![]() Since around 2006, the advent of genome-wide association studies and, more recently exome-sequencing, has provided the first detailed understanding of the genetic basis of complex traits. For example, an elegant 1999 analysis of allele-sharing in autistic siblings concluded from the lack of significant hits that there must be “a large number of loci (perhaps ≥15)”–this prediction was strikingly high at the time, but seems quaintly low now ( Risch et al., 1999, Weiner et al., 2016). Indeed, human geneticists expected that even complex traits would be driven by a handful of moderate-effect loci–thus giving rise to large numbers of mapping studies that were, in retrospect, greatly underpowered. As the number of genes grows very large, the contribution of each gene becomes correspondingly smaller, leading in the limit to Fisher’s famous “infinitesimal model” ( Barton et al., 2016).ĭespite the success of the infinitesimal model in describing inheritance patterns, especially in plant and animal breeding, it was unclear throughout the 20th century how many genes would actually be important for driving complex traits. This debate was largely resolved in a seminal 1918 paper by RA Fisher, who showed that if many genes affect a trait, then the random sampling of alleles at each gene produces a continuous, normally-distributed phenotype in the population ( Fisher, 1918). The biometricians believed that Mendelian genetics could not explain the continuous distribution of variation observed for many traits in humans and other species. ![]() In the early 1900s, there was fierce debate between the Mendelians-who were inspired by Mendel’s work on pea genetics and focused on discrete, monogenic phenotypes-and the biometricians, who were interested in the inheritance of continuous traits such as height. ![]() The longest-standing question in genetics is to understand how genetic variation contributes to phenotypic variation. ![]()
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