Annie Darwin's death, the evolution of tuberculosis and the need for systems epidemiology.

When Charles Darwin’s daughter Anne Elizabeth (‘Annie’, Photograph 1) died at the age of 10 years on April 23, 1851 her parents were devastated. Charles Darwin was a devoted father and constantly concerned about the health of his 10 children. His concerns were also motivated by fear of the consequences of marriage between relatives: Emma Wedgewood, his wife, was also his first cousin. The possible adverse effects of consanguineous marriage, which was not uncommon in England at that time, were a matter of debate. Annie’s death, and self-fertilization experiments in plants, made him suspect that ‘marriage between near relations is likewise injurious’. In 1870, Darwin motivated his mathematician son George to study the prevalence of close-kin marriages in patients in asylums in comparison with the prevalence of the general population. The study, which is reprinted in this issue of the journal, with several commentaries, was first published in 1875 and concluded that ‘the evil [of marriages between cousins] has been often much exaggerated’ and that ‘under favourable conditions of life, the apparent ill-effects were frequently almost nil’. Indeed, Annie died after a lingering illness, most likely of tuberculosis (TB) caused by Mycobacterium tuberculosis, and not of the consequences of a high coefficient of inbreeding (the F coefficient that features in one commentary). Of note, although