Unexplained infertility in Charles Darwin's family: genetic aspect.

Sir, The recent paper of Siristatidis and Bhattacharya (2007) argues that the term unexplained infertility (UI) appears sustainable from a clinical and practical perspective, in spite of some fuzziness. I agree with this conclusion having in mind complicated multi-step processes of gametogenesis, meiosis and fertilization. The UI term leaves a door open for diverse unexpected scenarios of reproductive errors. For instance, UI was observed in a two century examination of records of one Scottish family with paternally derived twinning (StClair and Golubovsky, 2002). Authors suggested an action of a certain dominant factor which being active in male gametes during fertilization promotes an increased incidence of dispermy with subsequent triploidy, partial and complete moles, chimeras and pregnancy failure (Golubovsky, 2003). The paradox consist here in the UI origin due to an ‘super-active’ male gametes but not due to an oligospermy or immotile sperm. The other important rationale is that the term UI keeps a door open for a retrospective reproduction analysis of infertility occurred in some famous historical figures and genealogies. Thus, George Washington, the founder of the USA, suffered from infertility and harbored great personal sadness. Basing on contemporary knowledge, Amory (2004) presented careful retrospective differential diagnosis for Washington’s UI, eliminating here at first a female origin of UI and elucidating possible role of some major categories of male infertility like Kleinfelter’s syndrome, endocrine and sexual dysfunction, anatomic defects like cryptorchism and toxic exposures. Genitourinary infection as a sequel of pulmonary tuberculosis seems more plausible according to biographic details. Certainly, the discussion of Washington’s UI cannot diminish his great historical status. The other striking case of UI demonstrates the Charles Darwin pedigree which I first regard here in genetic terms. Starting from the grand-father Erasmus Darwin, this family endowed the human civilization with two cousin genius—Francis Galton and Charles Darwin. Ironically, Galton the founder of eugenic movement was childless. And three children of Charles Darwin suffered from UI. I composed the relevant genetic genealogy scheme (Fig. 1) based on detailed biographies (Desmond and Moore, 1991; Browne, 1995). The Emma Nora Barlow, the daughter of Charles Darwin’s son Horace, lived 104 years (1885–1989) and first published in 1958 family tree with relevant reproduction data (Barlow, 1958). Charles Darwin was 30 when he married his 31-year-old cousin Emma Wedgwood. Charles and Emma were cousins and had common Wedgwood grandparents from the maternal part. Their first son William was born 11 months after marriage and eight more children were born in a period of next 11.5 years. Then, after 5 year lag-period Emma at age 48 delivered her last 10th child, Charles Waring, who died 2 years lately. Two daughters and five sons lived to adulthood. Elisabeth never married. From six siblings with long-term marriage history William, Henrietta and Leonard manifested UI. The male infertility of Leonard is accentuated by his two childless marriages (the duration of the first one was 16 years). There is serious reason to suggest that dramatic three children infertility in Darwin progeny is due to cousin marriage and segregation of a recessive mutation leading to male and female infertility. All three infertile children William, Henrietta and Leonard expressed normal vitality, living 75, 86 and 93 years, correspondingly. William was an active banker. Leonard became prominent war engineer and economist. Since 1911–1928 he was a chairman of British Eugenic Society. Curiously, other three fertile Darwin’s sons— George, Francis and Horace—made remarkable academic carrier and each was elected the Fellow of the Royal Society. What kind of recessive mutation in Darwin’s consanguineous marriage might lead in his progeny both to male and female infertility? A possible candidate is an inherited a gonadotropic hormone lesion. Similar family reproduction pattern was presented in recent description of a consanguineous family in which three siblings, two men and one woman, Figure 1: The fragment of family tree of Charles Darwin. The black color and double vertical lines designate the infertility in three siblings due to segregation a certain recessive meiotic mutation. Charles Darwin and Emma Wedgwood are indicated as heterozygous carriers of suggested mutation. The number of progeny of fertile Darwin’s children in the next generation is indicated in parenthesis Letters to the Editor