Recurrent gene flow between Neanderthals and modern humans over the past 200,000 years

Science, Год журнала: 2024, Номер 385(6705)

Опубликована: Июль 11, 2024

Although it is well known that the ancestors of modern humans and Neanderthals admixed, effects gene flow on Neanderthal genome are not understood. We develop methods to estimate amount human-introgressed sequences in apply whole-genome sequence data from 2000 three Neanderthals. have 2.5 3.7% human ancestry, we leverage revise estimates ancestry humans, show population sizes were significantly smaller than previously estimated, identify two distinct waves into Our provide insights genetic legacy recurrent between

Язык: Английский

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A multi-ancestry genetic study of pain intensity in 598,339 veterans

Nature Medicine, Год журнала: 2024, Номер 30(4), С. 1075 - 1084

Опубликована: Март 1, 2024

Язык: Английский

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DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 16

Опубликована: Янв. 5, 2024

Background The DLG3 gene encodes disks large membrane-associated guanylate kinase scaffold protein 3, which plays essential roles in the clustering of N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses. Previously, has been identified as causative X-linked intellectual developmental disorder—90 (XLID-90; OMIM# 300850). This study aims to explore phenotypic spectrum and genotype-phenotype correlation. Methods Trios-based whole-exome sequencing was performed patients with epilepsy unknown causes. To analyze correlations, previously reported variants were systematically reviewed. Results seven unrelated cases epilepsy. These had no hemizygous frequencies controls. All predicted be damaging by silico tools alter hydrogen bonds surrounding residues and/or stability. Four mainly presented generalized seizures, including tonic-clonic myoclonic other three exhibited secondary seizures focal seizures. Multifocal discharges recorded all during electroencephalography monitoring, four initially but multifocal after drug treating. Protein-protein interaction network analysis revealed that interacts 52 genes high confidence, majority disease-causing associated a wide neurodevelopmental disorder (NDD) Three locating outside functional domains achieved seizure-free, while poor control Analysis non-null higher percentages than those null variants, suggesting Significance suggested with/without NDD, expanding . observed correlation potentially contributes understanding underlying mechanisms driving variation.

Язык: Английский

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Biomarkers in Alzheimer’s disease progression: a longitudinal cohort study of NPTX2, GRIA1, and GRIA4

Aging advances., Год журнала: 2024, Номер 1(1), С. 52 - 59

Опубликована: Июль 24, 2024

Early diagnosis and intervention are vital for slowing Alzheimer’s disease progression improving the quality of life in older people. Mild cognitive impairment, an early stage disease, offers a key opportunity research intervention. However, current diagnostic methods typically applied after significant symptoms appear, limiting effectiveness The data middle-aged individuals collected from publicly available NCBI datasets GSE5281 GSE1297 were included this longitudinal cohort study. status changes participants over time assessed using standard assessment tools, such as Mini-Mental State Examination, along with mild impairment-specific tools. There was negative correlation between Examination scores expression levels neuronal pentraxin 2, glutamate receptor ionotropic AMPA 1 4. These results suggest that higher these genes associated more severe highlighting their potential biomarkers detection impairment. This study provides new insights into molecular mechanisms underlying decline people suggests directions future research.

Язык: Английский

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Behavioral evidence that repetitive responses in a Free-Movement Pattern Y-maze are associated with ageing-related deficit in working memory

Behavioural Processes, Год журнала: 2025, Номер unknown, С. 105152 - 105152

Опубликована: Янв. 1, 2025

Язык: Английский

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Genome-wide association meta-analyses of drug-resistant epilepsy

EBioMedicine, Год журнала: 2025, Номер unknown, С. 105675 - 105675

Опубликована: Апрель 1, 2025

Язык: Английский

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The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype

Frontiers in Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Март 2, 2023

Although the identification of numerous genes involved in neurodevelopmental disorders (NDDs) has reshaped our understanding their etiology, there are still major obstacles way developing therapeutic solutions for intellectual disability (ID) and other NDDs. These include extensive clinical genetic heterogeneity, rarity recurrent pathogenic variants, comorbidity with psychiatric traits. Moreover, a large intragenic mutational landscape is at play some NDDs, leading to broad range symptoms. Such diversity symptoms due different effects DNA variations have on protein functions impacts downstream biological processes. The type functional alterations, such as loss or gain function, interference signaling pathways, yet be correlated most genes. This review aims discussing current how molecular changes group I p21-activated kinases ( PAK1 , 2 3 ), which essential actors brain development function; contribute spectrum Identifying differences PAK structure, regulation spatio-temporal expression may help specific each . Deciphering variation affects these parameters will uncover mechanisms underlying mutation pathogenicity. prerequisite personalized approaches.

