Biology subjects

Arias, L.

Publications and source records attributed to Arias, L..

9 recordsLinked to original sources

bioRxiv2024

Impaired excitability of fast-spiking neurons in a novel mouse model of KCNC1 epileptic encephalopathy

The recurrent pathogenic variant KCNC1-p.Ala421Val (A421V) is a cause of developmental and epileptic encephalopathy characterized by moderate-to-severe developmental delay/intellectual disability, and infantile-onset treatment-resistant epilepsy with multiple seizure types including myoclonic seizures. Yet, the mechanistic basis of this disease, and of the KCNC1 disease spectrum, is unclear. KCNC1 encodes Kv3.1, a voltage-gated potassium channel subunit that is highly and selectively expressed in neurons capable of generating action potentials at high frequency, including parvalbumin-positive fast-spiking GABAergic inhibitory interneurons in cerebral cortex (PV-INs) known to be important for cognitive function and plasticity as well as control of network excitation to prevent seizures. In this study, we generate a novel transgenic mouse model with conditional expression of the Ala421Val pathogenic missense variant (Kcnc1-A421V/+ mice) to explore the specific physiological mechanisms of KCNC1 developmental and epileptic encephalopathy. Our results indicate that global heterozygous expression of the A421V variant leads to cognitive impairment, epilepsy, and premature lethality. We observe decreased PV-IN cell surface expression of Kv3.1 via immunohistochemistry, decreased voltage-gated potassium current density in PV-INs using outside-out nucleated macropatch recordings in brain slice, and profound impairments in the intrinsic excitability of cerebral cortex PV-INs (but not excitatory neurons) in current-clamp electrophysiology. In vivo two-photon calcium imaging revealed altered basal activity in Kcnc1-A421V/+ PV-INs and excitatory cells, as well as hypersynchronous discharges correlated with brief paroxysmal movements that were subsequently shown to be myoclonic seizures on electroencephalography. We found alterations in PV-IN-mediated inhibitory neurotransmission in young adult but not juvenile Kcnc1-A421V/+ mice relative to wild-type controls. Together, these results establish the specific impact of the recurrent Kv3.1-A421V variant on neuronal excitability and synaptic physiology across development to drive network dysfunction underlying KCNC1 epileptic encephalopathy.

neuroscience↗

bioRxiv2020

Reconstructing the human genetic history of mainland Southeast Asia: insights from genome-wide data from Thailand and Laos

Thailand and Laos, located in the center of Mainland Southeast Asia (MSEA), harbor diverse ethnolinguistic groups encompassing all five language families of MSEA: Tai-Kadai (TK), Austroasiatic (AA), Sino-Tibetan (ST), Hmong-Mien (HM) and Austronesian (AN). Previous genetic studies of Thai/Lao populations have focused almost exclusively on uniparental markers and there is a paucity of genome-wide studies. We therefore generated genome-wide SNP data for 33 ethnolinguistic groups, belonging to the five MSEA language families from Thailand and Laos, and analysed these together with data from modern Asian populations and SEA ancient samples. Overall, we find genetic structure according to language family, albeit with heterogeneity in the AA-, HM- and ST-speaking groups, and in the hill tribes, that reflects both population interactions and genetic drift. For the TK speaking groups, we find localized genetic structure that is driven by different levels of interaction with other groups in the same geographic region. Several Thai groups exhibit admixture from South Asia, which we date to [~]600-1000 years ago, corresponding to a time of intensive international trade networks that had a major cultural impact on Thailand. An AN group from Southern Thailand shows both South Asian admixture as well as overall affinities with AA-speaking groups in the region, suggesting an impact of cultural diffusion. Overall, we provide the first detailed insights into the genetic profiles of Thai/Lao ethnolinguistic groups, which should be helpful for reconstructing human genetic history in MSEA and selecting populations for participation in ongoing whole genome sequence and biomedical studies.

genomics↗

bioRxiv2019

The paternal and maternal genetic history of Vietnamese populations

Vietnam exhibits great cultural and linguistic diversity, yet the genetic history of Vietnamese populations remains poorly understood. Previous studies focused mostly on the majority Kinh group, and thus the genetic diversity of the many other groups has not yet been investigated. Here we analyze complete mtDNA genome sequences and 2.34 mB sequences of the male-specific portion of the Y chromosome from the Kinh and 16 minority populations, encompassing all five language families present in Vietnam. We find highly variable levels of diversity within and between groups that do not correlate with either geography or language family. In particular, the Mang and Sila have undergone recent, independent bottlenecks, while the majority group, Kinh, exhibits low levels of differentiation with other groups. The two Austronesian-speaking groups, Giarai and Ede, show a potential impact of matrilocality on their patterns of variation. Overall, we find that isolation, coupled with some limited contact involving some groups, has been the major factor influencing the genetic structure of Vietnamese populations, and that there is substantial genetic diversity that is not represented by the Kinh.

