Molecular evolution of HR, a gene that regulates the postnatal cycle of the hair follicle

Abstract

Hair is a unique mammalian trait that is absent in all other animal forms. Hairlessness is rare in mammals and humans are exceptional among primates in lacking dense layer of hair covering. HR was the first gene identified to be implicated in hair-cycle regulation. Point mutations in HR lead to congenital human hair loss, which results in the complete loss of body and scalp hairs. HR functions are indispensable for initiation of postnatal hair follicular cycling. This study investigates the phylogenetic history and analyzes the protein evolutionary rate to provide useful insight into the molecular evolution of HR. The data demonstrates an acceleration of HR sequence evolution in human branch and suggests that the ability of HR protein to mediate postnatal hair-cycling has been altered in the course of human evolution. In particular those residues were pinpointed which should be regarded as target of positive Darwinian selection during human evolution.

Figure 1. The evolutionary history was inferred using the Neighbor-Joining method.

Uncorrected p-distance was used. Numbers on branches represent bootstrap values (based on 1000 replications) supporting that branch; only the values ≥ 50% are presented here. All positions containing gaps and missing data were eliminated from the dataset (complete deletion option). There were a total of 399 positions in the final dataset. Scale bar shows amino acid substitution per site.

Figure 2. Molecular evolution of HR in primates.

Ka and Ks values were estimated for each branch of the HR tree with the reconstructed sequences at ancestral nodes. Number above the lineage indicates the minimum number of amino acid replacements to explain differences among reconstructed sequences. Ka/Ks ratios are shown below branches. Branch lengths are drawn arbitrarily and do not reflect evolutionary time.

Figure 3. Sliding window analysis of human-chimpanzee Ka-Ks along the Hairless coding region.

Ka-Ks was calculated at the sliding increment of 10 codons (30 nucleotides). Peaks (R1–R7) above the dotted line indicates an excess of non-synonymous substitutions over the neutral expectations (Ka-Ks > 0).

Figure 4. Domain organization of HR protein.

Schematic view of comparative organization of key functional domains of HR across human paralogous proteins and orthologous proteins from phylogenetically distant mammalian species. Protein lengths are drawn approximately to scale and domains are color coded. JmjC; Jumonji C, Zf; Zinc finger, TR-IDs; TR-interacting domains, ROR-IDs; ROR-interacting domains.