RESUMEN
Ancient genomic sequences have started to reveal the origin and the demographic impact of farmers from the Neolithic period spreading into Europe. The adoption of farming, stock breeding and sedentary societies during the Neolithic may have resulted in adaptive changes in genes associated with immunity and diet. However, the limited data available from earlier hunter-gatherers preclude an understanding of the selective processes associated with this crucial transition to agriculture in recent human evolution. Here we sequence an approximately 7,000-year-old Mesolithic skeleton discovered at the La Braña-Arintero site in León, Spain, to retrieve a complete pre-agricultural European human genome. Analysis of this genome in the context of other ancient samples suggests the existence of a common ancient genomic signature across western and central Eurasia from the Upper Paleolithic to the Mesolithic. The La Braña individual carries ancestral alleles in several skin pigmentation genes, suggesting that the light skin of modern Europeans was not yet ubiquitous in Mesolithic times. Moreover, we provide evidence that a significant number of derived, putatively adaptive variants associated with pathogen resistance in modern Europeans were already present in this hunter-gatherer.
Asunto(s)
Alelos , Fósiles , Inmunidad/genética , Pigmentación/genética , Población Blanca/genética , Agricultura/historia , Evolución Biológica , Cuevas , Color del Ojo/genética , Genoma Humano/genética , Genómica , Historia Antigua , Humanos , Intolerancia a la Lactosa/genética , Masculino , Polimorfismo de Nucleótido Simple/genética , Análisis de Componente Principal , Esqueleto , Pigmentación de la Piel/genética , España/etnologíaRESUMEN
Binding of melanocortin peptide agonists to the melanocortin-1 receptor of melanocytes results in eumelanin production, whereas binding of the agouti signalling protein inverse agonist results in pheomelanin synthesis. Recently, a novel melanocortin-1 receptor ligand was reported. A ß-defensin gene mutation was found to be responsible for black coat colour in domestic dogs. Notably, the human equivalent, ß-defensin 3, was found to bind with high affinity to the melanocortin-1 receptor; however, the action of ß-defensin as an agonist or antagonist was unknown. Here, we use in vitro assays to show that ß-defensin 3 is able to act as a weak partial agonist for cAMP signalling in human embryonic kidney (HEK) cells expressing human melanocortin-1 receptor. ß-defensin 3 is also able to activate MAPK signalling in HEK cells stably expressing either wild type or variant melanocortin-1 receptors. We suggest that ß-defensin 3 may be a novel melanocortin-1 receptor agonist involved in regulating melanocyte responses in humans.
Asunto(s)
Receptor de Melanocortina Tipo 1/agonistas , Transducción de Señal/efectos de los fármacos , alfa-MSH/análogos & derivados , beta-Defensinas/farmacología , Proteína de Señalización Agouti/farmacología , Anticarcinógenos/farmacología , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Células HEK293 , Humanos , Ligandos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanocitos/efectos de los fármacos , Melanocitos/metabolismo , Melanocitos/fisiología , Receptor de Melanocortina Tipo 1/metabolismo , Regulación hacia Arriba/efectos de los fármacos , alfa-MSH/farmacología , beta-Defensinas/agonistas , beta-Defensinas/metabolismoRESUMEN
The BRN2 transcription factor (POU3F2, N-Oct-3) has been implicated in development of the melanocytic lineage and in melanoma. Using a low calcium medium supplemented with stem cell factor, fibroblast growth factor-2, endothelin-3 and cholera toxin, we have established and partially characterised human melanocyte precursor cells, which are unpigmented, contain immature melanosomes and lack L-dihydroxyphenylalanine reactivity. Melanoblast cultures expressed high levels of BRN2 compared to melanocytes, which decreased to a level similar to that of melanocytes when cultured in medium that contained phorbol ester but lacked endothelin-3, stem cell factor and fibroblast growth factor-2. This decrease in BRN2 accompanied a positive L-dihydroxyphenylalanine reaction and induction of melanosome maturation consistent with melanoblast differentiation seen during development. Culture of primary melanocytes in low calcium medium supplemented with stem cell factor, fibroblast growth factor-2 and endothelin-3 caused an increase in BRN2 protein levels with a concomitant change to a melanoblast-like morphology. Synergism between any two of these growth factors was required for BRN2 protein induction, whereas all three factors were required to alter melanocyte morphology and for maximal BRN2 protein expression. These finding implicate BRN2 as an early marker of melanoblasts that may contribute to the hierarchy of melanocytic gene control.