Postdoctoral Fellowship: PRFB: Impact of MUC1 repeat copy number variation on glycosylation and function

This action funds an NSF Postdoctoral Research Fellowship in Biology for FY 2025. The fellowship supports research and training of the fellow that will contribute to biology in innovative ways. Mucus serves a critical protective role throughout the human body, forming barriers on organs exposed to external environments such as the lungs, stomach, and reproductive tissues.

This protective function is primarily mediated by specialized proteins known as mucins, characterized by long, repetitive segments extensively covered with sugar molecules essential for their function. Recent advances in DNA sequencing now enable precise investigation of these repeats at the genetic level. This research focuses on mucin-1 (MUC1), a crucial component of the mucus barrier in the uterus.

MUC1 acts as a gatekeeper for pregnancy as successful implantation of a fertilized embryo into the uterine wall requires the reduction of this barrier. The number of repeat segments within the MUC1 gene are known to vary substantially between individuals, influencing the size of the resulting MUC1 protein. However, the impact of this genetic variation on the structure of the attached sugars, the mucus barrier, and pregnancy remains unexplored.

By examining how variations in these repeats affect the structural and functional properties of the MUC1 protein, this project aims to deepen our understanding of complex genetic and protein variations, ultimately shedding new light on human evolution and pregnancy biology. The fellow will mentor students at Yale University, training them in evolutionary genetics and biochemistry techniques.

Additionally, public engagement through science communication events will broaden public understanding of genetics and enhance scientific literacy.

The goal of this project is to elucidate the evolutionary origins, genetic mechanisms, and functional consequences associated with variation in MUC1 exonic variable number tandem repeats (eVNTRs). Utilizing long-read sequencing data from global human populations and multiple primate species, this research will clarify the mutational processes and evolutionary forces driving MUC1 repeat copy number variation.

Functional experiments leveraging advanced biochemical and mass spectrometry approaches will determine how different MUC1 eVNTR alleles influence encoded protein glycosylation and molecular structure, mucus barrier integrity, and cellular adhesion properties important for embryo implantation. Collectively, this integrative approach will reveal how previously hidden genetic variation influences biological function at molecular and cellular levels, while broadly enhancing understanding of pregnancy biology.

The fellow will train undergraduate and graduate students in bioinformatics and mass spectrometry techniques related to the project and will host public seminars to promote broader appreciation of the importance of basic science.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.