In sexual species, selfish genes known as transposable elements (TEs) can spread within the genome to the detriment of the host. In fact, nearly 40% of the human genome is comprised of such elements. While generally harmful, TEs have a complex symbiotic relationship with their hosts. Recent studies in plants, fungi and animals have demonstrated the existence of an ancient, RNA-based immune system that protects against these selfish genes. Studies have also shown that the female germline plays a special role in genome defense by transmitting small silencing RNAs to ward against TE activation in the progeny. This form of trans-generational immunity defines a new mode of inheritance, but the mechanisms by which inherited silencing RNAs limit TE proliferation across generations are very poorly understood. The goal of this project is to determine how inherited silencing RNAs protect the genome of the offspring. This will have broad implications for our understanding of epigenetic and mutational phenomena.
Broader Impact: This project will provide training in interdisciplinary research at a time when technological advances are joining previously disparate fields of biology. Two undergraduate students currently in the lab are being trained in molecular genetics, evolutionary genetics, bioinformatics and cytogenetics. The University of Kansas has a strong commitment to the participation of underrepresented groups in biological research through the Office for Diversity in Science Training. This office currently coordinates five federally funded NIGMS Minority Opportunities in Research programs and one undergraduate trainee for this project is funded through this office. An additional broader impact also includes the production of genetics teaching modules on YouTube at: www.youtube.com/user/GeneticsBlumenstiel.
Intellectual Merit Transposable elements (TEs) are selfish elements that reside in genomes and carry the instructions for making copies of themselves. Their proliferative ability is demonstrated by the fact that approximately half the human genome is comprised of TEs or TE remnants. Due to their proliferative nature, TEs can cause mutations in genes and chromosomal damage. In response to this threat, a system of genome defense mediated by small RNAs keeps TE proliferation in check. piRNAs, a particular class of small RNAs derived from TE fragments, are used by the host to silence TEs and limit their proliferation. Using the fruit fly Drosophila virilis as a model, this project examined how transmission of piRNAs through the female germline maintains genome protection across generations. Several discoveries were made. First, we have shown how failure to transmit piRNAs for several classes of TEs can lead to a crisis in the germline in the next generation. In particular, when certain TEs are transmitted through sperm to the next generation, but protective piRNAs are not transmitted by the mother, many diverse TEs can become overexpressed in the germline. This can cause sterility. Interestingly, we have also found that this crisis in the germline is associated with defects in the specificity of piRNA mediated genome defense. In particular, in the face of global TE destabilization in the germline, the genome defense machinery mistakenly targets many normal genes. This can be considered a form of genomic autoimmunity. We have also found that particular regions of the maternal genome can play a crucial role in limiting this crisis. We have made several additional discoveries. First, we have found that natural selection favors an increased level of genome defense in species with higher TE content. In addition, we have developed a new method to measure the harm that TEs inflict in genomes. Overall, the work of this project provided new insights into the harm that TEs can inflict on hosts and the mechanisms by which protection of the genome is transmitted across generations. This has important implications for understanding mechanisms of genome instability and epigenetic inheritance of gene expression states. Broader impacts This work provided significant training for undergraduates and graduate students at the University of Kansas. Several undergraduate students trained by this grant have since gone on to continue their studies as Ph.D. students at other institutions. In addition, this project also supported the development of a YouTube channel for the training of undergraduates in the field of Genetics. An example video that has received 40,000 views can be seen here: www.youtube.com/watch?v=JOL6YF3Wifs
