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Color variation in Black Rats: (A) typical agouti color form in Rattus tanezumi from Chichijima Island, Ogasawara, Japan; and (B) a melanistic rat from Tokyo, representing Rattus rattus.
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We examined nucleotide changes that underlie coat color variation in Black Rats (the Rattus rattus species complex), which show polymorphism in dorsal fur color, including either grayish brown (agouti) or black (melanistic) forms. We examined the full coding sequence of a gene known to produce melanism in other vertebrates-melanocortin-1-receptor g...
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Seven donkey breeds are recognized by the French studbook and are characterized by a black, bay or grey coat colour including light cream-to-white points (LP). Occasionally, Normand bay donkeys give birth to dark foals that lack LP and display the no light points (NLP) pattern. This pattern is more frequent and officially recognized in A...
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... The hair color of this species, which is currently divided into three subspecies groups, i.e., M. m. castaneus (CAS: southern Asia, Southeast Asia and southern China), M. m. domesticus (DOM: western Asia and western Europe) and M. m. musculus (MUS: northern Eurasia) (e.g., Suzuki et al., 2013;Takada et al., 2013), varies both within and between the subspecies . An understanding of the genetic background of phenotypic variation would allow observations of coat color variation in wild populations to provide insights into phylogenetic background (Kambe et al., 2011;Suzuki, 2013;Kodama et al., 2015;Sasamori et al., 2017;Marín et al., 2018). There are two possible explanations for the hair color variation in the peripheral regions: the alleles of hair color in the source region may have been transmitted to the surrounding regions; or new alleles that arose in situ may have generated the diversity of hair color . ...
... To test these explanations, it would be useful to examine genetic variation in the hair color-related genes, understand their spatiotemporal dynamics, and construct an evolutionary scenario. Sequence variation in the coat color-related gene Mc1r (Nunome et al., 2010;Kambe et al., 2011;Kodama et al., 2015;Kuwayama et al., 2017) has been used for phylogenetic inference of rodents, including M. musculus. However, the Asip gene responsible for ventral coat color has not been analyzed in M. musculus. ...
While the house mouse (Mus musculus), widely distributed in Eurasia, is known to have substantial coat color variation between and within local populations, in both primary and secondary distribution areas, including the Japanese archipelago, the evolutionary history of the color variation is poorly understood. To address the ventral fur color variation, we quantified the lightness of museum skin specimens, and found that the southern subspecies, M. m. castaneus (CAS), has high and low lightness in dry and rainy geographic regions, respectively. The northern subspecies, M. m. musculus (MUS), has low and high levels of lightness in the high and middle latitudes of northern Eurasia, respectively. We examined sequence variation of the agouti signaling protein gene (Asip), which is known to be responsible for the ventral fur color. We performed phylogenetic analyses with 196 haplotype sequences of Asip (~180 kb) generated by phasing the whole-genome data of 98 wild mice reported previously. Network and phylogenetic tree construction revealed clustering of haplotypes representing the two subspecies, MUS and CAS. A number of subclusters with geographic affinities appeared within the subspecies clusters, in which the essential results were consistent with those reconstructed with whole mitochondrial genome data, indicating that the phased haplotype genome sequences of the nuclear genome can be a useful tool for tracing the dispersal of geographical lineages. The results of phylogeographic analysis showed that CAS mice with darker ventral fur possessed similar Asip haplotypes across the geographic distribution, suggesting that these haplotypes are major causes of the historical introduction of Asip haplotypes for darker ventral fur in mice from northern India to the peripheral areas, including the Japanese archipelago. Similarly, MUS in East Asia, which has a white abdomen, formed an Asip haplogroup with that from northern Iran, also with a white abdomen.
