Some problems in population genetics.

It has been known for a long time that patients suffering from rare diseases following a recessive mode of inheritance are, in a high proportion of cases, offspring of marriages between related partners who themselves are healthy. In such cases varying percentages of 'consanguineous marriages' have been reported. Such figures are useful as a general orientation. The great differences found between different reports reflect, however, the extent to which genealogical research into the pedigrees has been carried out, and it is the rate of firstcousin marriages among parents of systematically collected probands which is of the most practical importance. Only where data from first-cousin marriages can systematically be collected for the subject under investigation and compared with the rate of such marriages in the general population is the information of value. Garrod (1901, 1902) seems to have been the first clinician to observe that a high percentage of parents of patients with rare recessive diseases were firstcousins, since such marriages increase the probability for heterozygotes to come together, first-cousins having one-eighth of their genes in common. Furthermore, Garrod's clarifying discussions with biologists, for instance with Bateson, in these early days of rediscovery of the Mendelian laws do not lessen the greatness of Garrod's pioneer work; in fact the contrary is the case. It is Garrod's sharp observations combined with his theoretical reasoning that solved the puzzle and his concept of inborn errors of metabolism in this connexion was far ahead of his time. After Garrod many British clinicians have carried the fine tradition in human genetics further, and in ophthalmology, which has contributed so much to human genetics, in our day Sorsby has an intemational leading position as a clinical geneticist. The German physician Weinberg (1920, p. 40) seems to have been the first to deduce a correct formula for the relation between the prevalence of first-cousin marriages between the parents of recessive affected individuals (k), the prevalence of a recessive gene (r), and the prevalence of first-cousin marriages in the general population (c):