Alternatively spliced NFKB1 transcripts enriched in Andean Aymara modulate inflammation, HIF and hemoglobin

Area of Science:

• Genetics
• Human Adaptation
• Molecular Biology

Background:

• High-altitude populations exhibit physiological adaptations, including elevated hemoglobin levels.
• The genetic underpinnings of increased hemoglobin in Andean Aymara highlanders remain largely uncharacterized.

Purpose of the Study:

• To investigate the genetic and molecular basis for elevated hemoglobin concentrations in Aymara highlanders.
• To explore differential gene expression and splicing patterns associated with high hemoglobin in Aymara individuals.

Main Methods:

• Integrative analysis of whole-genome sequencing and granulocyte transcriptomics.
• Comparison between Aymara and European populations in Bolivia.
• Identification and characterization of alternative splicing events, specifically in NFKB1 (nuclear factor kappa B subunit 1).

Main Results:

• Aymaras exhibit differential gene expression and splicing linked to inflammatory and hypoxia pathways.
• Increased prevalence of NFKB1 (nuclear factor kappa B subunit 1) alternative splicing (AS-NFKB1) with 4th or 5th exon skipping in Aymaras.
• AS-NFKB1 transcripts correlated with elevated levels of inflammatory and HIF-regulated genes, including hemoglobin.
• Overexpression of AS-NFKB1 increased inflammatory and HIF-targeted gene expression, but attenuated NF-kB nuclear translocation under inflammatory stress.

Conclusions:

• Alternative splicing of NFKB1 (nuclear factor kappa B subunit 1) is associated with increased hemoglobin in Aymara highlanders.
• This splicing variant may represent a protective mechanism against excessive inflammation in high-altitude environments.