Fruit flies and forestalling famine: 2024 Comp Bio Seniors win Dean of the College awards

By Aspen Stuart-Cunningham

Two computational biology senior concentrators, Madeleine Pittigher and Smriti Vaidyanathan, are receiving awards from the Dean of the College for outstanding graduating seniors in the Computational Biology concentration.

One day in early May, Maddie Pittigher and Smriti Vaidyanathan, both graduating seniors in the Computational Biology concentration, received an email.

“I just got an email one day, telling me I was nominated for my dedication to my research and my performance in the Comp Bio Concentration,” says Maddie Pittigher. “I didn’t realize there were awards for that. I texted my parents right away.”

The Dean of the College Awards that Pittigher and Vaidyanathan are receiving honor graduating seniors who have shown great commitment to their undergraduate research. “It’s a nice recognition of all the work I’ve done,” Smriti Vaidyanathan says.

Both students recently completed Undergraduate Honor Theses on their computational biology research and were nominated for this award by their research advisors.

“I encourage everyone who is interested in research to do an Honors Thesis,” says Vaidyanathan, whose thesis is the culmination of three years of research in Erica Larschan’s lab. “I felt like I was tying together everything I learned throughout my degree, applying concepts from older classes and creating a complete narrative of my research journey. It was difficult, but it was very satisfying.

Maddie Pittigher in greenhouse — Maddie Pittigher with her research plants in the Brown greenhouse.

Smriti Vaidyanathan TAGC — Smriti Vaidyanathan with the other undergrads in the Larschan Lab at The Allied Genetics Conference.

Fruit flies and forestalling famine

Vaidyanathan’s research has focused on analyzing the interactions of a specific transcription factor involved in sex-specific splicing in fruit flies. “Generally, we want to find out how gene regulation manifests differently between different sexes, and what mechanisms are responsible for that difference,” says Vaidyanathan.

This work is important for better understanding diseases that manifest differently between sexes, like ALS or Alzheimer’s. “If we understand the gene regulation mechanisms between sexes better, we can treat the diseases better,” says Vaidyanathan.

Her research has revealed that the Prion-Like Domain, a specific domain within the transcription factor CLAMP, plays an important role in sex-specific splicing regulation. Vaidyanathan hopes that her research will “pave the way for future advancements in this area of study.”

Pittigher’s work in Mark Johnson’s lab focuses on the genes that relate to temperature sensitivity in plants, specifically the thale cress, a small plant in the mustard family. Her research aims to identify genes and pathways that contribute to extreme-temperature tolerance in plants. With climate change creating extreme temperatures and affecting crop production, identifying and controlling the genes that regulate temperature sensitivity will be very important to preserving food production and avoiding famine, her research abstract explains.

“It’s super exciting to be getting results that can have such a positive impact,” Pittigher says. “When I started this research, I didn’t know if I was really into plants,” she laughs, “but I realized that this is super cool and the outcome is really important.”

On to the next

Pittigher and Vaidyanathan will be continuing their education next year in PhD and Master’s programs, respectively. Starting in the fall, Pittigher will pursue a PhD in Computational Biology at UC San Diego, and Vaidyanathan will pursue her Master’s in Computer Science at Columbia.

“I’m looking forward to trying different types of projects and continuing doing biology research,” Pittigher says. “I’m also super excited about the change in the weather!”

Vaidyanathan will be turning to Computer Science for the time being, but she still has a strong commitment to biology. “This Master’s is more just expanding my computational toolkit,” she says. “I want to continue with research after Brown, probably at the intersection of CS and Bio–I’m really interested in understanding the origins of life. We’ll see what happens!”

Congratulations to Maddie Pittigher and Smriti Vaidyanathan for their receipt of the Dean of the College Award. We commend you for your hard work throughout your undergraduate career. We can’t wait to see what you will accomplish in the future.

See below for Pittigher’s and Vaidyanathan’s research abstracts.

Senior Thesis Research Abstracts

Maddie Pittigher Headshot

Maddie was in Mark Johnson's lab (MCB) and will be attending the Computational Biology PhD program at UC San Diego this fall.

