Demographic history and selection at HLA loci in Native Americans

Area of Science:

• Population Genetics
• Human Evolutionary Studies
• Immunogenetics

Background:

• The American continent was the last to be populated by modern humans.
• Native American populations exhibit genetic hallmarks of recent demographic events like expansions, bottlenecks, and natural selection.
• The Human Leukocyte Antigen (HLA) loci are critical for immune response and are under strong evolutionary pressure.

Purpose of the Study:

• To investigate how the demographic history of Native American populations has influenced genetic variation at HLA loci.
• To disentangle the relative contributions of demographic processes versus natural selection on HLA variation.
• To understand the unique HLA allele landscape observed in the Americas.

Main Methods:

• Assembled a dataset of 424 Native American individuals.
• Collected genome-wide microsatellite data and typing data for HLA-A, -B, -C, and -DRB1 loci.
• Analyzed genetic variation in relation to demographic history and selection signatures.

Main Results:

• Demographic history accounts for a substantial portion of HLA variation within and among Native American populations.
• Unique HLA alleles, present in the Americas but rare or absent globally, are consistent with demographic changes (bottlenecks and expansions).
• Despite demographic influences, significant signatures of natural selection are detectable at HLA loci across various timescales and populations.

Conclusions:

• Demographic history is a major driver of HLA genetic variation in Native American populations.
• The unique HLA allele composition in the Americas is largely explained by population history.
• Evidence for ongoing and past natural selection at HLA loci persists, alongside demographic effects.