Genetic changes shaping the human brain

Abstract

The development and function of our brain are governed by a genetic blueprint, which reflects dynamic changes over the history of evolution. Recent progress in genetics and genomics, facilitated by next-generation sequencing and single-cell sorting, has identified numerous genomic loci that are associated with a neuroanatomical or neurobehavioral phenotype. Here, we review some of the genetic changes in both protein-coding and noncoding regions that affect brain development and evolution, as well as recent progress in brain transcriptomics. Understanding these genetic changes may provide novel insights into neurological and neuropsychiatric disorders, such as autism and schizophrenia.

Figure 1. Emergence and Evolution of a Gene

(A) GPR56 exemplifies how a novel gene arises and evolves. GPR56 is critical to neocortical development, especially gyral patterning. Its protein-coding sequence arose when vertebrates and invertebrates diverged, probably by gene duplication of a pre-existing adhesion G protein-coupled receptor (GPCR) with a long N-terminal extracellular domain. When placental and non-placental mammals diverged, the number of noncoding elements was dramatically increased. The majority of the novel noncoding elements were derived from transposable elements. The placental Gpr56 gene obtained a critical noncoding element (red triangle) that constitutes a robust neural promoter, which drives regional expression in the neocortex. GPR56 continued to obtain new noncoding elements, alternative promoters, and untranslated exons in the primate lineage. Numerous transposon-derived noncoding elements are all over the human GPR56 gene. Most of them are likely to be evolutionarily recent, since the older insertions become mutated and unrecognizable. SINE, short interspersed nuclear elements; LINE, long interspersed nuclear elements; LTR, long terminal repeat elements; DNA, DNA repeat elements; Simple, simple repeats or micro-satellites. (B) Multiple alternative promoters of human GPR56 collectively drive gene expression in the entire neocortex (colored in blue). Loss of a specific noncoding element, which corresponds to the red triangle in panel (A), and thus loss of the associated promoter, ablate GPR56 expression, and cause neocortical malformation, in the areas surrounding the Sylvian fissure bilaterally (i.e., perisylvian polymicrogyria). The affected areas include Broca’s area, the primary language area for speech. Presumably, the novel noncoding elements enabled more precise and complex neocortical patterning mediated by GPR56. Adapted from (Bae et al., 2014).