When LUCA met gnomAD: genetic constraints on universal genes in humans.

LUCA, the last universal common ancestor, is the hypothetical most recent common ancestor of the three domains of life which share the universal genes (UG). It seems interesting to evaluate whether the UG phylogeny has had an impact on current Human gene constraints. A list of human homologs of UG was retrieved from the eggNOG database. We analyzed this LUCA gene (LG) group, and a random sample of 500 genes from the gnomAD database (RG group). Gene constraint metrics were retrieved from gnomAD and associations with Mendelian diseases and modes of inheritance were retrieved from OMIM. The LG group consisted of 277 genes and the RG group, 492 (8 genes were in LG group). 38.6% of the genes in the LG group and 25.2% of the genes in the RG group were associated with a Mendelian disease (p < 0.0001). The mode of inheritance was more often autosomal recessive (69.0 vs. 50.5%), and less often autosomal dominant (19.0 vs. 31.3%), or mixed (6.0 vs. 12.1%) for those associated with the LG group (p = 0.048). The LG group was significantly more constrained for missense variants (MOEUF, 0.919 vs. 0.997, p < 0.0001) and was borderline significantly more constrained for loss-of-function variants (LOEUF, 0.872 vs. 0.947, p = 0.051). These results suggest that the UG in humans differs from the rest of the genome in terms of constraints and associated Mendelian diseases. It suggests that phylogenic data can explain some of the characteristics of human genes and could help in interpreting variants.