Research Abstract

Rising temperatures have been found to limit crop productivity. This crop productivity relies on plant reproduction, in which the pollen tube growth phase plays a critical role. During this phase pollen grains germinate and elongate as tubes inside the pistil to fertilize ovules after pollination. The number of seeds and fruit biomass are directly proportional to the number of successful fertilizations. Extreme temperatures limit the ability of pollen to extend and fertilize ovules during this process, which limits crop productivity in plant varieties known as thermosensitive. Other varieties can continue to produce seeds and fruits at high temperatures known as thermotolerant. Thermotolerant varieties can be used to improve thermosensitive varieties at the genome level if we can discover genes and pathways that contribute to thermotolerance in high temperature improved varieties and activate only these pathways in thermosensitive varieties when they are needed.

To identify loci related to thermotolerance in certain varieties of Arabidopsis thaliana we used haploid selection mapping (HSM). HSM begins with a hybrid plant between a thermotolerant and thermosensitive variety. Each hybrid pollen grain, which is developed under optimal conditions, has a unique combination of thermotolerant and thermosensitive loci in its haploid genome. This pollen is then exposed to high temperatures during the pollen tube growth phase so only those that carry key thermotolerant genes will be able to fertilize ovules and create seeds. By sequencing a large pool of these progeny and deriving genomic markers from public data to calculate parental allele frequencies, we can identify loci that are selected for under high temperatures.

As part of this process, I identified genomic markers from public sequencing datasets using several computational tools. These markers were used to count parental allele frequencies in progeny developed from Columbia-0 and Hilversum-0 hybrid pollinations on Landsberg-ms1 pistils exposed to hot and cold temperatures during the pollen tube growth phase and fertilization. The allele frequencies were used to map regions of selection in the Arabidopsis genome. This mapping identifies potential loci that can be used to improve crop plants at the genome level without changing other traits that make them valuable crops. This will preserve our food production and avoid global famine that global warming may be leading us towards.

Smriti Vaidyanathan

Smriti was in Erica Larschan's lab (MCB, CCMB) and will be pursuing a MS in Computer Science at Columbia next year.

Research Abstract

Understanding sex-biased gene regulation, mainly focusing on alternative splicing, has broad implications for understanding sex biases in human diseases. Through the lens of Drosophila melanogaster, I explore the further role of CLAMP, a pivotal transcription factor involved in the regulation of sex-specific alternative splicing. CLAMP interacts with various RNA Binding Proteins (RBPs), notably Hrp38, a homolog of the human HNRNP1 (hnRNP family protein), which is crucial for alternative splicing and implicated in neurodegenerative disorders. Moreover, both CLAMP and Hrp38 possess Prion-Like Domains (PrLDs), enabling them to undergo phase separation and form nuclear condensates within Drosophila nuclei. These condensates exhibit mobile behavior and are central to this investigation. Specifically, this study focuses on the sex-specific interactions between CLAMP's PrLD and Hrp38 nuclear phase condensates, employing computational methods to unravel the intricate molecular processes underlying sex-specific splicing.

Using live-imaged videos captured via fluorescence microscopy, I quantify the dynamic behavior of Hrp38 nuclear condensates in both CLAMP Wild-Type and delPrLD backgrounds. This quantification is facilitated by an image-processing Fiji macro script and the MATLAB-based particle-tracking software developed by the Gebhardt Lab, TrackIt. Additionally, employing 3D z-stacks of in vivo fixed samples of larval tissue and fluorescently tagged samples, alongside 3D z-stacks of in vitro samples of purified Hrp38 with either CLAMP Wild-Type or delPrLD present in solution, I assess the 3D volumes of Hrp38 coordinates using a Python script that I developed.

My findings reveal sex-specific behaviors in Hrp38 dynamics, including an increase in the bound fraction of Hrp38 in female controls compared to males, a difference erased by the deletion of the CLAMP PrLD domain. Additionally, I observe other potential sex-specific differences, such as in particle speed and female condensates showing a higher median size in vivo than in males. Contrasting results emerge between in vivo and in vitro samples in CLAMP delPrLD backgrounds, highlighting the significant role of this domain in modulating Hrp38 condensate dynamics and implying more complex mechanisms at work. Finally, I propose a feedforward neural network (FNN) to automate image processing and thresholding for various samples, offering the potential for further research in this intriguing field. In conclusion, this thesis comprehensively explores the intricate mechanisms underlying sex-specific gene regulation and alternative splicing dynamics, paving the way for future advancements in this area of study.