Excavating past population structures by surname-based sampling: the genetic legacy of the Vikings in northwest

The genetic structures of past human populations are obscured by recent migrations and expansions and have been observed only indirectly by inference from modern samples. However, the unique link between a heritable cultural marker, the patrilineal surname, and a genetic marker, the Y chromosome, provides a means to target sets of modern individuals that might resemble populations at the time of surname establishment. As a test case, we studied samples from the Wirral Peninsula and West Lancashire, in northwest England. Place-names and archaeology show clear evidence of a past Viking presence, but heavy immigration and population growth since the industrial revolution are likely to have weakened the genetic signal of a 1,000-year-old Scandinavian contribution. Samples ascertained on the basis of 2 generations of residence were compared with independent samples based on known ancestry in the region plus the possession of a surname known from historical records to have been present there in medieval times. The Y-chromosomal haplotypes of these 2 sets of samples are significantly different, and in admixture analyses, the surnameascertained samples show markedly greater Scandinavian ancestry proportions, supporting the idea that northwest England was once heavily populated by Scandinavian settlers. The method of historical surname-based ascertainment promises to allow investigation of the influence of migration and drift over the last few centuries in changing the population structure of Britain and will have general utility in other regions where surnames are patrilineal and suitable historical records survive

Excavating past population structures by surname-based sampling: the genetic legacy of the Vikings in northwest England

The genetic structures of past human populations are obscured by recent migrations and expansions, and can been observed only indirectly by inference from modern samples. However, the unique link between a heritable cultural marker, the patrilineal surname, and a genetic marker, the Y chromosome, provides a means to target sets of modern individuals that might resemble populations at the time of surname establishment. As a test case, we studied samples from the Wirral peninsula and West Lancashire, in northwest England. Place names and archaeology show clear evidence of a past Viking presence, but heavy immigration and population growth since the Industrial Revolution are likely to have weakened the genetic signal of a thousand-year-old Scandinavian contribution. Samples ascertained on the basis of two generations of residence were compared with independent samples based on known ancestry in the region, plus the possession of a surname known from historical records to have been present there in medieval times. The Y-chromosomal haplotypes of these two sets of samples are significantly different, and in admixture analyses the surname-ascertained samples show markedly greater Scandinavian ancestry proportions, supporting the idea that northwest England was once heavily populated by Scandinavian settlers. The method of historical surname-based ascertainment promises to allow investigation of the influence of migration and drift over the last few centuries in changing the population structure of Britain, and will have general utility in other regions where surnames are patrilineal and suitable historical records survive

Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild type CFTR channels is reported. The design, synthesis and biological evaluation of compounds 7 to 33 to establish structure activity relationships (SAR) of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients

Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild type CFTR channels is reported. The design, synthesis and biological evaluation of compounds 7 to 33 to establish structure activity relationships (SAR) of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients