Genetic architecture of body size in mammals

Abstract

Body size, as measured by height in humans or weight in domestic species, is an archetypical quantitative or com plex trait that shows continuous variation. It has been extensively recorded and studied for over a century because of its importance to ecology, its relevance in farming, and because it is an important indicator of human growth and health [1]. The genetic architecture underlying body size was initially uncertain and Fisher proposed an infinitesimal model that was successfully applied for many years [2]. This model, with an infinite number of loci, each with infinitesimal effect, is not literally true but it does provide a good fit to the data. In more recent times the infinitesimal model has gradually been replaced by a finite number of loci, each with discrete mutations. However, observations now form almost two disjointed sets: one set in which individual mutations have large effects (that is, socalled Mendelian traits) and another set where variants have small effects. This review attempts to bridge the gap between these two sets of observations using body size as an example of an extensively studied complex trait in mammalian species.The genetic architecture underlying variation in complex traits is currently a topic of extensive debate. This is particularly true for human complex diseases but also for agriculture because of its impact in predicting future phenotypes (for example, [36]). Primarily it is the number, size and frequency of mutations that are under the most scrutiny. Taking the human disease example, some argue for a common disease common variant hypothesis where genetic susceptibility to disease is the result of many relatively highfrequency mutations each with small effect on disease susceptibility. However, others argue for a rare variant common disease hypo thesis where many lowfrequency mutations have large effects. As we shall see, observations on the genetic architecture underlying body size for humans and other mammals provide evidence for both hypotheses. Our discussion begins by describing the number, frequency and size of mutations with large effects for humans, mice and domesticated species. We then move onto genome wide association studies (GWASs) that have investigated segregating variation in these species. We find evidence for moderatetolarge effect mutations in domestic species but highlight that this category of mutations goes undetected in human studies. Finally, we apply simple evolutionary theory to explain the observed distribution of mutation effects for human stature. Our model implies that most of the segregating variation in human height is caused by mutations with smalltomoderate effects. Variants of large effect Family studies in humansIdentification of causative mutations for socalled Men delian traits has been possible by studying the segregation within families of mutations and phenotypes. Such mutations must have large effects so that individuals can be classified into genotype classes using their phenotype despite the background variation caused by ot...

Human pigmentation genes under environmental selection

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Complex Inheritance of Melanoma and Pigmentation of Coat and Skin in Grey Horses

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