Keller Valsecchi Lab
Research Publications Group Members BiographyBiology of gene dosage alterations
Research in our laboratory focuses on elucidating the fundamental mechanisms and physiological relevance of gene copy number for regulating cellular function in eukaryotes. We study the causes and consequences of gene dosage alterations and their impact on developmental, evolutionary and ageing processes. A major interest of ours lies in the evolution of sex chromosomes and the molecular diversity of compensatory mechanisms.
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. Similarly, aneuploidies, where entire chromosomes are gained or lost, increase dramatically in oocytes as women age and are a major cause of miscarriage and pregnancy loss.
This indicates that a precisely two-fold gene dosage is highly relevant for organismal development.
We find it particularly interesting to look at these pathogenic gene-dosage alterations in light of natural exceptions to the diploid state. Sex chromosomes are not detrimental, despite creating heterozygosity for hundreds of genes. The reason for this is dosage compensation (DC), which corrects for gene expression imbalances and ensures equal expression of X-linked genes in males and females. The evolution of sex chromosomes is mirrored by numerous other natural examples that induce dosage alterations at the individual gene level. However, the question of whether they are also subjected to compensatory buffering mechanisms like the ones acting on sex chromosomes has been comparably understudied to date.
Our group studies this fascinating paradox of how dosage alterations occur naturally but at the same time are potentially deleterious. In other words - how do cells juggle the good (evolving novel genes), the bad (expression imbalance) and the ugly (developmental delay and malignancies)?
Researchers in our group study gene dosage from two different angles:
(1) Evolutionary epigenetics of sex differences
Morphological and physiological differences between the sexes are widespread in nature and in some cases of high relevance to human health. For example, only female mosquitoes feed on blood and are thereby able to transmit malaria. Female and male mosquitoes differ in their X chromosomes, a genetic disequilibrium (XX versus XY) which is corrected by dosage compensation.
We have recently uncovered the master regulatory gene that controls dosage compensation in Anopheles gambiae. However, we are still left with many open questions - for example, does this novel pathway change the epigenome and transcription machinery to elicit a 2-fold fine-tuning effect, and if so how? And how can it specifically recognise the X chromosome?
Besides mosquitos, we also explore dosage compensation in other non-model organisms. We explore questions of differences between tissues, regulation throughout life and plasticity upon environmental changes. For example, we study how dosage compensation in crustaceans is established in the context of high and low saline conditions. Another project addresses how genetic and epigenetic variation in natural zebrafish populations influences thermal adaptation (collaboration with Adrian-Kalchhauser group, Bern). We anticipate that such findings will be highly relevant in the light of global warming and climate change. More generally, we are interested in understanding the mechanistic diversity and molecular principles acting on natural exceptions to the diploid state. We aim to uncover the functional relevance of dosage balancing during genome evolution and study the underlying molecular mechanisms in its natural context.
(2) Dosage sensitivity in development & ageing
Female and male individuals show pronounced differences in physiology and the pathophysiology of their ageing processes. Women generally live longer than men and many age-related diseases show sex-specific patterns. Our group is investigating to what extent the sex chromosome complement and allele-specific regulation are involved in the pathophysiology of ageing processes. Together with our collaborators at the University Medical Center Mainz (M. Felicia Basilicata & Susann Schweiger groups), we study whether the female “advantage” of having two X chromosomes can be unlocked under certain conditions to protect against genetic diseases, e.g. X-linked developmental disorders. Because dosage alterations occur at both a chromosome-wide and locus-specific level, we are exploring dosage sensitivity from a gene-by-gene viewpoint. More specifically, we are interested in the cellular consequences and functional relevance of alterations in gene paralogues, with a particular focus on dosage-sensitive RNA-binding proteins.
Experimental approaches and model systems
We use complementary approaches and methods, such as (but not limited to) genome engineering (CRISPR/Cas9), transcriptomics (RNA-seq, TT-seq, single-cell RNA-seq), epigenomics (ChIP-seq, Cut&Tag, CLIP), live and confocal microscopy, proteomics and biochemistry. About half of our group works with murine stem cells, human induced pluripotent stem cells (iPS), and various other mammalian cells and organoids. The others work with non-model organisms - currently the malaria mosquito Anopheles gambiae and the crustacean Artemia franciscana.
Recruiting
We are looking for highly proactive scientists at all career stages to join our group. Together, we build our success on teamwork, curiosity and enthusiasm for science. Alongside a stimulating environment and the freedom to explore your research projects, you will be provided mentoring and support for your career development.
Postdoc applicants are encouraged to contact us directly by email.
PhD applicants: please apply through the International PhD Programme.
We welcome undergraduate students or students interested in an internship of at least 3 months. Please send your CV and a brief motivation letter to us by email.