We made the first important steps to determine how recent retrotransposon insertions have shaped gene-regulatory pathways involved in human brain development. Using CRISPR/Cas9-mediated genetic deletion techniques to knock out KRAB zinc fingers from the human genome, we are starting to observe that some classes of primate-specific TEs have had a measurable influence on gene expression in embryonic stem cell-derived cortical organoids. These KRAB zinc fingers and the TEs that they have evolved to repress are currently investigated in more detail.
As one unexpected outcome of these experiments, we found that in addition to their role in repressing TEs, KRAB zinc finger genes are also important for regulation of genes independent from TE insertions. Two papers describing this phenomenon were published (Farmiloe et al., 2020; Haring et al., 2021).
We have become particularly interested in primate-specific TE insertions in genetic loci associated with human neurological diseases and have engaged in a number of collaborations to study their potential impact on the susceptibility of these diseases. We applied CRISPR/Cas9 to genetically delete or regulate specific TEs from our genome to assess their impact on gene regulating by analyzing the resulting changes on both epigenetic and transcriptomic level. Most of the analysis was done in cortical organoids to obtain a clear view of how the TE insertion has affected neuronal gene expression when it inserted in the locus at some point during primate evolution. In our publication (Van Bree et al., 2022) in Genome Research, we revealed that numerous SVA insertions, which are fixed in the human population, can exist in structurally different forms in the population. These different polymorphisms can have different effects on genes nearby, genes that are sometimes associated with increased risk for human diseases through GWAS. Because often the causal factor in these disease associeated loci remains unknown, our study puts forward polymorphisms in TEs such as SVAs as potential causal factors that can have a differential effect on genes nearby in different individuals, hence providing a way in which a disease associated gene in one individual may be under a different influence of the SVA insertion than another individual. This provides an explanation for the observed but poorly understood variability of susceptibility to many human neurodegenerative diseases. This study is the first to show that this is the case and has contributed in bringen the attention to the repetitive part of our DNA in search for causal susceptibility factors.
