Zach Kockler and Tanner Koomar Present in Genetics Student Seminar 7/10/17
Investigation of the Mechanism of BIR and ALT
Mentor: Anna Malkova
Break induced replication (BIR) is a homologous recombination-dependent mechanism that repairs double strand DNA breaks (DSBs) that are made in such a way that only one end of the break can find homology in the genome for repair. A natural situation where BIR was suggested to occur is in a process called alternative lengthening of telomeres (ALT) that is responsible for the telomere maintenance in the absence of telomerase. Overall, fifteen percent of malignant tumors maintain their telomeres by ALT, and is especially prevalent in osteosarcomas and malignant fibrous histiocytomas where it occurs in more than half of all cases. It has been shown that BIR begins with resection of the broken end that then invades homology forming a D-loop. This mechanism is unusual because at this D-loop, synthesis begins and progresses by a migrating bubble until the end of the chromosome resulting in conservative inheritance of the newly synthesized DNA. Though, BIR results in a repaired chromosome, it comes with deleterious effects that may be the result of accumulations of long stretches of ssDNA. These long stretches of ssDNA can lead to tangled toxic intermediates and may facilitate gross chromosomal rearrangements, as well as an increase mutagenesis, which was previously demonstrated to be 1000 times more as compared to S-phase replication. All these deleterious effects of BIR make it important for us to understand how BIR is carried out, and regulated.
Genes Implicated in Neurodevelopment Enriched for FOXP2 Binding Sites Associated with Language Ability
Tanner Koomar, Jacob Michaelson, PhD.
Specific Language Impairment (SLI) is a neurodevelopmental condition which causes linguistic deficits in children with otherwise normal development. SLI is relatively common (occurring in ~7% of the population) and demonstrably heritable (h2 ~ 0.6). Linkage, GWAS, and twin studies of SLI have produced mixed results with inconsistent replication, necessitating the integration of other forms of molecular data related to language ability. The transcription factor FOXP2 is robustly associated with language ability, with perturbations to the coding region of the gene resulting in severe language deficits. However, such coding changes in FOXP2 are exceedingly rare. Variation in FOXP2’s thousands of DNA binding sites is plentiful, on the other hand, making them attractive targets for interrogation in a common condition like SLI. In this work, genetic variants overlapping FOXP2 ChIP peak sites were extracted from the whole genome sequences of a cohort of ~280 children (140 SLI and 140 control), and ranked based on association with overall language ability. Variation in the FOXP2 locus was also tested for association with language ability. Some genes co-expressed with FOXP2 in the developing human brain and implicated in neurodevelopment, were enriched for high-ranking FOXP2 binding sites. Despite these intriguing results, this variation – and that in the FOXP2 locus itself – was only able to explain a fraction of differences in total language ability.