Keller Valsecchi/Huylmans

Supervisor: Claudia Keller Valsecchi

Co-Supervisor: Ann Kathrin Huylmans

Epigenetics and sex chromosomes through the lens of evolution
Many plants and animals contain a naturally tolerated monosomy, the heteromorphic sex chromosomes. In species, where the male is the heterogametic sex, males have only a single X and Y chromosome (e.g. humans or fruit flies). Conversely, there are other species (e.g. chicken or butterflies), where female oocytes contain either a Z or W chromosome, while males are homogametic, i.e. have identical chromosomal complements in their germ cells. To correct for dosage imbalance due to sex chromosomes, cells contain a gene regulatory mechanism termed Dosage Compensation (DC) (Ohno, 1966). Sex chromosomes evolve from autosomes, a process that occurs rapidly and is characterized by recurrent turnovers and decay. These ever-changing chromosomal landscape poses constant challenges for gene regulatory mechanisms such as DC, because the X/Z need to be distinguished from autosomes. 

More recently, the presence or absence of DC could be studied in various non-model organism. This revealed a fascinating diversity, with some species exhibiting complete DC; others, which exhibit DC only in certain stages or tissues; some with incomplete DC, where only certain dosage-sensitive genes are balanced; and others, where DC is completely absent (Furman et al., 2020). The underlying mechanisms and reasons for these differences across taxa are entirely unknown. Unfortunately, our understanding of how DC is executed at the molecular level is solely based on laboratory model-organisms. From our own discoveries, we infer that the regulatory mechanisms to achieve DC are probably as diverse and rapidly evolving as the sex chromosomes themselves (Keller Valsecchi, Marois, Basilicata et al., 2021).

This diversity will be the core of a PhD project in our group at the interface between evolution, epigenetics and gene regulation.

PhD project: Evolutionary diversity of dosage compensation mechanisms
The PhD project in our group aims at exploring the diversity of DC mechanisms across species from two different angles. On the one hand, you will explore DC from a chromatin accessibility-perspective: Because gene regulation involves the binding of regulatory factors and is associated with opening and closing of chromatin, probing DNA for changes in accessibility, for example by ATAC-seq, is a powerful approach to identify relevant regulatory regions. To overcome the challenges of genomics in non-model species, you will pursue your project with a modified version of the ATAC-technique allowing us to probe chromatin accessibility in situ followed by microscopy (ATAC-see, Chen et al., 2016). Importantly, this microscopy-based technique will enable us to get an unbiased look at the developmental, cell-type and tissue-dependent specificity and variability of X accessibility. Because all our knowledge about DC mechanisms arises from XY systems, a second angle in your project embraces DC in an organism with ZW sex chromosomes: the brine shrimp Artemia franciscana (Huylmans et al., 2019). The DC mechanism of artemia is entirely unknown. You will apply a multiomics strategy to characterize and identify DC factors during brine shrimp development. For our studies, it is an unprecedented advantage that the invertebrate artemia can be easily grown and is amenable to experiments in the lab and hence, could be used for genetic manipulations of putative DC candidates by RNAi or CRISPR/Cas9.

What will you learn?
During this project, you will become proficient in techniques related to epigenomics (RNA-/ChIP-seq/Cut&Run), spatial and in-situ genomics, genome engineering, microscopy, FISH techniques and bioinformatics. You will learn how to independently develop your ideas, pursue a research project and communicate your results in oral and written form. This includes developing skills such as critical thinking, working and collaborating in an international environment, project management, writing and public speaking, for example by attending international conferences. Besides the training program and courses of the Genevo RTG, we will support you in your career planning.

Who are you?
We are looking for a student with a strong interest in epigenetics, developmental biology and evolution. Our ideal candidate would like to combine wet lab, imaging/microscopy and computational approaches (pre-existing training is not necessary). In our team, 6 scientists from 6 different nationalities are working together on diverse aspects of gene dosage from evolution to disease. Hence, we would like to work with a candidate that is enthusiastic about moving this project forward in an international and multidisciplinary environment. If you are a team player and show a high degree of motivation and excitement for science, you will be the right person to join our group.

Publications relevant to this project
Ohno S. Sex Chromosomes and Sex-linked Genes. Springer, Berlin, Heidelberg; 1966.
Furman BLS, Metzger DCH, Darolti I, Wright AE, Sandkam BA, Almeida P, et al. Sex Chromosome Evolution: So Many Exceptions to the Rules. Genome Biol Evol. 2020;12: 750–763.
Keller Valsecchi CI, Marois E, Basilicata MF, Georgiev P, Akhtar A. Distinct mechanisms mediate X chromosome dosage compensation in Anopheles and Drosophila. Life Sci Alliance. 2021;4. doi:10.26508/lsa.202000996
Chen, X., Shen, Y., Draper, W. et al. ATAC-see reveals the accessible genome by transposase-mediated imaging and sequencing. Nat Methods (2016) 13, 1013–1020.
Huylmans AK, Toups MA, Macon A, Gammerdinger WJ, Vicoso B. Sex-Biased Gene Expression and Dosage Compensation on the Artemia franciscana Z-Chromosome. Genome Biol Evol. 2019;11: 1033–1044.