genetics↗

bioRxiv2019

Contrasting paternal and maternal genetic histories of Thai and Lao populations

The human demographic history of Mainland Southeast Asia (MSEA) has not been well-studied; in particular there have been very few sequence-based studies of variation in the male-specific portions of the Y chromosome (MSY). Here, we report new MSY sequences of [~]2.3 mB from 914 males, and combine these with previous data for a total of 928 MSY sequences belonging to 59 populations from Thailand and Laos who speak languages belonging to three major MSEA families: Austroasiatic (AA), Tai-Kadai (TK) and Sino-Tibetan (ST). Among the 92 MSY haplogroups, two main MSY lineages (O1b1a1a* (O-M95*) and O2a* (O-M324*)) contribute substantially to the paternal genetic makeup of Thailand and Laos. We also analyse complete mtDNA genome sequences published previously from the same groups, and find contrasting pattern of male and female genetic variation and demographic expansions, especially for the hill tribes, Mon, and some major Thai groups. In particular, we detect an effect of post-marital residence pattern on genetic diversity in patrilocal vs. matrilocal groups. Additionally, both male and female demographic expansions were observed during the early Mesolithic ([~]10 kya), with two later major male-specific expansions during the Neolithic period ([~]4-5 kya) and the Bronze/Iron Age ([~]2.0-2.5 kya). These two later expansions are characteristic of the modern AA and TK groups, respectively, consistent with recent ancient DNA studies. We simulate MSY data based on three demographic models (continuous migration, demic diffusion and cultural diffusion) of major Thai groups and find different results from mtDNA simulations, supporting contrasting male and female genetic histories.

genetics↗

bioRxiv2018

The genomic landscape of western South America: Andes, Amazonia and Pacific Coast

Studies of Native South American genetic diversity have helped to shed light on the peopling and differentiation of the continent, but available data are sparse for the major ecogeographic domains. These include the Pacific Coast, a potential early migration route; the Andes, home to the most expansive complex societies and to one of the most spoken indigenous language families of the continent (Quechua); and Amazonia, with its understudied population structure and rich cultural diversity. Here we explore the genetic structure of 177 individuals from these three domains, genotyped with the Affymetrix Human Origins array. We infer multiple sources of ancestry within the Native American ancestry component; one with clear predominance on the Coast and in the Andes, and at least two distinct substrates in neighboring Amazonia, with a previously undetected ancestry characteristic of northern Ecuador and Colombia. Amazonian populations are also involved in recent gene-flow with each other and across ecogeographic domains, which does not accord with the traditional view of small, isolated groups. Long distance genetic connections between speakers of the same language family suggest that languages had spread not by cultural contact alone. Finally, Native American populations admixed with post-Columbian European and African sources at different times, with few cases of prolonged isolation. With our results we emphasize the importance of including under-studied regions of the continent in high-resolution genetic studies, and we illustrate the potential of SNP chip arrays for informative regional scale analysis.

genetics↗

bioRxiv2018

A gradient in inner pressure of germline cells controls overlaying epithelial cell morphogenesis

It is unknown how growth in one tissue impacts morphogenesis in a neighboring tissue. To address this, we used the Drosophila ovarian follicle, where a cluster of 15 nurse cells and a posteriorly located oocyte are surrounded by a layer of epithelial cells. It is known that as the nurse cells grow, the overlying epithelial cells flatten in a wave that begins in the anterior. Here, we demonstrate that an anterior to posterior gradient of decreasing cytoplasmic pressure is present across the nurse cells and that this gradient acts through TGF{beta} to control both the triggering and the progression of the wave of epithelial cell flattening. Our data indicate that intrinsic nurse cell growth is important to control proper nurse cell pressure. Finally, we reveal that nurse cell pressure and subsequent TGF{beta} activity in the StC combine to increase follicle elongation in the anterior, which is crucial for allowing nurse cell growth and pressure control. More generally, our results reveal that during development, inner cytoplasmic pressure in individual cells has an important role in shaping their neighbors. Impact StatementCell shape change depends on extrinsic forces exerted by cytoplasmic pressure in neighbouring cells.

