The molecular basis of increased hemoglobin in Andean Aymara highlanders is unknown. We conducted an integrative analysis of whole-genome-sequencing and granulocytes transcriptomics from Aymara and Europeans in Bolivia to explore genetic basis of the Aymara high hemoglobin. Differentially expressed and spliced genes in Aymaras were associated with inflammatory and hypoxia-related pathways. We identified transcripts with 4th or 5th exon skipping of NFKB1 (AS-NFKB1), key part of NF-kB complex, and their splicing quantitative trait loci; these were increased in Aymaras. AS-NFKB1 transcripts correlated with both transcripts and protein levels of inflammatory and HIF-regulated genes, including hemoglobin. While overexpression of the AS-NFKB1 variant led to increased expression of inflammatory and HIF-targeted genes; under inflammatory stress, NF-kB protein translocation to the nucleus was attenuated, resulting in reduced expression of these genes. Our study reveals AS-NFKB1 splicing events correlating with increased hemoglobin in Aymara and their possible protective mechanisms against excessive inflammation.

Cell Biology Unit School of Medicine San Andres University National Academy of Sciences La Paz Bolivia

College of Veterinary Medicine and Research Institute for Veterinary Science Seoul National University Seoul Republic of Korea

Department of Biomedical Informatics School of Medicine University of Utah Salt Lake City UT USA

Department of Cell and Developmental Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Psychiatry School of Medicine University of Utah Salt Lake City UT USA

Division of Hematology and Hematologic Malignancies Huntsman Cancer Institute University of Utah and VA Hospital Salt Lake City UT USA

Verily Life Sciences South San Francisco CA USA

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