... The central pigment-determining system, the MC1R-ASIP system, is highly conserved among vertebrates (Bennett and Lamoreux, 2003), and amino acid substitutions in MC1R cause inter-/intraspecific color polymorphisms in several mammalian species, such as laboratory mice (Robbins et al., 1993), domestic dogs (Newton et al., 2000;Schmutz and Berryere, 2007a), domestic cats (Peterschmitt et al., 2009), horses (Marklund et al., 1996;Rieder et al., 2001), jaguars and jaguarundis (Eizirik et al., 2003) and martens (Ishida et al., 2013). In some cases, a single-nucleotide polymorphism is enough to cause striking diversity, from complete black (melanism) to white or bright yellow, representing both ends of the color spectrum (e.g., Hoekstra et al., 2006;Kambe et al., 2011;Ishida et al., 2013;Suzuki, 2013). However, the genetic changes underlying the variation in coat color seen in natural populations (e.g., Łopucki and Mróz, 2010;Tsuchihashi et al., 2011;Tomozawa et al., 2014;van der Geer, 2019) remain to be investigated. ...
The melanocortin-1 receptor gene (MC1R) controls production of the pigments eumelanin and pheomelanin. Changes in MC1R lead to variation in coat color in mammals, which can range from entirely black (melanism) to yellowish. In this study, we report a case of a wild-caught Norway rat (Rattus norvegicus) from Sado Island, Japan with a yellowish coat color. Upon sequencing the whole coding region of the Mc1r gene (954 bp), we found a 1-bp deletion at site 337 (c.337del), indicative of a frameshift mutation, which was characterized as a severe loss-of-function or null mutation. A spectrophotometer was used to measure coat color, revealing that the rat had a distinctly lighter coat, based on lightness score, than mice with homozygous similar loss-of-function mutations. This implies that loss-of-function mutations can yield different phenotypes in murine rodents. The loss-of-function-mutant rat exhibited a contrasting coat pattern consisting of darker and lighter colors along its dorsal and ventral sides, respectively. Similar patterns have been observed in homozygous MC1R-deficient mutants in other mammals, implying that the countershading pattern can still be expressed despite the absence of MC1R in the melanocyte.
... Mutations on MC1R are generally not lethal (Enshell-Seijffers et al. 2010). Gain-of-function Mc1r mutations are commonly found in the wild populations and domesticated animals and lead to melanistic phenotype through by single amino acid replacements (Våge et al. 1997;Theron et al. 2001;Kambe et al. 2011) and short amino acid segment deletions (Eizirik et al. 2003;Vidal et al. 2010). Loss-of-function MC1R mutations are known to cause yellowish color variants in wild and domestic populations of a number of species such as seals (Peters et al. 2016) and dogs (Everts et al. 2000;Newton et al. 2000;Schmutz et al. 2002). ...
A loss-of-function mutation in the melanocortin 1 receptor gene (MC1R), which switches off the eumelanin production, causes yellowish coat color variants in mammals. In a wild population of sables (Martes zibellina) in Hokkaido, Japan, the mutation responsible for a bright yellow coat color variant was inferred to be a cysteine replacement at codon 35 of the N-terminal extracellular domain of the Mc1r receptor. In the present study, we validated these findings by applying genome editing on Mc1r in mouse strains C3H/HeJ and C57BL/6N, altering the codon for cysteine (Cys33Phe). The resulting single amino acid substitution (Cys33Phe) and unintentionally generated frameshift mutations yielded a color variant exhibiting substantially brighter body color, indicating that the Cys35 replacement produced sufficient MC1R loss of function to confirm that this mutation is responsible for producing the Hokkaido sable yellow color variant. Notably, the yellowish mutant mouse phenotype exhibited brown coloration in subapical hair on the dorsal side in both the C3H/HeJ and C57BL/6N strains, despite the inability of the latter to produce the agouti signaling protein (Asip). This darker hair and body coloration was not apparent in the Hokkaido sable variant, implying the presence of an additional genetic system shaping yellowish hair variability.
... For example, higher proportions of the melanistic "rattus" (black) pelage occur in the South Island and upper North Island, corresponding with haplotype Rathap01, but are almost absent from Stewart Island, corresponding with Rathap07. The inheritance of pelage color is through known genetic markers unrelated to mtDNA haplotype (Kambe et al., 2011), but a geographical association between pelage color and haplogroup may arise due to the genetic makeup of different founding populations. Similarly, the rare occurrence in R. rattus of the Tyr25Phe mutation in VKorc1, which is associated with anti-coagulant resistance, also corresponds with the distribution of haplotype Rathap02 (Cowan et al., 2017). ...
Two species of invasive rats (Rattus norvegicus and R. rattus) arrived in New Zealand with Europeans in the mid to late eighteenth and nineteenth century respectively. They rapidly spread across the main islands of New Zealand and its offshore islands, displacing the historically introduced R. exulans. Today both species are widespread although the distribution of the sub-dominant R. norvegicus is patchy. Tissue samples were obtained from 425 R. rattus and 130 R. norvegicus across the New Zealand archipelago and neighboring islands. We sequenced a standard 545 base pair section of the mitochondrial D-loop in order to construct a modern phylogeography of the two species and to make inference on historical invasion pathways and spread across the country. We found limited diversity in R. norvegicus haplotypes, with two widespread haplotypes across New Zealand and its offshore islands most likely corresponding to two independent invasions, potentially with English and Chinese origins, respectively. In contrast we found widespread diversity in R. rattus haplotypes across New Zealand and its offshore islands, most likely corresponding to at least four independent invasions to the main North and South Islands, Great Barrier Island archipelago, and Stewart Island archipelago. The most common R. rattus haplogroup was found throughout New Zealand and many of its offshore islands, as well as neighboring islands in the Tasman Sea, and has been documented elsewhere across the Pacific, but with European origins. We also found both geographic partitioning and secondary invasions of haplotypes within the main North and South Island. In addition to distinct haplogroups differing by over three base pairs, which exhibit geographical partitioning suggestive of independent invasion events, for both species we also found instances of single base-pair differences within localities, elevating haplotype diversity. The geographical distribution of pelage color morphs also correlates with haplotype distribution, lending further support to the hypothesis and role of independent invasion events.
... While the Indus sites mostly encompass the northwest of India, they also extend to Uttar Pradesh in east and Maharashtra to the south (Dhavalikar 1982;Possehl 2003;Sali 1986) as illustrated in Fig. 1. Apart from previous reports confirming localities where multiple chromosome races had come into secondary contact (Yoshida 1980), recent reports confirming the occurrence of both lineage I and II in Japan and South Africa Chinen et al. 2005;Kambe et al. 2011) demonstrates high gene flow between them. This corroborates the view that the extant R. rattus population in India with a 2n = 42 karyotype, previously identified as R. tanezumi by Pages et al. (2010), Robins et al. (2007) and Aplin et al. (2003), is the ancestor of the most successful and widespread commensal RrC lineage I, 2n = 38 karyotype R. rattus population. ...
India is the origin to the world’s most notorious invasive mammal, the black rat Rattus rattus. All previous empirical phylogeographic studies were based on very few samples originating from India-creating a paucity of data to extrapolate from. In this first specific phylogeographic study of R. rattus attempted in India, samples were obtained from 18 localities within peninsular India with a focus on the East and West coasts, regions that spread commensal R. rattus globally. The displacement loop (D-loop) and the cytochrome b (Cytb) gene were sequenced in 45 R. rattus individuals. Maximum likelihood analysis was used to assign individuals to lineages. Coalescence and Bayesian methods were employed to estimate population genetic parameters, phylogeny and divergence respectively. The phylogeography of R. rattus was elucidated by constructing median joining networks by combining newly generated D-loop and Cytb gene sequences in the current study with available sequences in the database. Our findings provide key insights into the origin, expansion and migration patterns of the black rat in India, Eurasia and in the Indian Ocean region. The study reconfirms India as the centre of origin to the global R. rattus population and identifies the Gangetic region and East coast as focal points of ancestral R. rattus populations in India. Our newly generated data provide genetic evidence in support of the origin of commensalism in R. rattus in the ancient Indus Valley region and the further spread of these commensal house rats by medieval Arab sailors in the Indian Ocean and the Mediterranean.
