Molecular mechanisms underlying hair shape variation in the human population
Item statusRestricted Access
Embargo end date04/07/2021
Riddell, Jon Robert
Hair is one of the defining characteristics of mammals and functions in thermoregulation, protection, camouflage and social signalling. In humans, scalp hair is a distinctly variable trait, differing in colour, shape and density. Genome-wide association studies have identified two derived variants, that originated after human migration out of Africa and that are present at high frequency in East Asian populations, in the genes EDAR and PRSS53 as being associated with straight rather than curly hair. EDAR encodes Ectodysplasin A1 receptor, a transmembrane receptor involved in the development of ectodermal appendages such as hair, glands and teeth. The non-synonymous single nucleotide variant (SNV) (rs3827760) in EDAR has been shown to cause straighter, thicker hair fibres by increasing the signalling potency of EDAR, which ultimately leads to an increase in NF-κB activation. In Europeans, variants have also been identified in the first intron of EDAR that are associated with a decrease in beard thickness, highlighting the need to develop our understanding of the regulatory basis behind EDAR expression and its variation. PRSS53 is predicted to encode a serine protease and the variant associated with straight hair causes a glutamine to arginine substitution at position 30 (Q30R) of the protein. The derived allele has a frequency of 76% in the East Asian population, suggesting that it has undergone or is undergoing positive selection in this population. Another variant within PRSS53 (rs201075024), which causes a glycine to serine substitution at position 34 (G34S), also shows signs of positive selection and has a frequency of 54% in the South Asian population. This work investigates another nonsynonymous SNV (rs146567337) within EDAR which is present in Southeast Asian populations, and shows that this variant also leads to an increase in NF-κB activation, to a similar extent as that induced by the well-studied rs3827760. Through the generation of a Prss53 null mouse model, which exhibited a wavy coat and curly whiskers; the generation and phenotypic analysis of the hair and skin of Q30R and G34S mouse models; and cell-line based experiments testing the molecular effects of these derived variants, the work presented in this thesis proposes that hair shape is the driving force behind the selection of the variants within PRSS53 and EDAR. The characterisation of these variants will further develop our understanding of hair variation between human populations and thus, human evolution. Finally, this work identifies a potential model to study the regulation of EDAR expression using human induced pluripotent stem cells by differentiating them along an ectodermal lineage.