Comparing the selective landscape of TLR7 and TLR8 across primates reveals unique sites under positive selection inAlouatta

Abstract

Among primates, susceptibility to yellow fever (YFV), a single-stranded (ss) RNA virus, ranges from complete resistance to high susceptibility. Howler monkeys (genus Alouatta) are the most susceptible to YFV. In order to identify Alouatta-specific genetic factors that may be responsible for their susceptibility, we collected skin samples from howler monkey museum specimens of the species A. caraya and A. guariba clamitans. We compared the rate of nonsynonymous to synonymous (dN/dS) changes of Toll-like receptor (TLR) 7 and TLR8, the two genes responsible for detecting all ssRNA viruses, across the Primate order. Overall, we found that the TLR7 gene is under stronger purifying selection in howler monkeys compared to other New World and Old World primates, but TLR8 is under the same selective pressure. When we evaluated dN/dS at each codon, we found six codons under positive selection in Alouatta TLR8 and two codons under positive selection in TLR7. The changes in TLR7 are unique to A. guariba clamitans and are found in functionally important regions likely to affect detection of ssRNA viruses by TLR7/TLR8, as well as downstream signaling. These amino acid differences in A. guariba clamitans may play a role in YFV susceptibility. These results have implications for identifying genetic factors affecting YFV susceptibility in primates.

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“…Sample extraction and sequencing for samples AC_t1 and AGC_m1 (see Table ) were previously described (Torosin, Argibay, et al, 2020a; Torosin, Webster, et al, 2020b). Details on genomic sequence generation for the remaining samples are provided in Kuderna et al (2022).…”

“…Samples consisted of muscle tissue preserved in 70%–90% ethanol. The acquisition of samples for Alouatta caraya and Alouatta guariba clamitans from Argentina has been previously described (Torosin, Argibay, et al, 2020; Torosin, Webster, et al, 2020). Samples from Alouatta palliata , Ateles geoffroyi , Saimiri oerstedii , and Saguinus geoffroyi were biobanked at Kids Saving the Rainforest (KSTR), a wildlife rehabilitation facility in Quepos, Costa Rica in 2016–2017.…”

Positively selected variants in functionally important regions ofTLR7inAlouatta guariba clamitanswith yellow fever virus exposure in Northern Argentina

“…Despite a lack of polymorphism within species, we identified nonsynonymous differences between species. Of the three nonsynonymous substitutions we identified in TLR7 of A. guariba clamitans, we found evidence that two are under positive selection (TLR7 codons 538 and 721) (Torosin et al, 2019) (Table 5). These two variants were identified in all A. guariba clamitans in this study and are unique to the species.…”

“…Two of these sites cause a biochemical property difference in the amino acid sequence. Both of these sites have been found to be positively selected (Torosin et al, 2019) (Table 5). Four nucleotide variants in A. guariba clamitans result in a synonymous change (Table S6).…”

“…Previous work found positively selected genetic variants within Toll-like receptor (TLR) 7 and TLR8 in A. guariba clamitans and A. caraya that are unique to one or both species compared to Old and other New World primates (Torosin, Argibay, Webster, Corneli, & Knapp, 2019). Polymorphisms in TLR7 and TLR8 have been implicated in progression of other diseases, making these two genes strong candidates to study genetic variation that affects susceptibility to YFV (Mandl et al, 2011;Kawai & Akira, 2010;Cook, Pisetsky, & Schwartz, 2004).…”