Unique Loss of the PYHIN Gene Family in Bats Amongst Mammals: Implications for Inflammasome Sensing

Abstract

Recent genomic analysis of two bat species (Pteropus alecto and Myotis davidii) revealed the absence of the PYHIN gene family. This family is recognized as important immune sensors of intracellular self and foreign DNA and activators of the inflammasome and/or interferon pathways. Further assessment of a wider range of bat genomes was necessary to determine if this is a universal pattern for this large mammalian group. Here we expanded genomic analysis of this gene family to include ten bat species. We confirmed the complete loss of this gene family, with only a truncated AIM2 remaining in one species (Pteronotus parnellii). Divergence of the PYHIN gene loci between the bat lineages infers different loss-of-function histories during bat evolution. While all other major groups of placental mammals have at least one gene member, only bats have lost the entire family. This removal of inflammasome DNA sensors may indicate an important adaptation that is flight-induced and related, at least in part, to pathogen-host co-existence.

Figure 1. Evolution of the partial bat AIM2 and the PYHIN PYRIN domains.

(a) Nucleotide sequence alignment comparing the partial AIM2 identified in the Parnell’s mustached bat genome to the PYRIN domain of human AIM2. A frameshift mutation due to a four-base-pair deletion and several premature stop codons (asterisks) indicate the loss of the PYRIN domain function in the bat. Identical nucleotides are highlighted in dark blue and deleterious mutations are shown in red boxes. Human AIM2 protein sequence positions were labeled above the alignment. (b) Phylogenetic tree of PYRIN domains from PYHIN proteins across mammalian groups. The bat PYRIN sequence is highlighted in red. The tree was rooted with marsupial sequences. Dotted boxes indicate the three distinct clades containing marsupial PYRIN, AIM2 PYRIN and non-AIM2 PYRIN respectively. Bootstrap values below 50% are not shown and branch lengths are drawn to a scale of amino acid substitutions per site.

Figure 2. The PYHIN locus in bats and selected mammals.

(a) Genomic characterization of the PYHIN locus in bats and selected mammalian species. The common boundaries of the PYHIN locus are defined by the SPTA1 gene (blue) and the CADM3 gene (green) at the two ends. Big red arrows represent the members of the PYHIN gene family. PYHIN genes from horse or dog are arbitrarily named. Short diagonal lines indicate gaps in the two bats of Yinpterochiroptera that are bridged by each other’s scaffolds. Vertical lines in M. brandtii indicate an inter-scaffold gap. Other bat loci lie on a single scaffold. Olfactory receptor (OR) genes or pseudogenes (light blue) are also found to cluster at one end of the locus. ORs are labeled according to their family and subfamily using the HORDE system. OR6K6 homolog in black was identified across all the loci presented here. A scale bar is presented below the figure. (b,c) Pairwise sequence comparisons of the PYHIN locus between horse and E. fuscus or P. alecto as revealed by dot-plot analysis. On the X-axis is the horse PYHIN locus and on the y-axis is the locus of E. fuscus (b) or P. alecto (c) on the kilobase (kb) scale. The OR6K6 site and the region spanning the PYHIN gene cluster are indicated.