... signaling gene protein (Asip) and the melanocortin-1 receptor gene (Mc1r) (e.g., Hoekstra and Nachman, 2003;Hoekstra et al., 2004;Fontanesi et al., 2010;Suzuki, 2013), which are major determinants of red-yellow (pheomelanin) and black-brown (eumelanin) pigmentation (Tamate and Takeuchi, 1981;Klungland et al., 1995). Previous efforts to identify mutations related to phenotypic changes have identified a number of mutations in the amino acid coding region and promoter region of Mc1r and Asip (e.g., Hoekstra and Nachman, 2003;Fontanesi et al., 2010;Kambe et al., 2011;Sasamori et al., 2017;Nadeau et al., 2008). The Asip gene, along with amino acid coding regions embedded in exons 2, 3, and 4, has a long upstream noncoding region (> 100 kb) that harbors several promoter regions and the accompanying exon 1. Alterations in the promoter regions are expected to cause various degrees of color change by modulating the expression of the Asip gene. ...
In the agouti signaling gene protein (Asip) of the house mouse (Mus musculus), inverted repeat (IR) arrays are known to exist in a non-coding region adjacent to the ventral-specific promoter region and the accompanying two exons (exons 1A and 1A′), which are around 100 kb upstream from the amino acid coding regions of exons 2, 3, and 4. To determine the gene structure of mammalian Asip and to elucidate trends in its evolution, non-coding sequences of six rodent (mouse, rat, Chinese hamster, squirrel, Guinea pig, and naked mole rat) and three non-rodent (rabbit, human, and cow) species were retrieved from databases and compared. Our homology search analyses revealed the presence of three to five highly conserved non-coding elements (CNE). These CNEs were found to form IRs in rodents and lagomorphs. Combinations of IRs were further shown to build symmetric, long IR arrays. Intra- and inter-specific comparisons of the sequences of three universal CNEs showed homogeneity between CNE pairs within species. This implies that certain evolutionary constraints maintained the IR structure in the rodent and rabbit species.
... Coat color and pattern have long been considered important for understanding the complex systematics of the Rattus rattus species complex (RrC, sensu Aplin et al., 2011;e.g., De L'lsle, 1865;Morgan, 1909;Feldman, 1926;Caslick, 1956;Tomich and Kami, 1966;Kambe et al., 2011Kambe et al., , 2012. Recent phylogenetic studies have shown that the RrC consists of six well-differentiated mitochondrial (mtDNA) lineages (Robins et al., 2007;Pagès et al., 2010;Aplin et al., 2011), with two of these lineages (RrC lineages I and II) having attained near global distributions in association with human dispersal and trade . ...
... RrC lineage II is widely distributed throughout Japan ( Fig. 1; Chinen et al., 2005;Kambe et al., 2012) and is believed to have invaded during the Neolithic (Kowalski and Hasegawa, 1976;Kawamura, 1989), whereas RrC lineage I is a more recent introduction with a correspondingly limited distribution, including the Otaru city area on Hokkaido ( Fig. 1; Chinen et al., 2005;Kambe et al., 2012). Previous efforts to identify the gene(s) responsible for melanism in a polymorphic (agouti vs melanistic) population of RrC lineage I in Otaru demonstrated that a single substitution from G to A at site 280 (c.280G > A) of the coding region (exon 1) of Mc1r was responsible (Kambe et al., 2011). Subse-quent phylogenetic analyses of samples from across Japan (Kambe et al., 2011(Kambe et al., , 2013 revealed two distinct Mc1r phylogroups, which appear to correspond with RrC lineages I and II. ...
... Previous efforts to identify the gene(s) responsible for melanism in a polymorphic (agouti vs melanistic) population of RrC lineage I in Otaru demonstrated that a single substitution from G to A at site 280 (c.280G > A) of the coding region (exon 1) of Mc1r was responsible (Kambe et al., 2011). Subse-quent phylogenetic analyses of samples from across Japan (Kambe et al., 2011(Kambe et al., , 2013 revealed two distinct Mc1r phylogroups, which appear to correspond with RrC lineages I and II. The Mc1r c.280G > A mutation was mostly restricted to a haplotype belonging to RrC lineage I (Kambe et al., 2011), but was also found in heterozygous and homozygous states in melanistic rats from localities where RrC lineage II is dominant, such as Tokyo (Honshu) and the Ogasawara Islands ( Fig. 1; Kambe et al., 2011Kambe et al., , 2013. ...
