**2.2. Genetic basis for variation**

38 Thyroid Hormone

[18,19].

that in other human populations.

**2. Variation in thyroid hormone physiology in humans** 

Geographical variation in the frequency of euthyroid endemic goiter has been extensively investigated [10,11,12]. In addition to iodine deficiency, other factors, such as smoking, age, sex, goitrogens, and body mass index, can also influence the etiology of euthyroid endemic goiter [13]. Although genetic predisposition to euthyroid goiter has been demonstrated [12,13,14], the molecular genetic mechanisms underlying the variation in susceptibility to goiter are not well understood. Polymorphism at the thyroglobulin (*TG*) [15,16] and Na+/I<sup>−</sup> symporter (*NIS*) loci [17] are reportedly associated with euthyroid goiter; however, linkage mapping in different families could not connect euthyroid goiter with such genetic variation

Racial variation in the level of thyroid-stimulating hormone (TSH), one of the major hormones regulating synthesis and secretion of thyroid hormone, has been also found. Multiple studies have revealed that serum TSH levels are higher in whites and Mexican Americans than in blacks [20,21,22]. These results suggest that race-specific reference values of TSH are necessary for evaluation of thyroid hormone-related diseases. Currently, the genetic and ecological basis for the racial variation in TSH levels is not well understood. The serum levels of thyroxine-binding globulin (TBG), a major thyroid hormone-binding protein in plasma, are lower in Australian Aborigines than in Caucasians in Western Australia [23]. Aborigines have a TBG variant that has reduced affinity for thyroid hormone and is more susceptible to heat and acid denaturation [24,25,26]. Two amino acids are substituted in this variant, one of which is considered responsible for the low binding affinity for thyroid hormones [26]. Aborigines usually have lower T4 levels, but have normal TSH levels and normal or borderline T3 levels. Because Aborigines do not show any clinical symptoms of hypothyroidism, the homeostasis of thyroid hormone physiology in Aborigines differs from

Although the adaptive significance of the variations remain elusive in the above cases, some interpopulation variation may result from adaptive evolution to divergent environments. Serum free T4 levels are higher in indigenous Evenki women than in nonindigenous Russian women living in the same communities in central Siberia [27]. The variation in free T4 levels was correlated with the variation in basal metabolic rate both in Evenki and Russian men and women [27]. Similar cases were also found for indigenous Nenets and nonindigenous Russians: both showed significant increases in total T4 levels during winter, but the magnitude of the increase was significantly greater in the Nenets than in the Russians [27]. Because thyroid hormones play important roles in regulating metabolic rate and adaptation to cold environments [28,29], human populations inhabiting colder environments may acquire genetic basis for more efficient thyroid hormone-induced

thermogenesis and may therefore be genetically adapted to cold environments [30].

Interindividual differences in TSH levels are prevalent, and have been found to be associated with variation in life span. In Ashkenazi Jews and Northern Italians, healthy

**2.1. Interindividual, geographical, and racial variation** 

In addition to the case of TGB in Australian Aborigines [34], polymorphisms associated with variation in thyroid hormone physiology have been found in other populations [35]. Several studies have focused on candidate genes involved in thyroid hormone signaling pathways and revealed that single nucleotide polymorphisms (SNPs) of the TSH receptor (*TSHR*) [36], iodothyronine deiodinases (*DIO1*, *DIO2*, and *DIO3*) [36,37], thyroid hormone transporter and thyroid hormone receptor genes accounted for variation in serum TSH and thyroid hormone levels [38,39]. Genome-wide association studies have also identified several genes involved in thyroid hormone signaling. Three SNPs at intron 1 of the phosphodiesterase 8B (*PDE8B*) gene are significantly associated with serum TSH levels [40,41]. *PDE8B* encodes a high-affinity cAMP-specific phosphodiesterase catalyzing the hydrolysis and inactivation of cAMP. Because the *PDE8B* transcript is undetectable in the pituitary, it is thought that PDE8B may affect TSH levels through its effect on TSH-dependent thyroid hormone synthesis and secretion in the thyroid gland. Interestingly, other cAMP-specific phosphodiesterases have also been showed to be associated with variation in TSH levels [41]. Since there are only a few studies revealing the mechanisms by which SNPs modify thyroid hormone signaling [38], further studies are needed to confirm their actual contribution to the natural variation in thyroid hormone physiology.

