The mouse kinome: discovery and comparative genomics of all mouse protein kinases

Abstract

We have determined the full protein kinase (PK) complement (kinome) of mouse. This set of 540 genes includes many novel kinases and corrections or extensions to >150 published sequences. The mouse has orthologs for 510 of the 518 human PKs. Nonorthologous kinases arise only by retrotransposition and gene decay. Orthologous kinase pairs vary in sequence conservation along their length, creating a map of functionally important regions for every kinase pair. Many species-specific sequence inserts exist and are frequently alternatively spliced, allowing for the creation of evolutionary lineage-specific functions. Ninety-seven kinase pseudogenes were found, all distinct from the 107 human kinase pseudogenes. Chromosomal mapping links 163 kinases to mutant phenotypes and unlocks the use of mouse genetics to determine functions of orthologous human kinases.

Fig. 1.

Comparison of our kinase protein sequences with those of public databases. Each line indicates the number of matching sequences, at a given allowed sequence divergence; as the stringency is loosened, more genes are matched. The SUGEN line is set at 540, the total number of kinase genes. (Inset) The number of perfect matches, very similar matches (<2% difference), and unmatched (>98% difference).

Fig. 2.

Schematic of Wnk kinase protein sequences, with the kinase domain (KD) boxed in red and previously undescribed blocks of sequence highly conserved between mouse and human boxed in black. Percentage ortholog identity is given for each block and interblock region of lesser conservation.

Fig. 3.

Conservation within orthologous kinase domains is family-dependent. Diamonds indicate the mean kinase domain identity within selected families; bars indicate the range (data from Table 4).

Fig. 4.

ePK domain conservation is family-dependent. (A) The calmodulin-dependent kinase 2 family is highly conserved, with zero to one amino acid changes between mouse and human orthologs and 82–85% sequence identity between human and invertebrate orthologs. (B) Kinase domains of the PEK family are poorly conserved between human and mouse (68–90% identity) and highly divergent from invertebrate orthologs (29–43% identity). (C) Divergent members of well conserved families may indicate changed or lost function, as in MAST-like, a highly divergent member of the MAST family, which also displays high divergence between mouse and human orthologs. (Bar = 0.1 substitutions per site.) Hs, Homo sapiens; Mm, Mus musculus; Dm, Drosophila melanogaster; Ce, Caenorhabditis elegans; Sc, Saccharomyces cerevisiae.

Fig. 5.

CDK10ps is a retrotransposed pseudogene copy of CDK10, which was partially processed, losing the first six and the eighth introns before its reintegration into the genome.