SARS-CoV-2 infects humans through the binding of viral S-protein (spike protein) to human ACE2 (angiotensin I converting enzyme 2). The structure of the ACE2-S-protein complex has been deciphered and we focused on the 27 ACE2 residues that bind to S-protein. From human sequence databases, we identified 9 ACE2 variants at ACE2-S-protein binding sites. We used both experimental assays and protein structure analysis to evaluate the effect of each variant on the binding affinity of ACE2 to S-protein. We found one variant causing complete binding disruption, two and three variants, respectively, strongly and mildly reducing the binding affinity, and two variants strongly enhancing the binding affinity. We then collected the ACE2 gene sequences from 57 non-human primates. Among the six apes and 20 Old World monkeys (OWMs) studied we found no new variants. In contrast, all 11 New World monkeys (NWMs) studied share four variants each causing a strong reduction in binding affinity, the Philippine tarsier also possesses three such variants, and 18 of the 19 prosimian species studied share one variant causing a strong reduction in binding affinity. Moreover, one OWM and three prosimian variants increased binding affinity by > 50%. Based on these findings we proposed that the common ancestor of primates was strongly resistant to and that of NWMs was completely resistant to SARS-CoV-2 and so is the Philippine tarsier, whereas apes and OWMs, like most humans, are susceptible. This study increases our understanding of the differences in susceptibility to SARS-CoV-2 infection among primates.
Transcription factor binding sites (TFBSs) are essential for gene regulation, but the number of known TFBSs remains limited. We aimed to discover and characterize unknown TFBSs by developing a computational pipeline for analyzing ChIP-seq (chromatin immunoprecipitation followed by sequencing) data. Applying it to the latest ENCODE ChIP-seq data for human and mouse, we found that using the irreproducible discovery rate as a quality-control criterion resulted in many experiments being unnecessarily discarded. By contrast, the number of motif occurrences in ChIP-seq peak regions provides a highly effective criterion, which is reliable even if supported by only one experimental replicate. In total, we obtained 2,058 motifs from 1,089 experiments for 354 human TFs and 163 motifs from 101 experiments for 34 mouse TFs. Among these motifs, 487 have not previously been reported. Mapping the canonical motifs to the human genome reveals a high TFBS density ±2 kb around transcription start sites (TSSs) with a peak at −50 bp. On average, a promoter contains 5.7 TFBSs. However, 70% of TFBSs are in introns (41%) and intergenic regions (29%), whereas only 12% are in promoters (−1 kb to +100 bp from TSSs). Notably, some TFs (e.g., CTCF, JUN, JUNB, and NFE2) have motifs enriched in intergenic regions, including enhancers. We inferred 142 cobinding TF pairs and 186 (including 115 completely) tethered binding TF pairs, indicating frequent interactions between TFs and a higher frequency of tethered binding than cobinding. This study provides a large number of previously undocumented motifs and insights into the biological and genomic features of TFBSs.
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