Investigating the Temporal and Geographic Distribution of JAK-STAT Missense Variants Using Ancient Genomic Data

Hang Nguyen

Mentor: Dr. Markus Hoffmann, Biomedical Graduate Education, Georgetown University Medical Center.

Date/Time: August 25th, 2026 at 3:30 PM.

Abstract: The Janus kinase (JAK), signal transducer and activator of transcription (STAT) pathway is an evolutionarily conserved signaling pathway that allows communication of extracellular signals to the nucleus. It has an important role in cell signaling, gene expression regulation and is involved in multiple cellular functions like immune response, growth, and development. Therefore, mutations in this pathway can be pathogenic and a risk factor for cancers. Given the evolutionary conservation of the JAK-STAT pathway, this study sought to explore the temporal and geographic distribution of missense variants associated with the pathway using ancient genome data to provide insight into their evolutionary history.

In this project, we performed analyses using ancient genome datasets from David Reich Lab. The datasets were derived from 31 different studies and included 4695 samples representing 19 geographical subregions, with samples dating from the Upper Paleolithic period, approximately 31,000 BCE to the 20th century. Programs including convertf, PLINK, and bcftools were utilized to manage the format of ancient genome datasets and perform data harmonization across datasets. Variants were annotated using the command-line version of the Ensembl Variant Effect Predictor (VEP). Using in-house-generated Python scripts, we analyzed allele frequencies and visualized the temporal and geographical distribution of missense variants in genes from the JAK-STAT pathway, such as STAT1, STAT3, JAK3, TYK2, STAT5B, AND STAT6.

Notable missense variants that the Python scripts detected from the dataset are rs3213409 in JAK3, and rs34536443, rs12720356, and rs2304256 in TYK2. The JAK3 missense variant rs3213409 is classified as benign in dbSNP but some studies have reported associations between this variant to several cancer types, including acute lymphoblastic leukemia. High alternate allele frequencies of this variant were detected in ancient samples dating as far as approximately 6000 BCE in subregions such as Southern Asia, South America, and Western Europe. The TYK2 missense variants rs34536443, rs12720356, and rs2304256 are also classified as benign in dbSNP. Similar to the JAK3 missense variant, high alternate allele frequencies of these TYK2 variants were observed in samples dating as far back as approximately 10,000 BCE in regions such as Southern Asia and Western Asia. In later time periods, high alternate allele frequencies of these variants were also observed in several European subregions like Western Europe and Southern Europe.

By characterizing the distribution of important missense variants, the analysis offers new insights into the evolution and distribution of those missense variants over time and across different geographical regions. These findings could advance our understanding of migration patterns, genetic adaptation, immune evolution, and explain population differences.