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Gene duplication and genome duplication are considered to play significant roles in vertebrate evolution. Although DNA sequences are highly homologous in mammalian species, differences are present in the number of genes in gene families. With the exception of a few gene families, the involvement of particular gene families in mammalian functions is yet to be clarified. Our recent studies have revealed that a rat mutant strain, Hirosaki hairless rat (HHR), shows defects in certain mammalian functions, resulting from deletions of duplicated genes belonging to particular gene families. Mammals are characterized by a number of common traits, including lactation and hair growth (McClellan et al. 2008). Mammary glands are essential for mammals as organs to produce milk for their young. In eutherian placental mammals, embryonic and fetal development occur in the maternal uterus, and immuno-suppressive regulatory T cells (Tregs) are required to maintain successful pregnancy by inducing tolerance to the semiallogeneic fetus (Rowe et al. 2012; Jiang et al. 2014). Thus, Tregs, as well as mammary glands, are essential for mammalian development.
HHR is a mutant strain spontaneously derived from Sprague–Dawley rats (SDRs), and its inheritance is autosomal recessive (Fig. 1, Hanada et al. 1988; Akita et al. 2009). The hairless phenotype of HHRs is due to the deletion of an 80-kb genomic DNA, ranging from exon 9 of Kb25 (Krt85) to exon 9 of Krt2-25 (Fig. 2a). The breakpoints of Krt85 and Krt2-25 are within a 95-bp portion shared by the two genes, indicating that the deletion is due to non-allelic homologous recombination (Nanashima et al. 2008). Hard keratin-based hair, lactation, and mammary glands are all characteristics common in mammals (McClellan et al. 2008). Female HHRs show involution of the mammary glands at an early stage of lactation (Nanashima et al. 2005). Array comparative genomic hybridization revealed the deletion of 50 kb of genomic DNA from 1q21 in HHRs, including the Pla2g4c gene and neighboring LOC691813 gene (Fig. 2b, Nanashima et al. 2015). Both genes are highly homologous and their breakpoints are within a shared 149-bp region. Inhibition of Pla2g4c expression in rat mammary cells has revealed that it is involved in the prevention of apoptosis induction.
In the HHR thymus, the number of naturally occurring Treg (nTreg) was decreased. The Ly49 genes: Ly49s3, s4, i3, and i4, in the chromosome 4q42 region, are deleted in HHRs (Fig. 2c). Among these genes, the Ly49s3 gene is expressed in thymic dendritic cells in wild-type SDRs, but not in HHRs. CD4-positive SDR thymocytes can be differentiated to nTreg by co-culture with SDR dendritic cells, whereas HHR dendritic cells show deficient induction of nTreg differentiation (Yamada et al. 2013). The direct involvement of Ly49s3 in the induction of nTreg differentiation is demonstrated by forced expression of Ly49s3 in HHR dendritic cells.
Thus, basic hair keratin genes, Pla2g4c and Ly49, are deleted in HHRs, and these deletions result in alterations to mammalian functions. Interestingly, these genes are members of gene families that form gene clusters, suggesting that such clustered genes may be important for the development in mammals. Tandem gene duplication plays a major role in the formation of clustered genes (Liao and Chang 2014), and comparative sequence analyses of clustered gene families, such as the β-globin gene, in different mammals revealed species-specific differences in gene loss, fusion, and conversion (Strachan and Read 2004). These findings suggest that gene duplication may play an important role in vertebrate evolution and development in mammals.
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Acknowledgements
This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (25640058 to NN and 24500484 to TY), a Hirosaki University Grant for Exploratory Research by Young Scientists, and grant from the Karoji Memorial Fund for Medical Research of Hirosaki University Graduate School of Medicine.
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Nanashima, N., Yamada, T., Shimizu, T. et al. Involvement of Clustered Genes in Mammalian Functions: Their Relation in a Rat Mutant Strain. J Mol Evol 84, 159–161 (2017). https://doi.org/10.1007/s00239-017-9788-6
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DOI: https://doi.org/10.1007/s00239-017-9788-6