and birds (dove and quail). Our results confirmed the recently revised understanding of the relationships between avian and mammalian brains. We further found that songbird Area X, a striatal region necessary for vocal learning, was most similar to a part of the human striatum activated during speech production. The RA (robust nucleus of the arcopallium) analog of song-learning birds, necessary for song production, was most similar to laryngeal motor cortex regions in humans that control speech production. More than 50 genes contributed to their convergent specialization and were enriched in motor control and neural connectivity functions. These patterns were not found in vocal nonlearners, but songbird RA was similar to layer 5 of primate motor cortex for another set of genes, supporting previous hypotheses about the similarity of these cell types between bird and mammal brains. CONCLUSION Our approach can accurately and quantitatively identify functionally and molecularly analogous brain regions between species separated by as much as 310 million years from a common ancestor. We were able to identify analogous brain regions for song and speech between birds and humans, and broader homologous brain regions in which these specialized song and speech regions are located, for tens to hundreds of genes. These genes now serve as candidates involved in developing and maintaining the unique connectivity and functional properties of vocal-learning brain circuits shared across species. The finding that convergent neural circuits for vocal learning are accompanied by convergent molecular changes of multiple genes in species separated by millions of years from a common ancestor indicates that brain circuits for complex traits may have limited ways in which they could have evolved from that ancestor. Song-learning birds and humans share independently evolved similarities in brain pathways for vocal learning that are essential for song and speech and are not found in most other species. Comparisons of brain transcriptomes of song-learning birds and humans relative to vocal nonlearners identified convergent gene expression specializations in specific song and speech brain regions of avian vocal learners and humans. The strongest shared profiles relate bird motor and striatal song-learning nuclei, respectively, with human laryngeal motor cortex and parts of the striatum that control speech production and learning. Most of the associated genes function in motor control and brain connectivity. Thus, convergent behavior and neural connectivity for a complex trait are associated with convergent specialized expression of multiple genes.

A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations

The gene MECP2 is a well-known determinant of brain structure. Mutations in the MECP2 protein cause microencephalopathy and are associated with several neurodevelopmental disorders that affect both brain morphology and cognition. Although mutations in MECP2 result in severe neurological phenotypes, the effect of common variation in this genetic region is unknown. We find that common sequence variations in a region in and around MECP2 show association with structural brain size measures in 2 independent cohorts, a discovery sample from the Thematic Organized Psychosis research group, and a replication sample from the Alzheimers Disease Neuroimaging Initiative. The most statistically significant replicated association (P < 0.025 in both cohorts) involved the minor allele of SNP rs2239464 with reduced cortical surface area, and the finding was specific to male gender in both populations. Variations in the MECP2 region were associated with cortical surface area but not cortical thickness. Secondary analysis showed that this allele was also associated with reduced surface area in specific cortical regions (cuneus, fusiform gyrus, pars triangularis) in both populations.

A comprehensive transcriptional map of primate brain development

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey (Macaca mulatta) brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical division of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons. Cortical layers and areas acquire adult-like molecular profiles surprisingly late in postnatal development. Disparate cell populations exhibit distinct developmental timing of gene expression, but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, although approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny compared to monkey.

Association between mitochondrial DNA variations and Alzheimer's Disease in the ADNI cohort

Despite the central role of amyloid deposition in the development of Alzheimers disease (AD), the pathogenesis of AD still remains elusive at the molecular level. Increasing evidence suggests that compromised mitochondrial function contributes to the aging process and thus may increase the risk of AD. Dysfunctional mitochondria contribute to reactive oxygen species (ROS) which can lead to extensive macromolecule oxidative damage and the progression of amyloid pathology. Oxidative stress and amyloid toxicity leave neurons chemically vulnerable. Because the brain relies on aerobic metabolism, it is apparent that mitochondria are critical for the cerebral function. Mitochondrial DNA sequence changes could shift cell dynamics and facilitate neuronal vulnerability. Therefore we postulated that mitochondrial DNA sequence polymorphisms may increase the risk of AD. We evaluated the role of mitochondrial haplogroups derived from 138 mitochondrial polymorphisms in 358 Caucasian Alzheimers Disease Neuroimaging Initiative (ADNI) subjects. Our results indicate that the mitochondrial haplogroup UK may confer genetic susceptibility to AD independently of the apolipoprotein E4 (APOE4) allele.

Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (Pcombined = 3.2 × 10−8). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10−9) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5′ UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.

Association of Genetic Variants on 15q12 With Cortical Thickness and Cognition in Schizophrenia

CONTEXT Cortical thickness is a highly heritable structural brain measurement, and reduced thickness has been associated with schizophrenia, bipolar disorder, and decreased cognitive performance among healthy control individuals. Identifying genes that contribute to variation in cortical thickness provides a means to elucidate some of the biological mechanisms underlying these diseases and general cognitive abilities. OBJECTIVES To identify common genetic variants that affect cortical thickness in patients with schizophrenia, patients with bipolar disorder, and controls and to test these variants for association with cognitive performance. DESIGN A total of 597 198 single-nucleotide polymorphisms were tested for association with average cortical thickness in a genome-wide association study. Significantly associated single-nucleotide polymorphisms were tested for their effect on several measures of cognitive performance. SETTING Four major hospitals in Oslo, Norway. PARTICIPANTS A total of 1054 case individuals and controls were analyzed in the genome-wide association study and follow-up cognitive study. The genome-wide association study included controls (n = 181) and individuals with DSM-IV -diagnosed schizophrenia spectrum disorder (n = 94), bipolar spectrum disorder (n = 97), and other psychotic and affective disorders (n = 49). MAIN OUTCOME MEASURES Cortical thickness measured with magnetic resonance imaging and cognitive performance as assessed by several neuropsychological tests. RESULTS Two closely linked genetic variants (rs4906844 and rs11633924) within the Prader-Willi and Angelman syndrome region on chromosome 15q12 showed a genome-wide significant association (P = 1.1 x 10(-8) with average cortical thickness and modest association with cognitive performance (permuted P = .03) specifically among patients diagnosed as having schizophrenia. CONCLUSION This genome-wide association study identifies a common genetic variant that contributes to the heritable reduction of cortical thickness in schizophrenia. These results highlight the usefulness of cortical thickness as an intermediate phenotype for neuropsychiatric diseases. Future independent replication studies are required to confirm these findings.

Genetic identification of brain cell types underlying schizophrenia

With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs) and certain interneurons, but far less consistently to embryonic, progenitor or glial cells. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia.Integration of single-cell RNA sequencing with genome-wide association data implicates specific brain cell types in schizophrenia. Gene sets previously associated with schizophrenia implicate the same cell types, which include pyramidal cells and medium spiny neurons.

A Geographic Cline of Skull and Brain Morphology among Individuals of European Ancestry

Background: Human skull and brain morphology are strongly influenced by genetic factors, and skull size and shape vary worldwide. However, the relationship between specific brain morphology and genetically-determined ancestry is largely unknown. Methods: We used two independent data sets to characterize variation in skull and brain morphology among individuals of European ancestry. The first data set is a historical sample of 1,170 male skulls with 37 shape measurements drawn from 27 European populations. The second data set includes 626 North American individuals of European ancestry participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with magnetic resonance imaging, height and weight, neurological diagnosis, and genome-wide single nucleotide polymorphism (SNP) data. Results: We found that both skull and brain morphological variation exhibit a population-genetic fingerprint among individuals of European ancestry. This fingerprint shows a Northwest to Southeast gradient, is independent of body size, and involves frontotemporal cortical regions. Conclusion: Our findings are consistent with prior evidence for gene flow in Europe due to historical population movements and indicate that genetic background should be considered in studies seeking to identify genes involved in human cortical development and neuropsychiatric disease.