The occurrence of black fur, or melanism, in many mammalian species is known to be linked to DNA sequence variation in the agouti signaling protein (Asip) gene, which is a major determinant of eumelanin and pheomelanin pigments in coat color. We investigated 38 agouti (i.e., banded wildtype) and four melanistic Rattus rattus species complex (RrC) lineage II specimens from Okinawa Island, Ryukyu Islands, Japan, for genetic variation in three exons and associated flanking regions in the Asip gene. On Okinawa, a predicted loss-of-function mutation caused by a cysteine to serine amino acid change at p.124C>S (c.370T>A) in the highly conserved functional domain of Asip was found in melanistic rats, but was absent in agouti specimens, suggesting that the p.124C>S mutation is responsible for the observed melanism. Phylogeographic analysis found that Asip sequences from Okinawan RrC lineage II, including both agouti and melanistic specimens, differed from: 1) both agouti and melanistic RrC lineage I from Otaru, Hokkaido, Japan, and 2) agouti RrC lineages I and II from South Australia. This suggests the possibility of in-situ mutation of the Asip gene, either within the RrC lineage II population on Okinawa or in an unsampled RrC lineage II population with biogeographic links to Okinawa, although incomplete lineage sorting could not be ruled out.
... C oat color is one of the most important breeding traits in horses, goats and other domestic animals (Fontanesi et al., 2011). Among fiber-producing animals, the new breed of Liaoning goats that produce cashmere, also known as "fiber gem", possesses qualities such as high cashmere yield and good cashmere fineness (Kambe et al., 2011). Studies have identified a number of genes that regulate the fur color of cashmere goats. ...
KIT encodes a growth factor receptor that is expressed in the precursor of the melanophore. It plays an important role in the multiplication, migration and survival of melanophores. As of yet, no studies have addressed the diverse expression of the KIT gene and its protein in goats of different fur colors. The effect of KIT mutations on KIT protein expression was examined in white cashmere and black cashmere goats. A single A→G missense mutation in exon 13 differentiated cashmere goats with different colors. Only a histidine (H)→arginine (R) amino acid (AA) change was detected at KIT exon 13 in both the white cashmere goat and the black cashmere goat. Moreover, comparison with other species revealed three dramatic amino acid mutation areas. Our results also indicated that c-kit expression was higher in the white cashmere goat than in the black goat, and this significant difference was detected by q-PCR and western blotting. All cashmere goats of different colors examined by immunohistochemical analysis showed either weak (the black cashmere goat) or strong (the white cashmere goat) expression of the KIT protein. These findings suggested a relationship between mutations in KIT exon 13 and differential fur color in cashmere goats. These results lay the foundation for further research on exon 13 of the KIT gene and color regulation in cashmere goats.
... Accordingly, loss-of-function mutations in the cysteine-rich region of Asip result in the melanistic phenotype ( Schneider et al., 2012Schneider et al., , 2015), because such mutated Asip proteins are unable to suppress the activity of the agonist α-MSH for eumelanin production. Coat color and pattern have long been considered important for understanding the complex systematics of the Rattus rattus species complex ( RrC, sensu Aplin et al., 2011;e.g., De L'lsle, 1865;Morgan, 1909;Feldman, 1926;Caslick, 1956;Tomich and Kami, 1966;Kambe et al., 2011Kambe et al., , 2012). Recent phylogenetic studies have shown that the RrC consists of six well-differentiated mitochondrial (mtDNA) lineages ( Robins et al., 2007;Pagès et al., 2010;Aplin et al., 2011), with two of these lineages (RrC lineages I and II) having attained near global distributions in association with human dispersal and trade ( Aplin et al., 2011). ...
... RrC lineage II is widely distributed throughout Japan ( Fig. 1; Chinen et al., 2005;Kambe et al., 2012) and is believed to have invaded during the Neolithic ( Kowalski and Hasegawa, 1976;Kawamura, 1989), whereas RrC lineage I is a more recent introduction with a correspondingly limited distribution, including the Otaru city area on Hokkaido ( Fig. 1; Chinen et al., 2005;Kambe et al., 2012). Previous efforts to identify the gene(s) responsible for melanism in a polymorphic (agouti vs melanistic) population of RrC lineage I in Otaru demonstrated that a single substitution from G to A at site 280 (c.280G > A) of the coding region (exon 1) of Mc1r was responsible ( Kambe et al., 2011). Subsequent phylogenetic analyses of samples from across Japan ( Kambe et al., 2011Kambe et al., , 2013) revealed two distinct Mc1r phylogroups, which appear to correspond with RrC lineages I and II. ...
