Human genome variability, natural selection and infectious diseases

• Demographic history and natural selection shaped human genome diversity.
• Infections represented a major environmental selective pressure for human populations.
• Evolutionary analysis can identify risk variants for infection susceptibility.
• Selective pressures often target genes that impinge on the same pathway.
• Pathogen-driven selection targets are often accounted for by regulatory variants.

The recent availability of large-scale sequencing DNA data allowed researchers to investigate how genomic variation is distributed among populations. While demographic factors explain genome-wide population genetic diversity levels, scans for signatures of natural selection pinpointed several regions under non-neutral evolution. Recent studies found an enrichment of immune-related genes subjected to natural selection, suggesting that pathogens and infectious diseases have imposed a strong selective pressure throughout human history. Pathogen-mediated selection often targeted regulatory sites of genes belonging to the same biological pathway. Results from these studies have the potential to identify mutations that modulate infection susceptibility by integrating a population genomic approach with molecular immunology data and large-scale functional annotations.

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