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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM074108-09
Application #
8499346
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Janes, Daniel E
Project Start
2005-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$345,767
Indirect Cost
$145,143
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Ailion, Michael; Malik, Harmit S (2017) Genetics: Master Regulator or Master of Disguise? Curr Biol 27:R844-R847
Levin, Tera C; Malik, Harmit S (2017) Rapidly Evolving Toll-3/4 Genes Encode Male-Specific Toll-Like Receptors in Drosophila. Mol Biol Evol 34:2307-2323
Bull, James J; Malik, Harmit S (2017) The gene drive bubble: New realities. PLoS Genet 13:e1006850
Kasinathan, Bhavatharini; Ahmad, Kami; Malik, Harmit S (2017) Waddington Redux: De Novo Mutations Underlie the Genetic Assimilation of Stress-Induced Phenocopies in Drosophila melanogaster. Genetics 207:49-51
Kursel, Lisa E; Malik, Harmit S (2017) Recurrent Gene Duplication Leads to Diverse Repertoires of Centromeric Histones in Drosophila Species. Mol Biol Evol 34:1445-1462
McLaughlin Jr, Richard N; Malik, Harmit S (2017) Genetic conflicts: the usual suspects and beyond. J Exp Biol 220:6-17
Nuckolls, Nicole L; Bravo Núñez, María Angélica; Eickbush, Michael T et al. (2017) wtf genes are prolific dual poison-antidote meiotic drivers. Elife 6:
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 37:51-58
Cheng, Chao-Yin; Young, Janet M; Lin, Chih-Yi Gabriela et al. (2016) The piggyBac transposon-derived genes TPB1 and TPB6 mediate essential transposon-like excision during the developmental rearrangement of key genes in Tetrahymena thermophila. Genes Dev 30:2724-2736

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