Are you bravely deciding to do a postdoc in the US? And also interested in some combination of genomics, immunology, and transposons? If so, consider applying to my lab at the BioFrontiers Institute in Boulder, Colorado!

jobs.colorado.edu/jobs/JobDeta...

🧪🧬 #TESky #interferosky

All the credit for this discovery goes to postdoc @giuliapasquesi.bsky.social , who first noticed the isoform in her 2020 Lockdown Sideproject (tm). Her perseverance, creativity, and talent made this study possible and it was an honor to be a part of it. Watch out for her--she's on the job market! 😉

Beyond IFNAR2, our findings suggest that TE exonization may be a widespread yet hidden source of decoy isoforms that regulate immune signaling.

Our study shows how TE exonization gave rise to a primate-specific IFN decoy receptor, which acts as a dial to turn down IFN signaling in human cells. While IFN decoy receptors have evolved repeatedly in viruses (eg VACV B18), this is the first host-encoded IFN decoy receptor.

We also found that risk variants linked to severe COVID-19 in the IFNAR2 locus almost perfectly coincided with splicing QTLs associated with higher relative expression of the decoy. This suggests that variation in IFNAR2 splicing partly underlies individual variation in response to infection.

Giulia tested this by using CRISPR to dissect out each isoform in human cells, and did a battery of IFN assays. Whenever the short isoform was removed, cells showed more potent IFN responses, including immune gene activation, cytotoxicity, and antiviral effect against DENV-2 & SARS-CoV-2!

Giulia was surprised to see that the short isoform was ubiquitously expressed, often at >2x levels of the canonical isoform! Expression was conserved in other primates, and the protein was also detectable by mass-spec, suggesting that this isoform evolved an important immune function.

One caught her eye: a short isoform of the IFN receptor IFNAR2 formed by an exonized Alu. This isoform was first discovered over 20 yrs ago (Pfeffer et al 1997), yet has since been forgotten in the literature, presumably assumed to be silent in human cells.

Most introns are littered with TEs, which can become “exonized” and create cryptic isoform variants. Yet while thousands of exonization events have been detected, only a handful have been studied in detail, with most variants assumed to deleterious or nonfunctional.

Hi, I'm Ed 👋!
I'm an Assistant Professor at CU Boulder, where I study how transposons influence immune function and evolution. Posts on science, DEI, and pics including my dog and the blue skies of the American southwest

#AcademicSky #evosky