If genes involved in thyroid hormone pathways were targets of natural selection, we would be able to find some signatures of natural selection in the human genome. When natural selection increases the frequency of a new beneficial mutation in a population, the neighboring regions will reduce the genetic variation and increase the level of linkage disequilibrium [42]. Two genes involved in the thyroid hormone pathway, thyroid hormone receptor interactor 4 (*TRIP4*) and iodotyrosine deiodinase (*IYD*), showed a signature of selection in the genome of African Pygmies [43]. Importantly, a low frequency (9.4%) of goiter was reported for an African Pygmy population, although they inhabit an iodinedeficient region [44]. Because another population in the same region had a much higher frequency of goiter (42.9%), López Herráez et al. (2010) concluded that the signatures of selection in these genes might reflect genetic adaptations of Pygmies to iodine-deficient diets. Another study tried to identify the genes whose allele frequencies were significantly correlated with climate. The frequency of an SNP in *TRIP6* showed strong correlation with latitude [45].

The high rate of nonsynonymous (amino acid–altering) changes compared with the rate of synonymous (silent) changes also indicates that the genes might be under positive selection

[42]. By comparing the synonymous and nonsynonymous substitutions in the human and chimp genomes, putatively positively selected genes were screened [46]. Genes expressed in the thyroid gland have an excess of rapidly evolving genes compared with other tissues, except testis, which has more putatively positively selected genes [46]. Changes in thyroid hormone physiology may contribute to some of the physiological and morphological divergence between humans and apes [47,48].

Ecological Genetics of Thyroid Hormone Physiology in Humans and Wild Animals 41

Goiters were also observed in hatchery fishes and possibly resulted from iodine deficiency, because iodine treatment was able to cure the goiter [56]. In the case of the threespine stickleback *Gasterosteus aculeatus*, interpopulation variation in susceptibility to goiter when reared in fresh water was observed [57,58], although whether the goiter in the sticklebacks was caused by iodine deficiency is unknown. Interestingly, a mammalian species, *Auliscomys boliviensis*, inhabiting an environment severely depleted of iodine did not show goiter [59], suggesting that genetic variation in the susceptibility to endemic goiter exists

Latitudinal variation in plasma concentrations of thyroid hormone has been observed in both mammals and birds, and these variations might have evolved as adaptations to environments with divergent temperatures. Plasma total T4, free T4, and total T3 levels of sled dogs living in Alaska were higher than dogs in New York, especially in winter [60]. In addition, plasma T3 increased with increasing latitude in the northern cardinals *Cardinalis cardinalis*, whereas plasma T4 did not show a simple latitudinal cline: both southern and northern birds had higher T4 levels than birds living at an intermediate latitude [61]. In mammals, bottlenose dolphins *Tursiops truncatus* show variation in thyroid hormone concentrations between populations inhabiting different latitudes [62]: plasma total T3 and T4 were higher in dolphins from South Carolina with colder year-round temperatures than those from Florida with much warmer water temperatures. Since thyroid hormones play key roles in metabolism and heat generation, evolutionary adaptation to habitats with different temperatures may account for some of the latitudinal and geographical variation in thyroid hormone levels among natural populations. The genetic basis for the latitudinal

Several studies have demonstrated that variation in thyroid hormone physiology correlates with other potentially adaptive traits. Interspecies variation in tissue thyroid hormone levels and tissue sensitivity to thyroid hormone may be correlated with variation in the duration of the larval period in spadefoot toads [63]. For example, the tadpole of the desert-dwelling toad *Scaphiopus couchii* has higher tail and liver levels of thyroid hormone, and the tail tip is more sensitive to thyroid hormone *in vitro* than tail tips of other closely related species [63]. Because frog metamorphosis is controlled by thyroid hormone, the higher thyroid hormone levels and the higher sensitivity may explain the short larval period in this species. Rapid metamorphosis (i.e., the short period of water-dwelling at the tadpole stage) observed in the

desert toad is likely adaptive for survival in the deserts where water is scarce [64,65].

Thyroid hormones also play critical roles as yolk hormones in mammalian [66], bird [67], and teleost [68,69] development. In the bonnethead shark *Sphyrna tiburo*, the concentrations of T3 and T4 in the yolk from the Tampa Bay population were consistently higher than those in the yolk from the Florida Bay population [70]. The bonnethead shark in Tampa Bay develops faster and is larger at birth than that in Florida Bay [71]. Tampa Bay is located in a more northern region and is colder than Florida Bay. Because rapid growth is generally adaptive in colder environments [72,73], higher york thyroid hormone levels in the Tampa

among populations and species.

variation is currently unknown.

Bay population may be adaptive.
