Khoe-San harbor most divergent lineages in Homo sapiens. Khoe-San genomes show 25% unique variants absent elsewhere. Khoe-San exhibit highest heterozygosity and allelic diversity globally. After masking recent admixture, Khoe-San diversity still exceeds other Africans. Deepest split separates Khoe-San from other Africans and non-Africans at 200-300ka. Ju|'hoansi show least admixture and oldest divergence at 270ka. All Khoe-San groups received 10-30% eastern African-Eurasian admixture 1500 years ago. All human groups including Khoe-San suffered Ne reduction to 1/3-1/10 around 100-20ka coinciding with paleoclimate shifts. Non-Africans hit lowest Ne of 2000 during Out-of-Africa. Khoe-San private alleles shared only among themselves outnumber those in other groups. PCA separates Khoe-San distinctly from other Africans and non-Africans. Selection signals >300ka target brain genes like LPHN3 linked to neuron connectivity and ADHD. Early selection also hits immunity, sperm motility, skull morphology genes. Local Khoe-San selection enriches immune genes including MHC against endemic diseases like anthrax. Diet genes like FRRS1 for iron absorption selected in northern Khoe-San. Muscle genes like DTNB, SNTB1 under selection in Khoe-San. Khoe-San retain functional CASP12 at 48% vs 5% globally aiding inflammation control. Khoe-San carry functional FMO2 at 60% vs near fixation of loss elsewhere risking toxicity.