genetic_drift

I used the genome-scale CD4+ T-cell Perturb-seq atlas from Marson/Pritchard labs as an empirical genotype-phenotype map to ask how the architecture of the T-cell gene regulatory network shaped which Neanderthal variants survived in modern humans. Introgression frequencies came from the Li et al. 2024 IBDmix map across 1000 Genomes populations. I set out expecting a clean enrichment story, i.e. that strong T-cell regulators would carry excess archaic ancestry, and I got the opposite. After a properly matched null (constraint, gene length, local gene density, and a directly-measured "introgression desert" covariate replacing a gene-density proxy), the regulator effect is indistinguishable from zero at every resolution tested. Network topology metrics were directionally consistent with hub constraint but statistically redundant with the desert, which inverts the usual reading: the desert is not a nuisance confound but the integral of the genotype-phenotype map: the stabilizing-selection imprint of 50,000 years, consistent with theoretical work. Why it matters: it is a worked example of network-conditioned mutation-effect theory tested on real data, and an honest one: several hypotheses (context-dependence, three-way viral convergence, epistatic co-introgression) were tested and did not survive their controls, and the manuscript says so. The negative results constrain the field's expectations, and the 151 leads are a concrete, testable hypothesis set for follow-up.

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