About

Frank S. Lee, MD, PhD, is a Professor of Pathology and Laboratory Medicine at the University of Pennsylvania's Perelman School of Medicine. He serves as a Staff Pathologist in the Medical Pathology Section of the Division of Anatomic Pathology within the Department of Pathology and Laboratory Medicine. His research expertise centers on the molecular mechanisms of the hypoxic response, particularly the activation and regulation of Hypoxia Inducible Factor (HIF), a key transcription factor involved in cellular adaptation to low oxygen conditions. Dr. Lee's work investigates how the pathway is regulated by enzymes such as PHD2 and how genetic variations in this pathway contribute to high-altitude adaptation in human populations, including Tibetans and Andeans. His studies employ biochemical, molecular biological, and mouse model approaches to understand the physiologic relevance of these mechanisms, with a focus on implications for pregnancy complications like intrauterine growth restriction and preeclampsia.

Research topics

• Biology
• Genetics

Selected publications

• Rapid adaptive increase of amylase gene copy number in Indigenous Andeans

  Nature Communications · 2026-05-05

  articleOpen access

  The salivary amylase gene AMY1 exhibits remarkable copy number variation linked to dietary shifts in human evolution. While global studies highlight its structural complexity and association with starch-rich diets, localized selection patterns remain underexplored. Here, we analyze AMY1 copy number in 3,723 individuals from 85 populations, revealing that Indigenous Peruvian Andean populations possess the highest AMY1 copy number globally. A genome-wide analysis shows significantly higher amylase copy numbers in Peruvian Andean genomes compared to closely related populations. Further, we identify positive selection (selection coefficient of 0.0124, log likelihood ratio of 11.1543) at the nucleotide level on a haplotype harboring at least five haploid AMY1 copies, with a Peruvian Andean-specific expansion dated to around 10,000 years ago, coinciding with potato domestication in the region. Using ultra-long-read sequencing, we demonstrate that previously described recombination-based mutational mechanisms drive the formation of high-copy AMY1 haplotypes observed in Andean population. Our study provides a framework for investigating structurally complex loci and their role in human dietary adaptation.

  PublisherOA PDFDOI

• Under (Genetic Selection) Pressure: Human Tumors and Human Populations in Hypoxia

  Cancer Discovery · 2025-04-30 · 1 citations

  articleOpen access1st authorCorresponding

  Arenillas and colleagues report that pheochromocytomas and paragangliomas in the setting of chronic hypoxia due to cyanotic congenital heart disease harbor, at high frequency, somatic gain-of-function mutations in the EPAS1 gene, which encodes for one of the oxygen-labile subunits of the hypoxia-inducible factor complex. Interestingly, germline loss-of-function EPAS1 alleles are under natural selection in human populations subjected to a different chronic hypoxia condition, namely, high altitude. See related article by Arenillas et al., p. 1037.

  PublisherOA PDFDOI

• Rapid Adaptive Increase of Amylase Gene Copy Number in Indigenous Andeans

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-29 · 5 citations

  preprintOpen access

  The salivary amylase gene (AMY1) exhibits remarkable copy number variation linked to dietary shifts in human evolution. While global studies highlight its structural complexity and association with starch-rich diets, localized selection patterns remain under explored. Here, we analyzed AMY1 copy number in 3,723 individuals from 85 populations, revealing that Indigenous Peruvian Andean populations possess the highest AMY1 copy number globally. A genome-wide analysis showed significantly higher amylase copy numbers in Peruvian Andean genomes compared to closely related populations. Further, we identified positive selection (selection coefficient of 0.0124, log likelihood ratio of 11.1543) at the nucleotide level on a haplotype harboring at least five haploid AMY1 copies, with a Peruvian Andean-specific expansion coinciding with potato domestication (~6-10 kya). Using ultra-long-read sequencing, we demonstrated that previously-described recombination-based mutational mechanisms drive the formation of high-copy AMY1 haplotypes observed in Andean population. Our study provides a framework for investigating structurally complex loci and their role in human dietary adaptation.

