Non-coding DNA elements serve key organizing functions in eukaryotic genomes. These essential functions range from segregating chromosomes to ensuring transcriptional parity at sex chromosomes via dosage compensation and defending the germline against transposons. Centromeric and heterochromatic DNA is required for correct chromosome segregation, defects in which can lead to infertility as well as to aneuploidy - commonly found in birth defects like trisomy (e.g. Down's syndrome) and in transitions to cancer. Defects in dosage compensation lead to male inviability in Drosophila and to a range of defects in mammalian females. The inability to defend against germline transposition can result in both male and female sterility. Despite their importance, most of these 'organizing'DNA elements have proven intractable to genetic studies owing to their highly repetitive nature (centromeres, heterochromatin), poor definition (dosage compensation entry sites) and rapid evolution. Lack of suitable traditional comparative genomics methods has impeded research into these elements. Therefore, new methods and perspectives are needed to provide insight into these important segments of our genome. My lab has adopted a """"""""surrogate"""""""" approach to study the function and evolution of such DNA elements. By studying the selective pressures acting on the proteins that bind and, in many instances, epigenetically define the function of these elements, we obtain insight into the selective pressure on the DNA elements themselves. This approach gives unique insight into the evolutionary pressures shaping these DNA elements and the essential biological processes they carry out. This proposal aims to employ this novel approach to understand the biological forces shaping these evolutionarily and medically important components of eukaryotic genomes, using the Drosophila model genetic system.
Non-coding organizing DNA elements are essential for functions in chromosome segregation, dosage compensation and piRNA production. Defects in these processes can lead to infertility, inviability, birth defects and aneuploidy in transitions to cancer. My lab has adopted a surrogate approach to study the function and evolution of such DNA elements, providing unique insight into the evolutionary pressures shaping these DNA elements and the essential biological processes they carry out.
|Levine, Mia T; Vander Wende, Helen M; Hsieh, Emily et al. (2016) Recurrent Gene Duplication Diversifies Genome Defense Repertoire in Drosophila. Mol Biol Evol 33:1641-53|
|Molaro, Antoine; Malik, Harmit S (2016) Hide and seek: how chromatin-based pathways silence retroelements in the mammalian germline. Curr Opin Genet Dev 37:51-8|
|Kursel, Lisa E; Malik, Harmit S (2016) Centromeres. Curr Biol 26:R487-90|
|Drinnenberg, Ines A; Henikoff, Steven; Malik, Harmit S (2016) Evolutionary Turnover of Kinetochore Proteins: A Ship of Theseus? Trends Cell Biol 26:498-510|
|Patel, Maulik R; Miriyala, Ganesh K; Littleton, Aimee J et al. (2016) A mitochondrial DNA hypomorph of cytochrome oxidase specifically impairs male fertility in Drosophila melanogaster. Elife 5:|
|Zanders, Sarah E; Malik, Harmit S (2015) Chromosome segregation: human female meiosis breaks all the rules. Curr Biol 25:R654-6|
|Zanders, Sarah E; Malik, Harmit S (2015) R2d2 and Hyperdrive Mechanisms (in Mouse Meiosis). PLoS Genet 11:e1004950|
|Levine, Mia T; Vander Wende, Helen M; Malik, Harmit S (2015) Mitotic fidelity requires transgenerational action of a testis-restricted HP1. Elife 4:e07378|
|Phadnis, Nitin; Baker, EmilyClare P; Cooper, Jacob C et al. (2015) An essential cell cycle regulation gene causes hybrid inviability in Drosophila. Science 350:1552-5|
|Phadnis, Nitin; Malik, Harmit S (2014) Speciation via autoimmunity: a dangerous mix. Cell 159:1247-9|
Showing the most recent 10 out of 36 publications