Wilhelm Weinberg - Ascertainment Bias and Analysis of Phenotypic Variance

Ascertainment Bias and Analysis of Phenotypic Variance

Weinberg pioneered in studies of twins, developing techniques for analysis of phenotypic variation that partitioned this variance into genetic and environmental components. In the process, he recognized that ascertainment bias was affecting many of his calculations, and he produced methods to correct for it.

Weinberg observed that proportions of homozygotes in familial studies of classic autosomal recessive genetic diseases generally exceed the expected Mendelian ratio of 1:4, and he explained how this is the result of ascertainment bias. In his work with albino children, he recognized that in some families where both parents carry a recessive mutation, no disease occurs by chance. He reasoned that many carrier couples were not being counted, and he demonstrated methods for correcting results to produce the expected Mendelian ratios.

He discovered the answer to several seeming paradoxes caused by ascertainment bias. For example, he explained that the reason that parents as a whole are more fertile than their children is because children must necessarily come from fertile parents.

By the same token, he recognized that ascertainment was responsible for a phenomenon known as anticipation, the tendency for a genetic disease to manifest earlier in life and with increased severity in later generations. Weinberg recognized that this was because those later generations were the offspring of that selected group of earlier carriers that had successfully reproduced. Subsequent researchers have reasoned that such carriers who reproduce might be expected to carry favorable genetic modifiers that allowed them to reproduce successfully in spite of their disease. In a class of autosomal and X-linked dominant diseases known as trinucleotide repeat disorders (for example, Huntington’s disease), a molecular mechanism for anticipation has also been demonstrated. It is caused by the instability of repeating nucleotide sequences that tend to undergo expansion, causing disease at an earlier and earlier age as trinucleotide repeats accumulate.