Insights into Ciliary Genes and Evolution from Multi-Level Phylogenetic Profiling

Abstract

Cilia (flagella) are important eukaryotic organelles, present in the Last Eukaryotic Common Ancestor, and are involved in cell motility and integration of extracellular signals. Ciliary dysfunction causes a class of genetic diseases, known as ciliopathies, however current knowledge of the underlying mechanisms is still limited and a better characterization of genes is needed. As cilia have been lost independently several times during evolution and they are subject to important functional variation between species, ciliary genes can be investigated through comparative genomics. We performed phylogenetic profiling by predicting orthologs of human protein-coding genes in 100 eukaryotic species. The analysis integrated three independent methods to predict a consensus set of 274 ciliary genes, including 87 new promising candidates. A fine-grained analysis of the phylogenetic profiles allowed a partitioning of ciliary genes into modules with distinct evolutionary histories and ciliary functions (assembly, movement, centriole, etc.) and thus propagation of potential annotations to previously undocumented genes. The cilia/basal body localization was experimentally confirmed for five of these previously unannotated proteins (LRRC23, LRRC34, TEX9, WDR27, and BIVM), validating the relevance of our approach. Furthermore, our multi-level analysis sheds light on the core gene sets retained in gamete-only flagellates or Ecdysozoa for instance. By combining gene-centric and species-oriented analyses, this work reveals new ciliary and ciliopathy gene candidates and provides clues about the evolution of ciliary processes in the eukaryotic domain. Additionally, the positive and negative reference gene sets and the phylogenetic profile of human genes constructed during this study can be exploited in future work.

Genomes of early-diverging streptophyte algae shed light on plant terrestrialization

“…M. viride reproduces vegetatively by binary division of the flagellate cell, whereas C. atmophyticus forms scale-covered zoospores during asexual reproduction. A comparative analysis of the complement of flagellar genes in their genomes, using a stringent reciprocal-best-BLAST-hits analysis of 397 Chlamydomonas flagellar proteins as query 34 , detected 204 flagellar proteins in M. viride and 192 in C. atmophyticus ( Fig. 4 and Supplementary Table 25).…”

A Bayesian approach to mediation analysis predicts 206 causal target genes in Alzheimer’s disease

“…We found 774 protein-coding genes with significant non-zero effect (FDR < 10 −4 ), of which 206 are located in proximity of subthreshold GWAS SNPs (p < 10 −4 ; Supp Tab 1), of which 66 explain at least 5% of local genetic variance. We further discussed 21 genes in subthreshold / GWAS loci that explain 5% of local variance, which includes the peroxisome regulator and cytochrome complex genes (RHOBTB1 [21][22][23] , CYP27C1 and CYP39A1) and several microglial genes (LRRC23 24,25 , ELMO1 26-28 , RGS17 29 , CNTFR 30 ) which support functional roles of innate immune response in AD progression 2,31 .…”

Scalable Phylogenetic Profiling using MinHash Uncovers Likely Eukaryotic Sexual Reproduction Genes

“…Multiple successful applications of phylogenetic profiling in eukaryotes have been published in recent years, e.g. to infer small RNA pathway genes [8] , the kinetochore network [9] , ciliary genes [10] , or homologous recombination repair genes [11] .…”