We have described the near-complete inventories of KRTAP genes from the genomes of human, chimpanzee, and rhesus macaque representing primates, mouse and rat representing rodents, dog representing carnivore, opossum representing marsupial, and platypus as a monotreme, and conducted comprehensive analyses of the evolutionary patterns for this gene family, including phylogenetic classification, and the detection of gene conversion.
Among the mammals that we studied, the genomes of each species have members of most of the subfamilies suggesting that the majority of KRTAP gene subfamilies originated and diverged before the mammalian radiation (fig. ). Accordingly, the mammalian ancestor should also have had a high diversity of KRTAP genes and enjoyed a similar range and spectrum of hair characteristics that is seen in modern mammalian species. The genes for subfamilies that emerged in the early mammals account for about 74% total number of genes in present mammalian genomes. We advocate that the rapid emergence of the KRTAP gene family correlates with the evolution of mammalian hair and that the rapid emergence of plentiful hair contributed to the successful radiation of homothermal mammals by helping them to retain body heat since hair acts as an insulator [13
]. In contrast, Homo sapiens
has recently lost body hair function, presumably because humans can obtain heat and can keep cold out by using clothing. Despite a lack of hair, humans actually have a similar density of hair follicles to apes [15
], which possibly explains why human do not have a significant fewer number of KRTAP genes. Perhaps, the changes in human hair are due to the reduction in expression of the KRTAP genes. In contrast to humans, rodents have an expanded KRTAP gene family. Perhaps, mouse and rat need more hair as they are adapted to the nocturnal environment. Despite the proposed similar range and diversity of hair characteristics in the ancestor of mammals, the current traits, and content, of hair likely diverged significantly from their ancestral characteristics as KRTAP sequences have diverged dramatically among species due to gene conversion.
Both gene conversion and unequal crossing over have occurred during the evolution of the KRTAP. The evolution of several KRTAP gene subfamilies, such as subfamilies 1, 2 and 3 fit well with a model of punctuated equilibrium (table ), where morphological divergence as well as speciation occurs in a burst-like manner with rapid evolutionary change followed by long periods of constancy [55
]. These KRTAP genes show evidence for fewer gene duplication or loss events, suggesting that a low level of unequal crossing over has occurred within these subfamilies, and that gene conversion may predominate. In addition, the syntenic arrangement of genes of these subfamilies has not been disturbed by post-duplication rearrangement events, suggesting a strong constraint has been exerted upon their distribution. In contrast, other KRTAP genes, such as subfamilies 4 and 5 (table ) have evolved relatively dynamically likely including unequal crossing over as changes in the copy number of this subfamily is observed between species.
Changes in gene numbers within subfamilies between mammals may explain differences in the observed hair morphology between species. No genes of subfamily 9 were identified in opossum or platypus, suggesting that this subfamily originated after the divergence of placental and marsupial mammals. In a similar manner, genes of subfamily 12 emerged before the divergence of marsupials but after the divergence from monotremes (fig. ). Intriguingly, subfamily 13 has been lost on the marsupial lineage, and the subfamilies 24, 26 and 27 which are adjacent to subfamily 13 in the genome, are also not found in the opossum genome. We used Mapviewer from NCBI to identify genes flanking this cluster in the human genome and searched the opossum genome using BLAST to identify an orthologous genomic region. An ortholog of the human gene that flanks the human KRTAP genes is only about 13 kbp away from the remainder of the KRTAP cluster in the opossum genome, which indicates the loss of this region in the opossum was due to a deletion event. Subfamily 30, which is a member of the ultra-high sulfur (~50%) group, along with subfamily 34 are unique to rodents, thus may be partially responsible for the unique characteristics of hair in rodents. Subfamily 35 is mouse-specific, while subfamilies 32 and 33 are platypus-specific, which could account for species-specific hair characteristics.
The high-glycine/tyrosine (HGT) gene repertoire evolve more dynamically within mammals with increased levels of pseudogenization (fig. ), for example, mice possesses 56 genes, while primates have considerably fewer genes with only 27 and 25 genes in human and chimpanzee respectively. The gene number in platypus is likely to be underestimated because HGT cluster in platypus is shorter than that of other mammals (only about 100 kbp in platypus, but ~500 kbp in human, ~800 kbp in mouse, and ~350 kbp in opossum), and the incomplete nature of this genome sequence. However, the dynamics of HGT subfamilies does not appear to be due to unequal crossing over, as unequal crossing over should also generate a GC content bias that is not observed in these genes (personal communication, Gabriel Marais).
Tandemly arrayed paralogous genes with similar function can provide combinatorial complexity to biological diversity [56
]. This extraordinary evolutionary feature has been observed in many multigene families responsible for processes that face enormous external signals. For instance, the sensory system such as the olfactory receptor, vomeronasal receptor and sweet/umami receptor, bitter receptor genes, require a huge combination of diverse receptors for the diverse ligands they encounter in a tremendous range of molecular environments [57
]. Another classic example is the immunoglobulin and T-cell receptor protein superfamily which use recombination to generate large quantities of antigen recognition complexes to allow an immune responses to rapidly evolving pathogens [58
]. We therefore speculate that an analogous process occurs within the KRTAP gene family, where the KRTAP and keratin proteins have combined in unique combinations to generate the high diversity of hair phenotypes that are observed both between and within species, and even within individuals.