Fabre Alexandre, Mancini Julien
Aix Marseille Univ, INSERM, MMG, Marseille, France.
APHM, Multidisciplinary Pediatrics Department, Timone Enfant Hospital, Marseille, France.
Intractable Rare Dis Res. 2022 Aug;11(3):149-152. doi: 10.5582/irdr.2022.01063.
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 ( < 0.0001). The mode of inheritance was more often autosomal recessive (69.0 50.5%), and less often autosomal dominant (19.0 31.3%), or mixed (6.0 12.1%) for those associated with the LG group ( = 0.048). The LG group was significantly more constrained for missense variants (MOEUF, 0.919 . 0.997, < 0.0001) and was borderline significantly more constrained for loss-of-function variants (LOEUF, 0.872 0.947, = 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.
露卡（LUCA），即最后的普遍共同祖先，是生命三个域的假定最近共同祖先，这三个域共享通用基因（UG）。评估UG系统发育是否对当前人类基因限制产生影响似乎很有意思。从eggNOG数据库中检索了UG的人类同源基因列表。我们分析了这个露卡基因（LG）组，以及从gnomAD数据库中随机抽取的500个基因样本（RG组）。从gnomAD中检索基因限制指标，并从OMIM中检索与孟德尔疾病和遗传模式的关联。LG组由277个基因组成，RG组由492个基因组成（8个基因在LG组中）。LG组中38.6%的基因和RG组中25.2%的基因与孟德尔疾病相关（<0.0001）。对于与LG组相关的基因而言，遗传模式更常为常染色体隐性遗传（69.0对50.5%），较少为常染色体显性遗传（19.0对31.3%），或混合遗传（6.0对12.1%）（P = 0.048）。LG组对于错义变体的限制明显更大（MOEUF，0.919对0.997，P < 0.0001），对于功能丧失变体的限制接近显著更大（LOEUF，0.872对0.947，P = 0.051）。这些结果表明，人类中的UG在限制和相关孟德尔疾病方面与基因组的其他部分不同。这表明系统发育数据可以解释人类基因的一些特征，并有助于解释变体。
