Anti-EDAR monoclonal antibody, clone 243255 [Biotin]

Identifying genomic locations of natural selection from sequence data is an ongoing challenge in population genetics. Current methods utilizing information combined from several summary statistics typically assume no correlation of summary statistics regardless of the genomic location from which they are calculated. However, due to linkage disequilibrium, summary statistics calculated at nearby genomic positions are highly correlated. We introduce an approach termed Trendsetter that accounts for the similarity of statistics calculated from adjacent genomic regions through trend filtering, while reducing the effects of multicollinearity through regularization. Our penalized regression framework has high power to detect sweeps, is capable of classifying sweep regions as either hard or soft, and can be applied to other selection scenarios as well. We find that Trendsetter is robust to both extensive missing data and strong background selection, and has comparable power to similar current approaches. Moreover, the model learned by Trendsetter can be viewed as a set of curves modeling the spatial distribution of summary statistics in the genome. Application to human genomic data revealed positively selected regions previously discovered such as LCT in Europeans and EDAR in East Asians. We also identified a number of novel candidates and show that populations with greater relatedness share more sweep signals.

Hypohidrotic ectodermal dysplasia (HED) can be caused by mutations in the X-linked ectodysplasin A (ED1) gene or the autosomal ectodysplasin A-receptor (EDAR) and EDAR-associated death domain (EDARADD) genes. X-linked and autosomal forms are sometimes clinically indistinguishable. For genetic counseling in families, it is therefore important to know the gene involved. In 24 of 42 unrelated patients with features of HED, we found a mutation in ED1. ED1-negative patients were screened for mutations in EDAR and EDARADD. We found mutations in EDAR in 5 of these 18 patients. One mutation, p.Glu354X, is novel. In EDARADD, a novel variant p.Ser93Phe, probably a neutral polymorphism, was also found. Clinically, there was a difference between autosomal dominant and autosomal recessive HED patients. The phenotype in patients with mutations in both EDAR alleles was comparable to males with X-linked HED. Patients with autosomal dominant HED had features comparable to those of female carriers of X-linked HED. The teeth of these patients were quite severely affected. Hypohidrosis and sparse hair were also evident, but less severe. This study confirms Chassaing et al's earlier finding that mutations in EDAR account for approximately 25% of non-ED1-related HED. Mutations leading to a premature stop codon have a recessive effect except when the stop codon is in the last exon. Heterozygous missense mutations in the functional domains of the gene may have a dominant-negative effect with much variation in expression. Patients with homozygous or compound heterozygous mutations in the EDAR gene have a more severe phenotype than those with a heterozygous missense, nonsense or frame-shift mutation.