Biology subjects

Coutinho, A.

Publications and source records attributed to Coutinho, A..

3 recordsLinked to original sources

bioRxiv2025

Lipid Composition Controls the Huntingtin Exon1 Membrane-Association and Differentially Modulates its Flanking Regions Dynamics

The pathological expansion of the polyglutamine (polyQ) repeat within the first exon of huntingtin (Httex1) protein is a defining hallmark of Huntingtons disease (HD). Multiple evidence supports that the membrane recruitment of Httex1 is critical for its self-assembly and related toxicity in HD. In this work, we quantitatively examined the early steps of monomeric Httex1(23Q) association with lipid membranes and its impact on the conformational dynamics of the adjacent polyQ regions - the N-terminal N17 segment and C-terminal proline-rich region (PRR). A broad range of membrane physical properties was explored, including zwitterionic and anionic lipids, and also co-existing liquid-ordered and liquid-disordered phases. Two single cysteine mutants were engineered at the N- and C-termini of Httex1(23Q) and fluorescently-labeled with acrylodan or Atto 488 to probe their local polarity and flexibility, respectively. Our results indicate that Httex1- 23Q preferentially binds to negatively-charged lipid vesicles, and to a lower extent to liquid ordered/disordered phases. The N-terminal N17 segment inserts deeply into anionic membranes, adopting a less flexible state than in aqueous solution. At variance, the C-terminal PRR remains highly dynamic and solvent exposed in the Httex1-23Q membrane-bound state, preserving its intrinsic disordered features across all lipid compositions used. Altogether, our work provides unique insight into the distinct roles of each flanking polyQ region in mediating httex1-lipid binding, and how the lipid composition further modulates these early interaction steps.

biophysics↗

bioRxiv2017

Genomics of Mesolithic Scandinavia reveal colonization routes and high-latitude adaptation

Scandinavia was one of the last geographic areas in Europe to become habitable for humans after the last glaciation. However, the origin(s) of the first colonizers and their migration routes remain unclear. We sequenced the genomes, up to 57x coverage, of seven hunter-gatherers excavated across Scandinavia and dated to 9,500-6,000 years before present. Surprisingly, among the Scandinavian Mesolithic individuals, the genetic data display an east-west genetic gradient that opposes the pattern seen in other parts of Mesolithic Europe. This result suggests that Scandinavia was initially colonized following two different routes: one from the south, the other from the northeast. The latter followed the ice-free Norwegian north Atlantic coast, along which novel and advanced pressure-blade stone-tool techniques may have spread. These two groups met and mixed in Scandinavia, creating a genetically diverse population, which shows patterns of genetic adaptation to high latitude environments. These adaptations include high frequencies of low pigmentation variants and a gene-region associated with physical performance, which shows strong continuity into modern-day northern Europeans.

genomics↗

bioRxiv2017

Ancient genomes from southern Africa pushes modern human divergence beyond 260,000 years ago

Southern Africa is consistently placed as one of the potential regions for the evolution of Homo sapiens. To examine the regions human prehistory prior to the arrival of migrants from East and West Africa or Eurasia in the last 1,700 years, we generated and analyzed genome sequence data from seven ancient individuals from KwaZulu-Natal, South Africa. Three Stone Age hunter-gatherers date to ~2,000 years ago, and we show that they were related to current-day southern San groups such as the Karretjie People. Four Iron Age farmers (300-500 years old) have genetic signatures similar to present day Bantu-speakers. The genome sequence (13x coverage) of a juvenile boy from Ballito Bay, who lived ~2,000 years ago, demonstrates that southern African Stone Age hunter-gatherers were not impacted by recent admixture; however, we estimate that all modern-day Khoekhoe and San groups have been influenced by 9-22% genetic admixture from East African/Eurasian pastoralist groups arriving >1,000 years ago, including the Ju| hoansi San, previously thought to have very low levels of admixture. Using traditional and new approaches, we estimate the population divergence time between the Ballito Bay boy and other groups to beyond 260,000 years ago. These estimates dramatically increases the deepest divergence amongst modern humans, coincide with the onset of the Middle Stone Age in sub-Saharan Africa, and coincide with anatomical developments of archaic humans into modern humans as represented in the local fossil record. Cumulatively, cross-disciplinary records increasingly point to southern Africa as a potential (not necessarily exclusive) hot spot for the evolution of our species.

evolutionary biology↗