SUPR
Exploring the role of transposable elements in human brain evolution
Dnr:

NAISS 2025/22-161

Type:

NAISS Small Compute

Principal Investigator:

Johan Jakobsson

Affiliation:

Lunds universitet

Start Date:

2025-02-17

End Date:

2026-03-01

Primary Classification:

10609: Genetics and Genomics (Medical aspects at 30107 and agricultural at 40402)

Webpage:

Allocation

Abstract

The human brain is the largest and most complex of all primates possessing unique cognitive functions but also suffering from neurological disorders. However, little is known about primate brain development and the modifications enabling brain enlargement as primate tissues are not available at early developmental time points. Only few changes occurred in protein-coding genes; thus, significant differences must be present in gene regulatory processes. It is essential to analyse primate models to identify and understand molecular features unique to the human brain. Transposable elements (TEs) are mobile pieces of DNA comprising 50% of primate genomes. They have the capacity to contribute to genome evolution as they carry regulatory sequences and have been found to serve e.g. as enhancers and alternative promoters. Moreover, TEs are insertional mutagens leading to genetic disease. Hence, they are silenced by repressive marks including DNA methylation. Interestingly, methylation can sometimes spread and impact adjacent regions making TEs noteworthy candidates for methylome evolution. Due to their challenging analysis and lack of primate material, the role of TEs in primate brain development and human brain evolution has not been investigated thoroughly. Here, we propose that species-specific TE insertions can act as regulatory elements in primate brain development. Exploiting induced pluripotent stem cell-derived human and non-human primate cerebral organoids as a model for brain development, and combing Oxford Nanopore Technologies long-read DNA sequencing and RNA sequencing to detect global TE DNA methylation and expression in NPCs from cerebral organoids, we will analyse locus-specific methylation and expression of TEs and their effect on nearby genes. Using CRISPR-Cas9 genome editing, we will assess the impact of these putative regulator TEs on gene expression, revealing if their cis-regulatory effect contributed to primate brain development as well as human brain enlargement and gain of cognitive functions.