**Author details**

42 Thyroid Hormone

should be conducted.

interpopulation variation seen in the brook charr [87].

might act on the *TSH* locus.

**4. Conclusions and future directions**

Thyroid hormone is also implicated in the regulation of longevity in animals [74,75]. Longlived species of squirrels, deer mice, bats and mole-rats maintain low levels of thyroid hormone [76,77,78,79]. Hypothyroid Wister rats live longer than hyperthyroid rats [80]. Furthermore, investigations in the Ames and Snell dwarf mice have demonstrated that mutation at the *Prop-1* and *Pit-1* genes lead to defects in the generation of pituitary cells including thyrotrope and the dwarf mice have extended longevity [81,82,83,84,85]. Thus, it is possible that changes in the thyroid hormone pathway are involved in variation of life span among wild animals, as is observed among human races (see above). Further research on the genetic basis for the low thyroid hormone levels observed in the long-lived animals

Divergence in thyroid hormone physiology may also be important for adaptation of stickleback fishes to marine and freshwater environments [86]. Stream-resident populations of the threespine stickleback have repeatedly evolved from ancestral marine populations. First, Kitano et al. (2010) found plasma thyroid hormone levels and metabolic rate were lower in stream-resident populations than in ancestral marine populations [86]. Since thyroid hormones regulate metabolic rate in sticklebacks [86], it is likely that lower thyroid hormone in stream-resident sticklebacks is adaptive for permanent residency in small streams where oxygen and food are often scarce. In addition, the expression level of thyroid stimulating hormone *TSHß2* gene was significantly lower in the pituitary gland of streamresident fish than in that of marine fish. Allele-specific expression analysis with F1 hybrids revealed that some of the differences in *TSHß2* expression levels were caused by *cis*regulatory changes at the *TSHß2* locus. Importantly, a signature of natural selection was found at *TSHß2* locus: several SNPs within the *cis*-regulatory region exhibited marked differences in the allele frequency between marine and stream-resident populations. Thus, changes in the thyroid hormone pathways may play important roles in genetic adaptation to freshwater environments. In other fishes exhibiting alternate life history style, such as the brook charr *Salvelinus fontinalis* anadromous and resident forms show differences in thyroid hormone concentrations, although genetic factors seem to be of little importance in the

Other than the *TSH* loci in sticklebacks, there are few studies that have examined whether thyroid hormone-related genes are under selective pressure in wild animal populations. However, domestication seems to be a strong artificial selection on thyroid hormone-related genes. Very strong selective sweeps were found at the *TSHR* loci in chickens [88] and sheep [89]. Because TSH is found to regulate photoperiodic control of reproduction [90,91,92,93,94], artificial selection favoring continuous reproduction under domestication

We found similar features in the patterns of variation in thyroid hormone physiology in humans and other animals. First, genetic variation in the susceptibility to endemic goiter exists among populations and species. Second, some of the latitudinal and racial variation in Asano Ishikawa and Jun Kitano\* *Ecological Genetics Laboratory and JST PRESTO, National Institute of Genetics, Mishima, Japan* 
