The lingering effects of Neanderthal introgression on human complex traits

Area of Science:

• Human Genetics
• Evolutionary Biology
• Population Genetics

Background:

• Genetic variants from Neanderthal interbreeding influence modern human complex traits.
• Studying these introgressed variants is challenging due to unique population genetic properties.
• Previous research suggested elevated heritability of traits influenced by Neanderthal DNA.

Purpose of the Study:

• To rigorously assess the contribution of introgressed Neanderthal variants to heritable trait variation.
• To analyze the impact of Neanderthal variants on a wide range of human phenotypes.
• To identify specific genetic regions where Neanderthal variants likely affect traits.

Main Methods:

• Developed novel methods to analyze introgressed Neanderthal variants and their contribution to trait variation.
• Applied these methods to 235,592 Neanderthal variants and 96 phenotypes in UK Biobank data (approx. 300,000 individuals).
• Utilized customized fine-mapping to pinpoint regions with likely phenotypic effects from introgressed variants.

Main Results:

• Introgressed Neanderthal variants contribute significantly to trait variation (0.12% on average).
• These variants show a 59% depletion compared to modern human variants, indicating purifying selection.
• Identified 112 regions with 4303 variants where introgressed variants likely affect phenotypes, impacting immune, developmental, and metabolic genes.

Conclusions:

• Neanderthal introgressed variants significantly contribute to human trait variation, particularly in immune, developmental, and metabolic pathways.
• Purifying selection appears to reduce the overall impact of these variants compared to modern human variants.
• Fine-mapping identified specific regions where Neanderthal variants exert a substantial phenotypic effect, refining our understanding of their functional role.