I have conducted research and published during my Ph.D. in Genetics at Stanford University in the lab of Dmitri Petrov, when I was a Staff Research Associate at UC Berkeley in the lab of Zac Cande, and when I was working towards a B.A. in Molecular & Cellular Biology and did Undergraduate Research at UC Berkeley in the lab of Abby Dernburg. A full list of my publications can be found on PubMed.
Genetics Ph.D. at Stanford University in the lab of Dmitri Petrov
During my PhD I have employed mathematical models, experimental methods, and population genomics tools in order to investigate genomic patterns and evolutionary fates of new mutations.
Characterizing the spectrum of new mutations using experimental and genomic approaches
I am currently submitting for publication a first-author paper from the last chapter of my dissertation at Stanford University, under the title Precise estimates of mutational rates and biases in the fruit fly Drosophila melanogaster. In this work I, along with co-authors Susanne Tilk, Jane Park, Mark Siegal, and Dmitri Petrov, characterize the spectrum of new mutations using both experimental and population genomics methods.
Describing the staggered sweep phenomenon using mathematical models and forward simulations
Frequency trajectories of a beneficial mutation genetically linked to a recessive deleterious allele. Blue trajectories indicate simulations in which the beneficial mutation successfully reached fixation, and red trajectories indicate simulations in which it went extinct. PNAS 2015 May 19;112(20):E2658-66
The other major first-author paper of my PhD is entitled ‘Obstruction of adaptation in diploids by recessive, strongly deleterious alleles’ and was published in 2015 in the journal PNAS (PDF available here). In this work I, along with co-authors Jamie Blundell and Dmitri Petrov, describe a phenomenon in which a beneficial mutation linked to a deleterious hitchhiker is able to initiate a selective sweep in the population, however before the beneficial mutation can reach fixation it is stalled at intermediate frequency due to heterozygote advantage. We call this a staggered sweep, and it is driven by recessive deleterious mutations hidden in natural populations at low frequency.
A deleterious mutation that is recessive is hidden in individuals containing only one copy (i.e., heterozygotes); however, individuals containing two copies (i.e., homozygotes) suffer negative effects. This class of mutation is responsible for a number of human genetic disorders, including cystic fibrosis and Tay-Sachs, in addition to causing the widespread phenomenon of inbreeding depression. Evidence suggests that recessive deleterious mutations may be abundant in nature, likely due to their ability to persist for long timescales at moderate frequencies. In this work we propose a model for the dynamics of a new adaptive mutation which lands on a chromosome containing a recessive deleterious allele, and perform extensive forward simulations validating our model. We find that recessive deleterious mutations can significantly slow adaptation, as well as alter signatures of selection in the genome.
A review of the population genetics of drug resistance evolution in viral, bacterial, and eukaryotic pathogens
Reconstructed from the work of Nubel et. al. (2008 PNAS). Minimum-spanning tree constructed from core genomic sequences of 135 isolates of the ST5 S. aureus clone collected globally, where (A) is colored according to geographic location, and (B) is colored according to SCCmec element type within the isolate. Mol Ecol 2016 Jan;25(1):42-66
I was pleased to contribute, as a co-first-author, to a review on how population genetic tools are currently being applied to the study of drug resistance evolution, which was published in 2016 in the journal Molecular Ecology. This work sought to bridge the gap between population geneticists and infectious disease biologists, providing a primer on both research areas while suggesting some exciting possibilities for next steps in the field.
The primary chapter I contributed to focused on the methicillin-resistant Staphylococcus aureus (MRSA) bacteria, describing how population structure analyses of core and accessory genomes have allowed insights into the evolution of drug resistance.
S. aureus reproduces clonally, yet drug resistance is often acquired via the spread of mobile genetic elements (or horizontal gene transfer), such as the gene cassette SCCmec that confers methicillin resistance. While the genealogy of the core genome of MRSA reveals that relatively few lineages have spread across the globe, phylogenetic analysis of SCCmec reveals that methicillin resistance arises on a more local scale. As can be seen in the Figure to the left, while different SCCmec types are present across the globe, the acquisition events tend to occur at the tips of the tree, suggesting that methicillin resistance evolves within a local S. aureus strain as opposed to occurring once and then disseminating globally.
Staff Research Associate in the lab of Zac Cande
Before beginning my graduate work at Stanford University, I worked in the lab of Zac Cande for two years (2008-2010) as a Research Associate at the University of California, Berkeley. During this time I was a second-author on three different projects which probed for evolutionary conserved cytoskeletal and nuclear dynamics in the basal eukaryotes Giardia intestinalis and Naegleria gruberi.
Figure 4 from our paper (Paredez et. al. 2011 PNAS), showing that when Giardia actin (GiActin) is knocked down (KD) using morpholinos, cytoskeletal functions like cell shape, polarity, and cytoskinesis are all compromised. Arrowheads indicate unbundled caudal flagella, arrows indicate failed cytokinesis. PNAS 2011 Apr 12;108(15):6151-6156
I was second-author on a paper published in PNAS in 2011 that described the structure and function of the actin cytoskeleton in the parasite Giardia lamblia, finding that the actin cytoskeleton had evolutionarily conserved functions, despite lacking canonical actin-binding proteins. This work was done with the mentorship of Alex Paredez, now at University of Washington with his own lab.
I also contributed as a second-author to work published in the Journal of Cell Science in 2012, which investigated how Giardia lamblia, thought to lack meiosis, achieves low heterozygosity between its two diploid nuclei. We showed that G. lamblia is able to exchange chromosomal material via nuclear fusion, which occurs simultaneously with encystation and the expression of several meiotic gene homologs. This suggests that new allelic combinations may be generated via homologous recombination in the absence of meiosis.
The last work I contributed in the Cande Lab was a second-author paper published in Eukaryotic Cell in 2010 that used Naegleria gruberi to characterize the assembly of basal bodies, which are microtubule-organizing centers (MTOC). The organism N. gruberi is cool because it can exist as either an amoeba (lacking a cytoskeleton) or a flagellate (containing a cystoskeleton). When it rapidly differentiates into a flagellate it must generate a cytoskeleton de novo, and in this work we showed that basal body assembly occurs via stepwise incorporation of conserved proteins, indicating that the mechanism and structure of MTOC assembly is conserved throughout eukaryotic evolution.
Undergraduate Research in the lab of Abby Dernburg
During my undergraduate career at UC Berkeley I also worked in the lab of Abby Dernburg for one year (2007). During that time I co-authored a paper published in Developmental Cell in 2011 which described the role of plk-2 in orchestrating chromosome dynamics during meiosis in the nematode C. elegans.
Zoe June Assaf, PhD 