Язык: Английский

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Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

Brain, Год журнала: 2023, Номер 147(4), С. 1436 - 1456

Опубликована: Ноя. 9, 2023

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins regulates N-myristoylation via N-myristoyltransferase enzymes (NMTs). However, its precise function cells still unclear, as consequence ACBD6 defects on human pathophysiology. Using exome sequencing extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants ACBD6. We generated zebrafish Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 characterized myristic acid alkyne (YnMyr) chemical proteomics model organisms cells, latter also being subjected further to peroxisomal localization studies. (23 males 22 females), aged 1-50 years, typically present complex progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) mild cerebellar ataxia (85%) associated gait (94%), limb spasticity/hypertonia (76%), oculomotor (71%) behavioural abnormalities (65%), overweight (59%), microcephaly (39%) epilepsy (33%). most conspicuous common disorder was dystonia frequently leading early-onset postural deformities (55%) cervical (31%). A jerky tremor upper limbs (63%), head parkinsonism/hypokinesia developing advancing age (32%) simple motor vocal tics were among other frequent disorders. Midline brain malformations including corpus callosum (70%), hypoplasia/agenesis anterior commissure (66%), short midbrain small inferior vermis (38% each) well hypertrophy clava (24%) neuroimaging findings. Acbd6-deficient models effectively recapitulated many clinical phenotypes reported patients disorders, neuromotor impairment, seizures, microcephaly, craniofacial accompanied delay increased mortality over time. Unlike ACBD5, did not show ACBD6-deficiency altered parameters patient fibroblasts. Significant differences YnMyr-labelling observed for 68 co- 18 post-translationally N-myristoylated patient-derived similarly acbd6-deficient X. models, Fus, Marcks Chchd-related implicated neurological diseases. study provides evidence that pathogenic lead distinct neurodevelopmental syndrome cognitive

Язык: Английский

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Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes

Brain, Год журнала: 2023, Номер 147(5), С. 1837 - 1855

Опубликована: Ноя. 30, 2023

Abstract AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded GRIA1–GRIA4 genes, which only GRIA3 is X-chromosomal. Increasing numbers missense variants are reported patients with neurodevelopmental disorders (NDD), but a few have been examined functionally. Here, we evaluated impact on AMPAR function one frameshift and 43 rare identified NDD electrophysiological assays. Thirty-one alter receptor show loss-of-function gain-of-function properties, whereas 13 appeared neutral. We collected detailed clinical data from 25 (from 23 families) harbouring 17 these variants. All had global developmental impairment, mostly moderate (9/25) severe (12/25). Twelve seizures, including focal motor (6/12), unknown onset (4/12), impaired awareness (1/12), (atypical) absence (2/12), myoclonic (5/12) generalized tonic-clonic (1/12) atonic seizures. The epilepsy syndrome was classified as epileptic encephalopathy eight patients, without seizures intellectual disability four patients. Limb muscular hypotonia 13/25, hypertonia 10/25. Movement were 14/25, hyperekplexia non-epileptic erratic myoclonus being most prevalent feature (8/25). Correlating functional phenotype features revealed for GRIA3-associated NDDs distinct phenotypes Gain-of-function associated more outcomes: younger at time seizure (median age: 1 month), hypertonic often movement disorders, hyperekplexia. Patients older 16 months), hypotonic sleeping disturbances. Loss-of-function disease-causing both sexes affected males carried de novo hemizygous inherited healthy mothers, females heterozygous

Язык: Английский

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Monoallelic de novo variants in DDX17 cause a neurodevelopmental disorder

Brain, Год журнала: 2024, Номер unknown

Опубликована: Окт. 15, 2024

Abstract DDX17 is an RNA helicase shown to be involved in critical processes during the early phases of neuronal differentiation. Globally, we compiled a case series 11 patients with neurodevelopmental phenotypes harbouring de novo monoallelic variants DDX17. All our had phenotype, whereby intellectual disability, delayed speech and language, motor delay predominated. We performed utero cortical electroporation brain developing mice, assessing axon complexity outgrowth electroporated neurons, comparing wild-type Ddx17 knockdown. then undertook ex vivo on progenitors quantitatively assess axonal development at single cell resolution. Mosaic ddx17 crispants heterozygous knockouts Xenopus tropicalis were generated for assessment morphology, behavioural assays measurements. further transcriptomic analysis neuroblastoma SH-SY5Y cells, identify differentially expressed genes DDX17-KD cells compared controls. Knockdown mouse neurons showed migration as well decreased complexity. Mouse primary revealed reduced upon knockdown vitro. The phenotype was replicated crispant tadpoles heterozygotes. Heterozygous clear defects impaired neurobehavioral phenotype. Transcriptomic identified statistically significant number control cells. have potential neurodevelopment disease-causing gene not previously associated genetic disease, provide evidence role both mammalian non-mammalian species controlling expression key genes.

Язык: Английский

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