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. Author manuscript; available in PMC: 2019 Jun 21.
Published in final edited form as: Sci Immunol. 2018 Dec 21;3(30):eaau6759. doi: 10.1126/sciimmunol.aau6759

Figure 2: IL12RB2 and IL23R are evolving under weak purifying selection, and homozygous complete loss-of-function mutations of these genes occur rarely in the general population.

Figure 2:

A,B) Graphic representation of all genes of the human genome according to the log10 of their (A) neutrality index (NI) or (B) gene damage index (GDI, (31)). IL12RB2 (blue), IL23R (red), and IL12RB1 (grey) are each indicated by a dashed vertical line. C, D) All homozygous variations found in gnomAD for IL12RB2 (C) and IL23R (D) are plotted according to their CADD score (y-axis) and minor allele frequency (MAF, x-axis). The dashed line indicates the mutation significance cutoff (MSC, (26)) for each gene. E) LCL- BSTAT4 cells were left non-transduced (NT), or were transduced with retroviruses generated with an empty vector (EV) or vectors containing V5-tagged WT or mutant versions of IL12RB2, including the 16 mutations indicated. These IL12RB2 mutations are present in at least one individual in the gnomAD database. Cells were left unstimulated, or were stimulated with IL-12 or IFN-α. Cell lysates were prepared, and western blotting was performed with antibodies against pSTAT4, total STAT4, and GAPDH. F) LCL-BSTAT4 cells were left non-transduced (NT), or were transduced with retroviruses generated with an empty vector (EV) or vectors containing V5-tagged WT or mutant versions of IL23R, for the 14 mutations indicated. With the exception of the C115Y mutation found in kindred B, these IL23R mutations are each present in at least one individual in the gnomAD database. Cells were left unstimulated, or were stimulated with IL-23 or IFN-α. Cell lysates were prepared, and western blotting was performed with antibodies against pSTAT3, total STAT3, and GAPDH.