... Previous efforts to identify the gene(s) responsible for melanism in a polymorphic (agouti vs melanistic) population of RrC lineage I in Otaru demonstrated that a single substitution from G to A at site 280 (c.280G > A) of the coding region (exon 1) of Mc1r was responsible ( Kambe et al., 2011). Subsequent phylogenetic analyses of samples from across Japan ( Kambe et al., 2011Kambe et al., , 2013) revealed two distinct Mc1r phylogroups, which appear to correspond with RrC lineages I and II. The Mc1r c.280G > A mutation was mostly restricted to a haplotype belonging to RrC lineage I ( Kambe et al., 2011), but was also found in heterozygous and homozygous states in melanistic rats from localities where RrC lineage II is dominant, such as Tokyo (Honshu) and the Ogasawara Islands ( Fig. 1; Kambe et al., 2011Kambe et al., , 2013). ...
... We also examined the variation in chromosome number in representative individuals of the six species. A nuclear gene, the melanocortin-1-receptor (Mc1r) gene, which is one of the most important genes in the evolution of pigmentation in vertebrates, including rodent species (Nachman et al., 2003;Hoekstra et al., 2005), has been used to assess the phylogenetic groups of the R. rattus SC (Kambe et al., 2011(Kambe et al., , 2012Suzuki, 2013;Yasuda et al., 2014), and we examined the variation of Mc1r sequences (954 bp) in this taxon. The present study was performed to fill some of the gaps in our understanding of the inter-and intraspecies phylogenetic relationships of the six species of rats and mice mentioned above. ...
... We ignored singletons in the separation of haplotypes and in the construction of a network tree. The neighbor-net tree was generated from the Mc1r sequences from Manipur and 12 sequences identified previously (alleles 1-12; Kambe et al., 2011Kambe et al., , 2012. The resulting tree (Fig. 3) exemplified two distinct clusters representing the "rattus" and "tanezumi" groups, consistent with our previous studies (Kambe et al., 2011(Kambe et al., , 2012. ...
... The neighbor-net tree was generated from the Mc1r sequences from Manipur and 12 sequences identified previously (alleles 1-12; Kambe et al., 2011Kambe et al., , 2012. The resulting tree (Fig. 3) exemplified two distinct clusters representing the "rattus" and "tanezumi" groups, consistent with our previous studies (Kambe et al., 2011(Kambe et al., , 2012. The Manipur sequences were located at six different positions in the network, showing their apparent demarcation into two clusters designated "rattus" (Group I) and "tanezumi" (Group II). ...
The Indian subcontinent and Southeast Asia are hotspots of murine biodiversity , but no species from the Arakan Mountain system that demarcates the border between the two areas has been subjected to molecular phylogenetic analyses. We examined the mitochondrial cytochrome b gene sequences in six murine species (the Rattus rattus species complex, R. norvegicus, R. nitidus, Berylmys manipulus, Niviventer sp. and Mus musculus) from Manipur, which is located at the western foot of the mountain range. The sequences of B. manipulus and Niviventer sp. examined here were distinct from available congeneric sequences in the databases, with sequence divergences of 10–15%. Substantial degrees of intrapopulation divergence were detected in R. nitidus and the R. rattus species complex from Manipur, implying ancient habitation of the species in this region, while the recent introduction by modern and prehistoric human activities was suggested for R. norvegicus and M. musculus, respectively. In the nuclear gene Mc1r, also analyzed here, the R. rattus species complex from Manipur was shown to possess allelic sequences related to those from the Indian subcontinent in addition to those from East Asia. These results not only fill gaps in the phylo-genetic knowledge of each taxon examined but also provide valuable insight to better understand the biogeographic importance of the Arakan Mountain system in generating the species and genetic diversity of murine rodents.
