- Genomic insights into body size evolution in Carnivora support Peto ’ s paradox. - Background: The range of body sizes in Carnivora is unparalleled in any other mammalian order — the heaviest species is 130,000 times heavier than the lightest and the longest species is 50 times longer than the shortest.. - However, the molecular mechanisms underlying these huge differences in body size have not been explored.. - Results: Herein, we performed a comparative genomics analysis of 20 carnivores to explore the evolutionary basis of the order ’ s great variations in body size. - these genes were defined as body size associated genes (BSAGs). - Fourteen positively-related BSAGs were found to be associated with obesity, and three of these were under rapid evolution in the extremely large carnivores, suggesting that these obesity-related BSAGs might have driven the body size expansion in carnivores. - For small carnivores, we identified 15 rapidly evolving genes and found six genes with fixed amino acid changes that were reported to reduce body size.. - Conclusions: This study brings new insights into the molecular mechanisms that drove the diversifying evolution of body size in carnivores, and provides new target genes for exploring the mysteries of body size evolution in mammals.. - Keywords: Carnivora, Body size associated genes, Peto ’ s paradox, Rapidly evolving genes, Fixed amino acid changes. - Carni- vores are well-known for their dietetic preferences, car- nassial dentition, skull shape and body size [2].. - Body size is closely related to factors such as habitat, life history, metabolism and risk of extinction [3]. - In terms of feeding habits, prey size and di- versity increase with body size in predatory carnivores.. - Importantly, the range of carnivore body size is unparalleled in any other. - The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. - If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. - The largest carnivore—the male southern elephant seal (Mirounga leonina)—is more than 4,000 kg in body mass and over 5.8 m in length [11, 12], whereas the smallest carnivore—the least weasel (Mustela nivalis)—is only 29 g in body mass and 0.114 m in length [13, 14]. - The difference between these two species is huge—over 130,000-fold in body mass and 50-fold in length—making the carnivores a good tar- get for investigating the mechanism of mammalian body size evolution.. - In contrast, a large body size can also bring a multi- tude of benefits, including the ability to exploit vast food resources, increased competitiveness, increased defense against predation, and extended longevity [18, 19]. - How- ever, a larger body size means more cells, which in turn theoretically means a higher risk of cancer, assuming that each cell has an equal risk of mutating [20]. - Until now, the molecular mechanisms regulating the body size of carnivores remain poorly explored. - Previous studies mainly focused on the intraspecific variation in body size, especially in the domestic dog (Canis lupus familiaris). - The constantly updated high-quality genomes of carni- vores provide new opportunities for studying the mech- anism behind the huge variations in body size among carnivores. - In the present study, a comparative genomic analysis was performed on 20 high-quality carnivore ge- nomes. - carnivores and identified fixed amino acid changes in different body size groups. - Using the results of from the above analyses, we hope to provide some novel insights into the molecular mechanism behind body size evolution in carnivores and mammals.. - Genome-scanning of BSAGs and functional enrichment A total of 6,667 one-to-one orthologous genes were identified in the genomes of the 20 carnivores and one cow (Fig. - these were de- fined as body-size-associated genes (BSAGs. - For instance, seven genes (ADAM10, DBN1, NTRK3, PPIB, MAP2K5, WNT2 and ZFPM2) that play key roles in maintaining normal organ or body development were enriched in the GO term. - “Branch model” implemented in Codeml of the program PAML 4.9e was used to identify rapidly evolving genes (REGs) in the small- and extremely large-body-sized groups (hereafter, any reference to a “small” or “large”. - group refers to body size). - In the small group, a total of 15 BSAGs were found to be under rapid evolution (Table S6). - In the end, after false discovery rate (FDR) correction, only five REGs were still significant: MAS1, CATSPERG, YTHDC2, SLC25A28 and ADGRF2 (Table S6. - By contrast, 60 REGs were placed in the extremely large group (Table S6). - Fixed amino acid changes in the extremely small group Identifying fixed amino acid changes in a certain group may help explain the molecular mechanism behind the occurrence of a specific phenotype. - In the present study, we identified six fixed amino acid changes in six genes in extremely small carnivores (CDC7, ENG, LIG4, MMP2, POLE and TSPAN8. - 4), but none in the small or extremely large carnivores. - These sites were lo- cated in the functional domains of their respective pro- teins identified by Pfam. - For instance, a unique change, S513L, was located in the protein kinase domain of CDC7, and another mutation (S784P) was found in the DNA ligase IV domain of LIG4. - or the ratio of enriched genes to all genes in the cluster. - Obesity-related genes contributing to increasing body size in carnivores. - Thus, we could partly resolve the evolu- tionary mechanism of body size variation and identify key candidate genes that influence body size changes in Carnivora. - For instance, SNPs in Table 1 Twenty-one tumor suppressor genes that are significantly associated with the evolution of body size in Carnivora and their roles in cancer. - CERS2 ceramide synthase 2 Plays a role in the regulation of cell growth c and suppresses tumor cell invasion [24]. - Encodes the protein that forms a complex with ERCC1 and is involved in the 5 ’ incision made during nucleotide excision repair c. - This gene is also a candidate tumor suppressor and is located in the critical loss of heterozygosity (LOH) region c. - STAG1 a stromal antigen 1 Plays a crucial role in the control of chromosome segregation during cell division as well as in DNA repair and replication [29]. - TET1 a tet methylcytosine dioxygenase 1 Encodes a demethylase that plays a role in the DNA methylation process and gene activation c TRMT2A tRNA methyltransferase 2 homolog A Plays the inhibitory role in cell proliferation and cell cycle control [30]. - Our results revealed that