Research in our laboratory focuses on elucidating the fundamental mechanisms and the physiological relevance of gene copy numbers for regulating cellular function in eukaryotes. We are interested in the causes and consequences of gene dosage alterations and their potential impact on developmental and pathogenic processes.

Why do diploid organisms contain a maternal as well as a paternal genome complement?

Sexual reproduction enables genetic variation within a population. The diploid state provides a “fail-safe” mechanism: When genes are perturbed in heterozygosity, the other allele can provide robustness and allow development to continue.

However, recent advances in diagnostics and large-scale genome sequencing efforts have revealed that a surprisingly large number of human genes are highly intolerant to heterozygous loss-of-function mutations, putting this traditional view into question. Furthermore, aneuploidies are a principal cause of miscarriage and early pregnancy loss, with the notable exception of chromosome 21 trisomy. This chromosome-wide imbalance is viable, but causes a genetic disorder known as Downs’ syndrome.

These findings indicate that integrating information from both the paternal and maternal alleles appears to be much more relevant than previously anticipated. This applies particularly to cells growing in multicellular and tissue contexts that are constantly exposed to dynamic environmental signals.

This creates a fascinating paradox, considering that gene and whole chromosome duplications are a major driver for the evolution of novel traits, for example in the vertebrate brain. How do cells juggle the good (evolving novel genes), the bad (expression imbalance) and the ugly (developmental delay and malignancies)?

The answer might lie with cellular mechanisms that are co-opted for regulating non-diploid alleles. One beautiful example is dosage compensation, which balances the X chromosome dosage difference between males (XY) and females (XX).