Doctoral Dissertation Research: Cold adaptation and gene expression

Trustees Of Boston University, Boston

Investigators

Abstract

In the past ~450,000 years, members of the genus Homo migrated multiple times from equatorial Africa to more seasonal and cold climates. Non-shivering thermogenesis – a process by which brown fat generates heat – was likely a key part of the success of our genus in adapting to these environments and helping to facilitate these geographic expansions. The product of the gene UCP1, a protein called thermogenin, drives this process. Nonhuman primates have also expanded from Africa into colder latitudes over the past ~300,000 years. Previously, the investigators found signals of selection in the regulation of this gene in some nonhuman primates. In this doctoral dissertation research project, the investigators validate and expand those findings by using innovative methods and previously collected samples. Students from groups underrepresented in STEM disciplines receive training and professional development through this project. Using an established protocol newly validated for specific species, the investigators chemically convert archived wild nonhuman primate fibroblast cell lines into chemically induced brown adipose (ciBA) cells. Outcomes of the conversion are verified by quantifying RNA expression of UCP1 (which is uniquely expressed in brown adipose) via RT-qPCR, with Oil Red O staining and immunofluorescence staining to observe lipid droplet formation and the completeness of culture conversion. The ciBA are then exposed to norepinephrine to stimulate a cold response in the cell lines, and UCP1 gene expression with and without the cold response are compared using bulk RNA sequencing. Results are used to test the prediction of a derived allele dosage effect in UCP1 expression across four loci, such that each derived allele, previously found to have appeared at higher frequencies in colder climates, will be associated with a significant increase in UCP1 expression. Analyses consider potential covariates like sex, BMI, and body weight. Validation of the investigators previous results suggest that the NST system has undergone positive selection in response to colder climates in nonhuman primates and inform our understanding of this process in our own genus. 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.