Evolution Of Genes Related To The Hippo Signaling Pathway In Mammals And Their Relationship To Body Siz

During the Cenozoic period,a large number of new mammalian groups were differentiated.These new groups developed rapidly in the process of radiation adaptation and formed a variety of mammals.In the long-term evolution of mammals,a series of changes have taken place in their morphological and physiological,and body size is one of the most significant changes.The size difference of the mammals is huge,in nature,there are only 1.7g of slit-faced bat(Craseonycteris thonglongyai)and blue whales(Balaenoptera musculus)weighing more than 130t,the two types differ by many orders of magnitude.However,the process of controlling the size of the body is complicated,and after years of research,some genes,signaling pathways and hormones related to body size have been discovered.Among them,Hippo signaling pathway is one of the important pathways to control the size of the body,this signaling pathway plays a key role in the regulation of body size by regulating cell proliferation,growth,differentiation and apoptosis.However,the molecular mechanism of Hippo signaling pathways in mammals to promote tissue growth and regulate organ size remains unclear.In this study,we analyzed the evolutionary characteristics of 22 Hippo signaling pathway genes in 33 mammal species to explore the relationship between Hippo signaling pathway genes and body shape evolution.In this study,the coding sequences of 23 candidate genes from 33 representative mammals(Cetartiodactyla,Perissodactyla,Carnivora,Chiroptera,Primates,Rodentia,etc.)were obtained from the NCBI or Ensemble database and performed BLAST program.Then we use three Maximum Likelihood(ML)methons,including Site model,FEL(fixed effect likelihood)and FUBAR(fast unconstrained bayesian approximation)were used selection pressure analysis.The results showed that a total of 35 codons from six genes(DCHS1,DCHS2,LATS2,RASSF1,SAV1,TAZ)were detected to be positively selection in mammals.Further,11 positive selection sites were detected by two ML methods at least and 90.9%(10/11)of the positive selection sites were detected to be radical changes at the protein-level by TreeSAAP,and most of these sites were located in or close to the important functional regions of the protein,such as DNA binding domain,zinc finger domain.We used the Branch model and the Branch site model to explore which positive selections occurred in those branches.The upstream regulatory genes DCHS1,DCHS2,FAT4 and FRMD6 of the Hippo pathway are detected in relatively small-sized species,such the last common ancestor of primate and rodent and toothed whale ancestors,suggesting that the Hippo signaling pathway may enhance LATS1/2 kinase phosphorylate and inactivate the transcriptional coactivator YAP by through mutation of the upstream regulatory gene,and the YAP may remain in the cytoplasm and unable to achieve transcriptional function.The downstream genes TAZ,TEAD1,and TEAD4,are mainly detected in larger species such as Weddell seals,grey whales,and Antarctic minke whales,suggesting that these genes may enhance the transcription of related to body size genes,leading to the increase of mammalian body size.Therefore,the evolution of these genes may be related to the mammals body size.To explore the convergence molecular mechanisms in mammals with body size,we used the PAML software package to reconstruct the ancestral sequences and search for convergent/parallel amino acid substitution sites in two any different mammals.A total of 24 parallel sites were detected in 8 Hippo pathway-associated genes(DCHS1,DCHS2,FAT4,LATS1,LATS2,TEAD1,TEAD2,WWC1)among mammals.The mutations of these eight genes are related to the development and growth of mouse and human body size or organs size.Therefore,it’s speculated that these 8 genes play a similar role in the large body size species and jointly achieve the increase of body size.In summary,the evolutionary changes in the Hippo signaling pathway-related genes provide molecular evidence for the further study of the mechanism of Hippo signaling and body size control in mammals.