developmental biology↗

bioRxiv2018

Cultural Innovations influence patterns of genetic diversity in Northwestern Amazonia

Human populations often exhibit contrasting patterns of genetic diversity in the mtDNA and the non-recombining portion of the Y-chromosome (NRY), which reflect sex-specific cultural behaviors and population histories. Here, we sequenced 2.3 Mb of the NRY from 284 individuals representing more than 30 Native-American groups from Northwestern Amazonia (NWA) and compared these data to previously generated mtDNA genomes from the same groups, to investigate the impact of cultural practices on genetic diversity and gain new insights about NWA population history. Relevant cultural practices in NWA include postmarital residential rules and linguistic-exogamy, a marital practice in which men are required to marry women speaking a different language.\n\nWe identified 2,969 SNPs in the NRY sequences; only 925 SNPs were previously described. The NRY and mtDNA data showed that males and females experienced different demographic histories: the female effective population size has been larger than that of males through time, and both markers show an increase in lineage diversification beginning ~5,000 years ago, with a male-specific expansion occurring ~3,500 years ago. These dates are too recent to be associated with agriculture, therefore we propose that they reflect technological innovations and the expansion of regional trade networks documented in the archaeological evidence. Furthermore, our study provides evidence of the impact of postmarital residence rules and linguistic exogamy on genetic diversity patterns. Finally, we highlight the importance of analyzing high-resolution mtDNA and NRY sequences to reconstruct demographic history, since this can differ considerably between males and females.

genetics↗

bioRxiv2017

Enhanced Astrocyte Responses are Driven by a Genetic Risk Allele Associated with Multiple Sclerosis

Epigenetic annotation studies of genetic risk variants for multiple sclerosis (MS) implicate dysfunctional lymphocytes in MS susceptibility; however, the role of central nervous system (CNS) cells remains unclear. We investigated the effect of the risk variant, rs7665090G, located near NFKB1, on astrocytes. We demonstrated that chromatin is accessible at the risk locus, a prerequisite for its impact on astroglial function. The risk variant was associated with increased NF-{kappa}B signaling and target gene expression driving lymphocyte recruitment in cultured human astrocytes and astrocytes within MS lesions, and with increased lesional lymphocytic infiltrates. In MS patients, the risk genotype was associated with increased lesion volumes on MRI. Thus, we established that the rs7665090G variant perturbs astrocyte function resulting in increased CNS access for peripheral immune cells. MS may thus result from variant-driven dysregulation of the peripheral immune system and the CNS, where perturbed CNS cell function aids in establishing local autoimmune inflammation.\n\nOne Sentence SummaryThe NF-{kappa}B relevant multiple sclerosis risk variant, rs7665090G, drives astrocyte responses that promote lesion formation.

neuroscience↗

bioRxiv2017

High Resolution Mitochondrial DNA Analysis Sheds Light On Human Diversity, Cultural Interactions And Population Mobility In Northwestern Amazonia

ObjectivesNorthwestern Amazonia (NWA) is a center of high linguistic and cultural diversity. Several language families and linguistic isolates occur in this region, as well as different subsistence patterns: some groups are foragers while others are agriculturalists. In addition, speakers of Eastern Tukanoan languages are known for practicing linguistic exogamy, a marriage system in which partners must come from different language groups. In this study, we use high resolution mitochondrial DNA sequencing to investigate the impact of this linguistic and cultural diversity on the genetic relationships and structure of NWA groups.\n\nMethodsWe collected saliva samples from individuals representing 40 different NWA ethnolinguistic groups and sequenced 439 complete mitochondrial genomes to an average coverage of 1030x.\n\nResultsThe mtDNA data revealed that NWA populations have high genetic diversity with extensive sharing of haplotypes among groups. Moreover, groups who practice linguistic exogamy have higher mtDNA diversity, while the foraging Nukak have lower diversity. We also find that rivers play a more important role than either geography or language affiliation in structuring the genetic relationships of populations.\n\nDiscussionContrary to the view of NWA as a pristine area inhabited by small human populations living in isolation, our data support a view of high diversity and contact among different ethnolinguistic groups; movement along rivers has probably facilitated this contact. Additionally, we provide evidence for the impact of cultural practices, such as linguistic exogamy, on patterns of genetic variation. Overall, this study provides new data and insights into a remote and little-studied region of the world.

evolutionary biology↗