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

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 [18,19].

Ecological Genetics of Thyroid Hormone Physiology in Humans and Wild Animals 39

oldest-old people of around 100 years of age had higher TSH levels than elderly controls of around 70 years of age [31,32]. In addition, follow-up studies revealed that participants with abnormally high TSH levels had a lower mortality rate than those with normal or low TSH levels [33]. The offspring of Ashkenazi Jewish centenarians had significantly higher TSH levels, suggesting that higher TSH levels and longevity have heritable components [32];

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

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

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

however, the molecular mechanisms of this variation are unknown.

contribution to the natural variation in thyroid hormone physiology.

**2.2. Genetic basis for variation** 

latitude [45].

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 that in other human populations.

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 oldest-old people of around 100 years of age had higher TSH levels than elderly controls of around 70 years of age [31,32]. In addition, follow-up studies revealed that participants with abnormally high TSH levels had a lower mortality rate than those with normal or low TSH levels [33]. The offspring of Ashkenazi Jewish centenarians had significantly higher TSH levels, suggesting that higher TSH levels and longevity have heritable components [32]; however, the molecular mechanisms of this variation are unknown.
