Biology subjects

van den Berg, P.

Publications and source records attributed to van den Berg, P..

3 recordsLinked to original sources

bioRxiv2026

Who are my Neighbours? Selection Targets Robustness to Full Replication Events, Not to Individual Mutations

Theory predicts that populations should evolve mutational robustness the ability to maintain a constant phenotype despite mutations. However, selection does not operate on individual mutations but on phenotypes resulting from entire replication events, which may involve a variable number of mutations. We therefore distinguish mutational robustness from replicative robustness, defined as the probability that a replication event produces similarly fit offspring. Mutational and replicative robustness may seem closely aligned at first sight, but we show with an evolutionary simulation model that they can be selected in opposite directions. Our results show that while genomes with high redundancy and/or large amounts of non-coding DNA are mutationally robust, they are replicatively fragile because their size increases the number of mutations per replication. This is especially relevant when genomes are at risk of severe disruption from chromosomal rearrangements. Our results expose limits of the fitness landscape metaphor in the context of robustness evolution: neutral plateaus may be mutationally robust but replicatively unstable and therefore disfavoured by selection, whereas narrow peaks arising from densely encoded genomes can replicate more reliably. Our results identify replicative robustness as a distinct target of selection that depends not only on tolerance to individual mutations but also on their overall likelihood of occurring.

evolutionary biology↗

bioRxiv2019

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform specific start-loss mutations of essential genes can cause genetic diseases

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early onset, therapy resistant seizures and developmental delay. Here we report on 12 individuals from 10 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly and visual disturbance. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A>G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in brain cell types, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modelled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE. Importantly, it also shows that isoform specific start-loss mutations causing expression loss of a tissue relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.

genetics↗

bioRxiv2017

Pervasive Discordance Between mRNA And Protein Expression During Embryonic Stem Cell Differentiation

During in vitro differentiation, pluripotent stem cells undergo extensive remodeling of their gene expression profile. While studied extensively at the transcriptome level, much less is known about protein dynamics. Here, we measured mRNA and protein levels of 7459 genes during differentiation of embryonic stem cells (ESCs). This comprehensive data set revealed pervasive discordance between mRNA and protein. The high temporal resolution of the data made it possible to determine protein turnover rates genome-wide by fitting a kinetic model. This model further enabled us to systematically identify dynamic post-transcriptional regulation. Moreover, we linked different modes of regulation to the function of specific gene sets. Finally, we showed that the kinetic model can be applied to singlecell transcriptomics data to predict protein levels in differentiated cell types. In conclusion, our comprehensive data set, easily accessible through a web application, is a valuable resource for the discovery of post-transcriptional regulation in ESC differentiation.

systems biology↗