Advances in genetic tools and sequencing technology in the past few years have vastly expanded our understanding of the genetics of neurodevelopmental disorders. Recent high-throughput sequencing ...analyses of structural brain malformations, cognitive and neuropsychiatric disorders, and localized cortical dysplasias have uncovered a diverse genetic landscape beyond classic Mendelian patterns of inheritance. The underlying genetic causes of neurodevelopmental disorders implicate numerous cell biological pathways critical for normal brain development.
Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci ...with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations—identified by whole-genome and targeted “HAR-ome” sequencing—showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior.
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•Human accelerated regions exhibit regulatory activity during neural development•De novo CNVs impacting HARs are enriched in individuals with ASD•Biallelic HAR mutations underlie up to 5% of consanguineous ASD cases•Regulatory mutations reveal novel genetic architecture of ASD
Mutations in genomic loci that have undergone accelerated evolution in humans are associated with increased risk for autism.
Transgenic mice expressing a stabilized β-catenin in neural precursors develop enlarged brains with increased cerebral cortical surface area and folds resembling sulci and gyri of higher mammals. ...Brains from transgenic animals have enlarged lateral ventricles lined with neuroepithelial precursor cells, reflecting an expansion of the precursor population. Compared with wild-type precursors, a greater proportion of transgenic precursors reenter the cell cycle after mitosis. These results show that β-catenin can function in the decision of precursors to proliferate or differentiate during mammalian neuronal development and suggest that β-catenin can regulate cerebral cortical size by controlling the generation of neural precursor cells.
Abstract
Aging is a mysterious process, not only controlled genetically but also subject to random damage that can accumulate over time. While DNA damage and subsequent mutation in somatic cells were ...first proposed as drivers of aging more than 60 years ago, whether and to what degree these processes shape the neuronal genome in the human brain could not be tested until recent technological breakthroughs related to single-cell whole-genome sequencing. Indeed, somatic single-nucleotide variants (SNVs) increase with age in the human brain, in a somewhat stochastic process that may nonetheless be controlled by underlying genetic programs. Evidence from the literature suggests that in addition to demonstrated increases in somatic SNVs during aging in normal brains, somatic mutation may also play a role in late-onset, sporadic neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. In this review, we will discuss somatic mutation in the human brain, mechanisms by which somatic mutations occur and can be controlled, and how this process can impact human health.
Ray Guillery had broad research interests that spanned cellular neuroanatomy, but was perhaps best known for his investigation of the connectivity and function of the thalamus, especially the visual ...pathways. His work on the genetics of abnormal vision in albino mammals served as an early paradigm for genetic approaches for studying brain connectivity of complex species in general, and remains of major relevance today. This work, especially on the Siamese cat, illustrates the complex relationship between genotype and physiology of cerebral cortical circuits, and anticipated many of the issues underlying the imperfect relationship between genes, circuits, and behavior in mammalian species including human. This review also briefly summarizes studies from our own lab inspired by Ray Guillery's legacy that continues to explore the relationship between genes, structure, and behavior in human cerebral cortex.
Ray Guillery's pioneering studies on visual projection abnormalities in albino mammals was one of the first well‐documented example of genes regulating neural circuits. These studies set the stage for broader consideration of the roles of genes in defining brain structure (see figure). But they also highlighted the limits of genes in defining circuitry, revealing “nongenetic” reorganization of higher‐order connections to early genetically defined misrouting of primary retinal connections.
NUT midline carcinoma (NMC), a subtype of squamous cell cancer, is one of the most aggressive human solid malignancies known. NMC is driven by the creation of a translocation oncoprotein, BRD4-NUT, ...which blocks differentiation and drives growth of NMC cells. BRD4-NUT forms distinctive nuclear foci in patient tumors, which we found correlate with ∼100 unprecedented, hyperacetylated expanses of chromatin that reach up to 2 Mb in size. These "megadomains" appear to be the result of aberrant, feed-forward loops of acetylation and binding of acetylated histones that drive transcription of underlying DNA in NMC patient cells and naïve cells induced to express BRD4-NUT. Megadomain locations are typically cell lineage-specific; however, the cMYC and TP63 regions are targeted in all NMCs tested and play functional roles in tumor growth. Megadomains appear to originate from select pre-existing enhancers that progressively broaden but are ultimately delimited by topologically associating domain (TAD) boundaries. Therefore, our findings establish a basis for understanding the powerful role played by large-scale chromatin organization in normal and aberrant lineage-specific gene transcription.
We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most ...kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6–12.0, p = 2.4 × 10-7). We estimate there are 130–234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.
► Association of duplications of the Williams syndrome region, 7q11.23 ► Replication of findings of increased de novo CNVs in autism spectrum disorders ► Strong association with ASD at 7q11.23, 15q11.2-13, 16p11.2, and NRXN1 ► Prediction of 130–234 ASD-related de novo CNV regions
Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify ...probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders.
The study of human developmental microcephaly is providing important insights into brain development. It has become clear that developmental microcephalies are associated with abnormalities in ...cellular production, and that the pathophysiology of microcephaly provides remarkable insights into how the brain generates the proper number of neurons that determine brain size. Most of the genetic causes of ‘primary’ developmental microcephaly (i.e., not associated with other syndromic features) are associated with centrosomal abnormalities. In addition to other functions, centrosomal proteins control the mitotic spindle, which is essential for normal cell proliferation during mitosis. However, the brain is often uniquely affected when microcephaly genes are mutated implying special centrosomal‐related functions in neuronal production. Although models explaining how this could occur have some compelling data, they are not without controversy. Interestingly, some of the microcephaly genes show evidence that they were targets of evolutionary selection in primates and human ancestors, suggesting potential evolutionary roles in controlling neuronal number and brain volume across species. Mutations in DNA repair pathway genes also lead to microcephaly. Double‐stranded DNA breaks appear to be a prominent type of damage that needs to be repaired during brain development, yet why defects in DNA repair affect the brain preferentially and if DNA repair relates to centrosome function, are not clearly understood. WIREs Dev Biol 2012, 2:461–478. doi: 10.1002/wdev.89
This article is categorized under:
Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing
Gene Expression and Transcriptional Hierarchies > Cellular Differentiation
Nervous System Development > Vertebrates: Regional Development
Birth Defects > Craniofacial and Nervous System Anomalies
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