Research
The importance of newly evolved genes in sperm function
The widespread use of genome sequencing has allowed researchers to identify functionally important genes based on patterns of conservation between species. A typical pattern is that the oldest genes have the most important functions, since these genes have been maintained (sometimes for hundreds of millions of years) by natural selection. However, emerging research has shown that genes that are specific to just a few species or phylogenetic lineages can also become essential for an organism's fitness. Many new genes arise by gene duplication events, while others arise "de novo" from previously non-coding DNA sequences. From whichever evolutionary source, these new genes often become expressed in the testis. Our current research examines the roles of four genes that likely arose de novo and are found only in the genus Drosophila. Despite these genes' young ages, they have evolved essential functions in male reproduction, such that if any one of these genes is perturbed, male flies become sterile.
Research in our lab is integrative across biology: we use techniques from the fields of genetics, genomics, evolutionary biology, cell biology and biochemistry. A typical approach is to first disrupt the expression of a de novo gene through genetic manipulation such as RNA interference or CRISPR/Cas9 genome editing. We then measure the effects of gene loss on fertility through mating assays. If the genetic disruption reduces male fertility, we next perform cell biological phenotypic assays to understand what is going wrong. For example, we can dissect fly testes (they're transparent!) to examine morphology and sperm production; create versions of the target gene that have fluorescent tags that allow us to track where in the cell the encoded protein goes; and use evolutionary and bioinformatic analyses to predict which portions of the protein might be most important for function. Students working in our lab get hands-on experience with many of these techniques and present their findings at lab meetings, departmental and college-wide poster sessions, and national research conferences.
An example: the newly evolved atlas gene is important for packaging sperm DNA
In September 2021, we published a paper in PLOS Genetics that included six of our lab students (and our awesome lab manager) as co-authors. We described a newly evolved gene that we named atlas and detailed its role in packaging the DNA in fly sperm nuclei. Like many animals (including humans), male flies must tightly condense the DNA that sperm transmit to eggs during fertilization. They do this by "handing off" DNA from one type of protein to another to another; with each hand off, the nuclei become more and more condensed. We discovered that the Atlas protein is essential for this DNA "hand off" process. Without the atlas gene (and the protein it encodes), sperm nuclei become misshapen before reaching their final condensed form, and the final steps of sperm production appear to grind to a halt.
Here is the experiment we did to show that Atlas is present in the condensing sperm nuclei. With guidance from our Biology department colleague, Prof. Alexis Hill, we first used CRISPR to create a version of the atlas gene that was fused to the gene encoding the trackable green fluorescent protein (GFP). We then dissected the testes of males that expressed the Atlas-GFP "fusion protein" and imaged them in our department's confocal microscope. We stained the testes with a dye (shown as blue below) that labels DNA, which allowed us to visualize the condensation steps. We could then observe when Atlas appeared and disappeared:
The top row shows nuclei that are in the process of condensing. They don't look like the round nuclei you typically see in textbook pictures! But they also aren't fully condensed yet. There is no green protein present, showing that Atlas is not yet on the scene.
In the second row, you can see the nuclei becoming more condensed (narrower), and at the left, you now see Atlas-GFP's arrival. We discovered that Atlas is only present in the nuclei for a narrow window of time.
In the third row, the nuclei have become even more thin and needle-like. And Atlas's job appears to be done -- Atlas-GFP can now be seen leaving the nuclei (it's getting pushed down the sperm tails and won't ultimately be found in mature sperm). It's amazing how a protein that is present for such a short time in such a specific process can nonetheless have a huge impact on male fertility! It's also remarkable that some fly species don't have the atlas gene at all, and yet they still accomplish this process.
We are currently researching questions like: How long ago did atlas take on this essential role? Which specific parts of the Atlas protein are the most critical for its function? And, how do testes cells "decide" when to produce the Atlas protein?
Research opportunities for Holy Cross students:
We strive to make the lab a welcoming environment for students of diverse backgrounds and interests! No specific training is required to work in the lab, and students have started research with us in each of the four years of their Holy Cross careers. I meet each week with every student in the lab to plan experiments, discuss results, and provide mentoring about potential careers. We also meet every week or two as a whole lab to discuss relevant scientific papers and to hear about each other's research. When someone from the lab is preparing to give a poster or a talk, we meet additionally to support the student and offer constructive feedback and encouragement. I try to craft student projects in consultation with students, taking into account their specific interests and goals. My general philosophy is to design projects that use similar techniques, so students can seek out help and advice from each other, but to give each student their own research question so that they can develop intellectual independence. Over 35 students have worked in the lab to date, and lab alumni have gone on to a wide range of exciting careers, including graduate school, lab research, medical school and other health professions programs, and the biotech industry.
If our research topics and lab community sound interesting to you, I encourage you to contact me to learn more about working in the lab! The lab is currently full, but we expect to have some openings in the 2024-25 academic year and for summer research in 2025. If you would like to discuss future research possibilities, or to talk more generally about finding research opportunities in the Biology department or off campus, I would be happy to meet with you. Please just send me an email.
FAQs about joining the lab and finding a research home
Do I have to wait until I'm an upper-class student to do research?
No! We very much welcome interest from younger students who have taken (and hopefully enjoyed!) Biology 161 and/or 162.
What Biology classes do I need to have taken in order to do research?
Some experience with our introductory sequence is necessary for 1st and 2nd year students, but we also know that students in their first two years are often busy with fulfilling distribution and major requirements. Thus, it is okay if you don't come into the lab with very many Bio classes under your belt. For 3rd and 4th year students, it is expected that you take Genetics (preferably with lab) as soon as possible. Other classes that are helpful to take at some point include: Cell Biology (preferably with lab), Biochemistry (preferably with lab), Evolution, Applied Evolution and/or Biostatistics.
Do I need to be a Biology major to do research?
Because we have limited space in our department's research labs, we sometimes give preference to Biology majors. We also find that students understand their projects in greater depth as they take additional upper-level Biology courses. However, because of the nature of some of our projects, I would also be happy to speak with students with an interest in statistics, computer science or biophysics. If you are concentrating in Biochemistry or minoring in Neuroscience, we could certainly speak about project ideas that might be relevant to one of those areas.
Do I have to be interested in graduate school to do research?
No! Certainly it is important for students who may want to pursue a PhD or masters to gain research experience, but our lab welcomes students with a range of career goals -- including graduate school, medical school, the biotech industry, and genetic counseling -- and those students still trying to figure out what they might wish to do after graduation. When possible, we try to tailor students' projects to the kind of work they wish to do after Holy Cross.
How can I participate in the Summer Research Program?
Holy Cross runs an excellent, full-time summer research program (SRP), and we have had consistently great summer students! While the SRP is advertised by the college to students at the start of the Spring Semester, it is typical in the Biology department for top priority for the SRP to go to students who are already working in a lab the preceding semester and who plan to continue working in the lab the following year. Thus, the time to think about the SRP is in the early- to mid-fall semester before the summer you would like to participate.