Wie beeinflusst pränatales Testosteron die Digit Ratio?

Eine interessante Studie in „Human Genetics“ untersucht näher, wie der Mechanismus funktioniert mit dem pränatales Testosteron die Digit Ratio beeinflusst:

Men and women differ statistically in the relative lengths of their index and ring fingers; and the ratio of these lengths has been used as a biomarker for prenatal testosterone. The ratio has been correlated with a wide range of traits and conditions including prostate cancer, obesity, autism, ADHD, and sexual orientation. In a genome-wide association study of 979 healthy adults, we find that digit ratio is strongly associated with variation upstream of SMOC1 (rs4902759: P = 1.41 9 10-8 ) and a meta-analysis of this and an independent study shows a probability of P = 1.5 9 10-11. The protein encoded by SMOC1 has recently been shown to play a critical role in limb development; its expression in prostate tissue is dependent on sex hormones, and it has been implicated in the sexually dimorphic development of the gonads. We put forward the hypothesis that SMOC1 provides a link between prenatal hormone exposure and digit ratio.

Quelle: Genetic association suggests that SMOC1 mediates between prenatal sex hormones and digit ratio (PDF)

Erst einmal zur dortigen Darstellung der Forschung zu diesem Zusammenhang:

Digit ratio in humans is established during the first trimester of development (Malas et al. 2006), coinciding with a period of high testosterone production in males (Abramovich 1974). Furthermore, it appears to remain stable across the lifespan (McIntyre et al. 2005). Until recently, evidence for Manning’s biomarker hypothesis had come entirely from correlational studies (McIntyre 2006). For instance, males and females with congenital adrenal hyperplasia, a condition resulting in elevated androgen production, have been found to have lower, more masculinised, digit ratios (Brown et al. 2002; Okten et al. 2002). Also, men with complete androgen insensitivity syndrome, due to non-functional androgen receptors, show feminized digit ratios (Berenbaum et al. 2009). Furthermore, a significant relationship has been shown between digit ratio at age 2 and the ratio of testosterone to oestrogen, measured in amniotic fluid (Lutchmaya et al. 2004). However, the most convincing evidence comes from experimental animal studies, which now confirm that prenatal hormones control 2D:4D development (Talarovicova´ et al. 2009; Zheng and Cohn 2011). Zheng and Cohn (2011) showed that digit ratio in mice is determined by the ratio of testosterone to oestrogen acting on the fourth digit in a narrow window early in development.

Und der Weg auf dem der dort vorgestellte Mechanismus funktionieren soll:

Given the clear role of SMOC1 in limb development and given that it is associated with variation in digit ratio in the normal population, what could be the mechanism by which it controls the phenotype? How should we reconcile our finding with the prenatal sex hormone theory? Zheng et al. showed that digit ratio is determined by the ratio of testosterone to oestrogen acting on the fourth digit, which is rich in androgen and oestrogen receptors. They found that activity of these receptors regulated the expression of skeletogenic genes that control chondrocyte proliferation, and that this happened differentially in the second and fourth digits (Zheng and Cohn 2011). The androgen and oestrogen receptors regulate gene expression by acting as nuclear receptors: activation by steroids causes the receptor to enter the nucleus and bind to its target DNA as a transcription factor. Of special interest, therefore, is the finding that SMOC1 is up-regulated by androgen (Love et al. 2009; Schaeffer et al. 2008) and down-regulated by oestrogen (Coleman et al. 2006) in prostate tissue. SMOC1 has also been shown to have a role in the sexually dimorphic development of the gonads (Pazin and Albrecht 2009). It is thus plausible that prenatal testosterone and oestrogen affect the expression of SMOC1, thus controlling digit ratio.

Interessantes auch zu den Unterschieden zwischen verschiedenen Völkern:

There are ethnic differences in digit ratio: populations of African origin have lower digit ratios than Caucasians, whereas Chinese populations have higher ratios than Caucasians (Manning et al. 2004). It is therefore interesting that the polymorphism in SMOC1 parallels ethnic differences in digit ratio. Although the frequency of the C allele at rs4902759 is 0.46 in the European population of the 1000 Genomes project and 0.48 in our own European sample, its frequency is 0.85 in African populations and 0.19 in Asians (1000 Genomes Project Consortium 2010). The difference in digit ratio between Africans and Chinese is of a similar order to the effect size for the two alleles at rs4902759. Thus, the ethnic differences in digit ratio could be derived from the distribution of the SMOC1 polymorphism between populations.

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