Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains

Abstract

Left-right laterality is an important aspect of human -and in fact all vertebrate- brain organization for which the genetic basis is poorly understood. Using RNA sequencing data we contrasted gene expression in left- and right-sided samples from several structures of the anterior central nervous systems of post mortem human embryos and foetuses. While few individual genes stood out as significantly lateralized, most structures showed evidence of laterality of their overall transcriptomic profiles. These left-right differences showed overlap with age-dependent changes in expression, indicating lateralized maturation rates, but not consistently in left-right orientation over all structures. Brain asymmetry may therefore originate in multiple locations, or if there is a single origin, it is earlier than 5 weeks post conception, with structure-specific lateralized processes already underway by this age. This pattern is broadly consistent with the weak correlations reported between various aspects of adult brain laterality, such as language dominance and handedness.

Figure 1

Relation between effects of age and side on gene expression (as t-values) for the brain structures aged 5–5.5pcw and aged 7.5–13pcw. Each dot is an individual gene. X-axis: left-right differential expression t-value, with positive values indicating genes with higher right-sided expression. Y-axis: age-effect t-value, where positive t-values indicate genes which increase in expression with age. A positive age-side correlation therefore indicates that the right side of a structure leads the left side in the transcriptional changes which both sides follow. R- and p-values can be found in the main text. Note that for the midbrain and the forebrain t-values for age and side were not computed on the same samples (see main text).

Figure 2

Schematic representation of the embryonic central nervous system around age 5–5.5pcw. The lighter shade of grey indicates the side of the structure that has a higher expression of genes that increase in expression with age (the ‘faster’ side). Two top processes from the GO-enrichment analysis are shown for each side of each structure. Multiple GO-terms have sometimes been collapsed into a single process. Spinal cord and hindbrain were previously described in De Kovel et al..

Figure 3

Schematic representation of anterior sub-structures of the foetal brain at 7.5–13pcw. The lighter shade indicates the side of the structure that has a higher expression of genes that also increase in expression with age (i.e. the ‘faster’ side). For each side and each structure, the top two biological processes showing higher expression than the contralateral side are shown. (Multiple GO-terms have sometimes been collapsed into a single process for illustrative purposes).