  PublisherOA PDFDOI

• The effect of perioperative erythropoietin‐stimulating agents and intravenous iron on patient outcomes following solid organ transplantation: A systematic review

  Transfusion Medicine · 2025-12-10

  reviewOpen access1st author

  Solid organ transplant is associated with high rates of anaemia and transfusion, but there is little comparative data on interventions such as erythropoietin-stimulating agents (ESAs) and intravenous (IV) iron. We conducted a systematic review examining the association of ESAs and IV iron with outcomes in adults undergoing solid organ transplant. This review was registered with PROSPERO (CRD42023474722). EMBASE and MEDLINE were searched from inception to April 11, 2025. Identified studies included adults (≥18 years of age) undergoing heart, liver, lung, or kidney transplant who received any ESA and/or IV iron before, during, or up to 1 month following solid organ transplant surgery compared to patients who did not. Article screening, full text review and data extraction were performed by two independent reviewers. The primary outcome of interest was transfusion volume, with secondary outcomes including haematological parameters, graft-related outcomes and rates of major morbidity and mortality. Results were analysed descriptively and compiled into tables, and the risk of bias was assessed using the CLARITY framework. From 1693 studies identified, 22 were included (kidney transplant, n = 16; heart transplant or Left Ventricular Assist Device as a bridge to transplant, n = 4; liver transplant, n = 2). Due to heterogeneity in design, interventions and outcomes, meta-analysis was not attempted. The quality of evidence was graded as Very Low. On the whole, a comprehensive strategy implementing ESAs and IV iron may improve haematological parameters and facilitate transfusion avoidance. High-quality prospective studies assessing the impact of protocols for haemoglobin optimisation and transfusion avoidance in solid organ transplant are needed.

  PublisherOA PDFDOI

• Adaptive Increase of Amylase Gene Copy Number in Peruvians Driven by Potato-rich Diets

  Research Square · 2025-03-24

  preprintOpen access
  PublisherOA PDFDOI

• Incidental autopsy finding of retiform hemangioendothelioma of the spleen

  Formosan Journal of Surgery · 2024-06-28

  articleOpen access

  Koga, Shunsuke MD, PhD; Tirado, Fernanda DO; Pillai, Vinodh MD, PhD; Lee, Frank S. MD, PhD; Cooper, Kumarasen MD, MBChB, DPhil Author Information

  PublisherDOI

• Hypoxia Inducible Factor pathway proteins in high-altitude mammals

  Trends in Biochemical Sciences · 2023-11-29 · 25 citations

  reviewOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Faculty Opinions recommendation of The transcriptional and regulatory identity of erythropoietin producing cells.

  Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · 2023-05-17

  dataset1st authorCorresponding
  PublisherDOI

• High-Altitude Andean H194R <i>HIF2A</i> Allele Is a Hypomorphic Allele

  Molecular Biology and Evolution · 2023-07-01 · 16 citations

  articleOpen accessSenior author

  For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies have provided evidence for positive selection acting in Andeans on the HIF2A (also known as EPAS1) locus, which encodes for a central transcription factor of the hypoxia-inducible factor pathway. However, the precise mechanism by which this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes, we confirm evidence for positive selection acting on HIF2A and a unique pattern of variation surrounding the Andean-specific single nucleotide variant (SNV), rs570553380, which encodes for an H194R amino acid substitution in HIF-2α. Genotyping the Andean-associated SNV rs570553380 in a group of 299 Peruvian Andeans from Cerro de Pasco, Peru (4,338 m), reveals a positive association with increased fraction of exhaled nitric oxide, a marker of nitric oxide biosynthesis. In vitro assays show that the H194R mutation impairs binding of HIF-2α to its heterodimeric partner, aryl hydrocarbon receptor nuclear translocator. A knockin mouse model bearing the H194R mutation in the Hif2a gene displays decreased levels of hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. We conclude the Andean H194R HIF2A allele is a hypomorphic (partial loss of function) allele.

  PublisherOA PDFDOI

• Faculty Opinions recommendation of Mechanisms governing target search and binding dynamics of hypoxia-inducible factors.

  Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · 2022-12-08

  dataset1st authorCorresponding
  PublisherDOI

Recent grants

• High Altitude Adaptation: A Model for Chronic Hypoxia

  NIH · $1.5M · 2014–2020

• NIH Grant R01DK055672

  NIH · $877k · 2004

• NIH Grant R01GM071459

  NIH · $1.1M · 2011

• Control of Erythropoiesis by the Oxygen Sensor PHD2

  NIH · $1.6M · 2021–2026

• NIH Grant R01GM090301

  NIH · $1.9M · 2014

Frequent coauthors

• A. Poulos

  University of Sydney

  81 shared

• Michael J. Pitt

  81 shared

• Deborah A. Rathjen

  Women's and Children's Hospital

  81 shared

• Neil A. Trout

  81 shared

• Rolf H. Prager

  Flinders University

  81 shared

• Harmeet Singh

  81 shared

• Hubertus Jersmann

  University of Adelaide

  81 shared

• Zhihua Huang

  Second Affiliated Hospital of Inner Mongolia Medical University

  81 shared

Labs

• Pathology and Laboratory MedicinePI

Education

• Ph.D., Biological Chemistry

  Harvard University

  1991

• M.D.

  Harvard Medical School

  1991

• A.B.

  Harvard College

  1983