Search

Although traces of archaic hominin DNA persist in all human populations outside Africa, these traces have been systematically depleted from the most functionally important regions of the human genome. This depletion suggests that many Neanderthal and Denisovan alleles had harmful effects on the fitness of hybrid individuals, but the nature of these harmful effects is poorly understood. Here, we show that Neanderthal and Denisovan alleles likely dysregulated gene expression in specific human tissues, causing systematic depletion of archaic introgression from enhancer regions annotated by the ENCODE RoadMap project. Highly pleiotropic enhancers that show activity in many tissues are more depleted of introgression than tissue-specific enhancers, and Neanderthal depletion is highly correlated with Denisovan depletion across sets of enhancers active in particular tissues. Fetal brain and fetal muscle are the tissues most depleted of archaic SNPs in their regulatory regions, and by analyzing the site frequency spectra of enhancers compared to control regions, we deduce that brain and muscle enhancers are likely depleted of introgression for different reasons. Brain enhancers appear to accumulate deleterious mutations unusually quickly, which may have caused inbred archaic populations to accumulate disproportionately large amounts of genetic load in these regions. In contrast, fetal muscle enhancers show no evidence of high deleterious mutation rates, and we hypothesize that their depletion of archaic DNA resulted from divergent selection for higher muscle mass in Neanderthals and Denisovans compared to humans.

Fluorescent in situ hybridization (FISH) is a powerful method for the targeted visualization of nucleic acids in their native contexts. Recent technological advances have leveraged computationally designed oligonucleotide (oligo) probes to interrogate >100 distinct targets in the same sample, pushing the boundaries of FISH-based assays. However, even in the most highly multiplexed experiments, repetitive DNA regions are typically not included as targets, as the computational design of specific probes against such regions presents significant technical challenges. Consequently, many open questions remain about the organization and function of highly repetitive sequences. Here, we introduce Tigerfish, a software tool for the genome-scale design of oligo probes against repetitive DNA intervals. We showcase Tigerfish by designing a panel of 24 interval-specific repeat probes specific to each of the 24 human chromosomes and imaging this panel on metaphase spreads and in interphase nuclei. Tigerfish extends the powerful toolkit of oligo-based FISH to highly repetitive DNA., Competing Interests: Competing Interest Statement The authors declare no competing interests.The authors declare no competing interests.