MAP2K5 (mitogen-activated protein kinase kinase 5) was enriched in the GO cluster. - pellucida-like domain containing 1) is 0.68632 in the ex- tremely large carnivores, 5.5 times that identified in the control group. - Thus, the 14 obesity- related BSAGs identified in this study may contribute to increased body size and accumulated body fat in large carnivores.. - It is worth noting that some genes may not show cor- relation between evolutionary rates and body size across. - 4 The fixed amino acid changes in extremely small carnivores observed in six genes related to the phenotype of reduced body size. - These genes may have been overlooked in the present analysis. - Further analysis should be performed in the future to focus on some spe- cific lineages with significant body size variation, which will reveal more mechanisms underlying body size evo- lution of Carnivora.. - walruses and polar bears — were reported to live 40 or more years in the wild [51]. - Within certain carnivore taxa, body size and lifespan also seem to be positively-correlated [21]. - For instance, sea otters (about 27.4 kg) may live as many as 27 years in the wild, whereas ferrets (about 975.6 g) live a much shorter time—about 11.1 years [21]. - In the present study, we identified a total of 100 BSAGs in carnivores that were related to the cancer control process, including tumor suppressor, DNA re- pair and immunity (Table S5). - We do not discuss differ- ences in the expression levels of cancer-related BSAGs among carnivores. - related genes to the total number of functional genes in the human genome . - The evolu- tionary rates of these two genes are significantly positively-correlated with both body size parameters, suggesting that large carnivores have a higher evolution- ary rate than do small ones.. - The evolution- ary rate of ADAM11 (ADAM metallopeptidase domain 11) was 0.48527 in the extremely large carnivores, 15.4 times greater than that identified in the background group. - Here, we obtained 100 cancer-related genes that were significantly associ- ated with body size evolution in carnivores, including 15 cancer-related REGs that were identified in the ex- tremely large group and which might protect the animal. - These six genes have been shown to be related to the phenotype of reduced body size. - or low expression of the CDC7 protein leads to reduced body size with decreased cell proliferation in mice [61]. - A Fixed amino acid mutation was separately found in the MMP2 (S579T) and POLE (E701D) genes. - in the body weight of males fed a normal chow diet [67]. - Furthermore, the changes in S513L in CDC7 and S784P in LIG4 affect polarity and might cause rad- ical changes in the three-dimensional structure and function of proteins [68]. - These six unique changes ex- amined in the extremely small carnivores might have re- stricted body size growth.. - Though body size regulation is an inherently complex process involving many genes and signaling pathways, and not all genes function in the same way in different species and show the same evolutionary pattern, the amino acid sites with fixed changes in different body size groups could still reveal whether the body size variations in different carnivores is driven by common genes or shared mechanism to some degree. - Mammalian order Carnivora exhibits a huge variation in body size—with an over 130,000-fold difference in body mass between the heaviest and lightest species and 50- fold difference in body length between the longest and shortest—but the molecular mechanisms underlying the disparities remain poorly explored. - Here we scanned the genomes of 20 representative carnivores and found a total of 337 genes associated with body size. - Our ana- lyses showed that 14 obesity-related genes and three rap- idly evolving genes might drive body size expansion. - a lack of correlation between body size and cancer risk—. - based on 100 body-size-associated genes associated with cancer control and 15 cancer-related genes under rapid evolution in carnivores. - This study brings new insights into the molecular mecha- nisms that drove the diversifying evolution of body size in carnivores, and provides new target genes for explor- ing the mysteries of body size evolution in mammals.. - PGLS scanning the body-size-associated genes (BSAGs) PGLS implemented in the “Caper” package in R [75] was used to test the potential association between the evolu- tionary rates of each gene and each piece of phenotype data (i.e. - 0.05) are defined as body-size- associated genes (BSAGs).. - The evolutionary rate ω—the ratio of non-synonymous (d N ) to synonymous substitutions (d S )—was estimated using the free-ratios model (model = 1) implemented in. - [83]) databases to explore potential biological functions of each BSAG in association with body size.. - To test whether divergent selective pressures acted on carnivores with contrasting body size based on the BSAGs determined above, we divided the 20 species into three groups: The first was small body-sized carnivores (body mass <. - A two-ratio model (model = 2) that allows different ω values within the foreground and background branches was used to evaluate the selective pressures in the three groups of species. - To explore how changes in single amino acid sites contrib- ute to body size development, we scanned all the ortholo- gous genes set for the fixed amino acid changes in the small group (body mass <. - Amino acid sites that were the same in the three extremely small species and were consistently different in other carnivores were selected. - Pfam 1.6 [86] was used to determine whether the changes were located in the functional domains of the protein.. - BSAGs: Body size associated genes. - Walker ’ s Mammals of the World. - The evolution and distribution of species body size.. - Body size and metabolic rate. - Basal rate of metabolism, body size, and food habits in the order Carnivora. - Carnivore body size: ecological and taxonomic correlates.. - Seals of the world. - Mammals of the Soviet Union. - Sexual dimorphism in the body size of mustelids (Carnivora): the roles of food habits and breeding systems. - The evolution of body size: what keeps organisms small?. - Allometry of the distribution of adipose tissue in Carnivora. - ADAM family proteins in the immune system. - Inactivation of the PTEN/MMAC1/. - The protein kinase complement of the human genome. - Variation in the size of foxes in Scotland
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