Finger and toe ratios in humans and mice: implications for the aetiology of diseases influenced by HOX genes

Abstract

The differentiation of gonads, fingers, and toes is influenced by HOXA and HOXD genes. Therefore variation in the development of the gonads, and their fetal products such as testosterone, may be reflected in the morphology of the fingers and toes. One trait, the relative length of the second and fourth digits (2D:4D), shows sex differences (lower values in males) which are determined early, and 2D:4D has been found to correlate with fetal growth, sperm counts, family size, autism, myocardial infarction, and breast cancer. HOX genes are highly conserved in mammals and they influence the differentiation of all the fingers and toes. We suggest that (a) 2D:4D and other ratios of finger and toe length show sex differences throughout the mammals including humans and mice, (b) finger and toe ratios correlate with sex determination, the fetal production of sex steroids, and fetal programming of disease, and (c) HOX gene influences on sex determination, the morphogenesis of the urinogenital system, fertility, haematopoiesis, and breast cancer suggests that finger and toe ratios in humans and mice may correlate with many sex dependent diseases.

Introduction

The Homeobox or HOX genes have a fundamental role in embryonic development and represent a highly conserved family of transcription factors (1). Humans and mice have 39 HOX genes which are organised into four clusters HOXA through to HOXD. The differentiation of the urinogenital system (including the gonads) and the fingers and toes is influenced by two groups of HOX genes, HOXA and HOXD [2], [3]. Defects in the digits and urinogenital system may result from mutation in these groups of genes. For example the hand–foot–genital syndrome in humans is caused by mutations in HOXA13 (4). This syndrome is characterised by displaced urethral openings and a divided uterus together with abnormalities of the second and fifth digits, short first metacarpals, fusion of the wrist bones, and short great toes. Similarly deregulation of HOXD13 expression leads to syndactyly and causes genital malformations in mice and humans [5], [6].

The relationship between gonad differentiation and the formation of fingers and toes led to the suggestion that patterns of digit and toe morphology may correlate with gonad function in the fetus and adult [7], [8]. The most obvious candidate for such an association is the ratio of the length of the second digit (the ‘index’ finger) to that of the fourth digit (the ‘ring’ finger) i.e., the 2D:4D ratio. It has been known for over 100 years that males have on average lower values of 2D:4D (shorter 2D in relation to 4D) than do females (9). Manning et al. (1998) suggested that the sex difference in 2D:4D indicates an interaction between gonad and digit differentiation such that 2D:4D is established early and probably in utero, high prenatal levels of testosterone produced from week eight by the fetal testes may lead to low 2D:4D ratios while high prenatal oestrogen is associated with high values of 2D:4D, men with high 2D:4D have an increased chance of azoospermia and 2D:4D is negatively correlated with sperm numbers per ejaculate. Subsequent work has shown low 2D:4D to be associated with (a) large families in males (10), (b) traits in which there is an excess of males, e.g., left-handedness (11), autism, and Asperger’s syndrome (12), (c) homosexuality in men (13) and women (14), (d) an increase in the proportion of males within families (15), (e) high sporting ability in men (16), (f) protection against early myocardial infarction in males (17) (g) protection against early presentation of breast cancer in women (18), and (h) a high length and a low head circumference/length ratio at birth among boys who had above median placental weight (19).

However, 2D:4D ratio may not be the only correlate of in utero conditions to be found in the distal skeleton. HOXA and HOXD influence the differentiation of all the fingers and toes. Therefore we may be missing other valuable predictors of fetal growth and differentiation. Moreover, HOX genes are highly conservative throughout the mammals with similar patterns of effects in humans and rodents (1). We suggest that sex differences in digit and toe ratios relate to HOX gene function, and gonad formation/function during fetal growth in both humans and mice.