Phylogeography of human Y-chromosome haplogroup Q3-L275 from an academic/ citizen science collaboration

Background: The Y-chromosome haplogroup Q has three major branches: Q1, Q2, and Q3. Q1 is found in both Asia and the Americas where it accounts for about 90% of indigenous Native American Y-chromosomes; Q2 is found in North and Central Asia; but little is known about the third branch, Q3, also named Q1b-L275. Here, we combined the efforts of population geneticists and genetic genealogists to use the potential of full Y-chromosome sequencing for reconstructing haplogroup Q3 phylogeography and suggest possible linkages to events in population history. Results: We analyzed 47 fully sequenced Y-chromosomes and reconstructed the haplogroup Q3 phylogenetic tree in detail. Haplogroup Q3-L275, derived from the oldest known split within Eurasian/American haplogroup Q, most likely occurred in West or Central Asia in the Upper Paleolithic period. During the Mesolithic and Neolithic epochs, Q3 remained a minor component of the West Asian Y-chromosome pool and gave rise to five branches (Q3a to Q3e), which spread across West, Central and parts of South Asia. Around 3–4 millennia ago (Bronze Age), the Q3a branch underwent a rapid expansion, splitting into seven branches, some of which entered Europe. One of these branches, Q3a1, was acquired by a population ancestral to Ashkenazi Jews and grew within this population during the 1st millennium AD, reaching up to 5% in present day Ashkenazi. Conclusions: This study dataset was generated by a massive Y-chromosome genotyping effort in the genetic genealogy community, and phylogeographic patterns were revealed by a collaboration of population geneticists and genetic genealogists. This positive experience of collaboration between academic and citizen science provides a model for further joint projects. Merging data and skills of academic and citizen science promises to combine, respectively, quality and quantity, generalization and specialization, and achieve a well-balanced and careful interpretation of the paternal-side history of human populations

A társadalmak környezeti sebezhetősége, ellenálló- és alkalmazkodó képessége:a korai történelmi példáktól a sérülékenység globalizációjáig (Environmental vulnerability, resilience and adaptation capacities of societies: their historical examples and globalization)

Detailed phylogenetic tree of the haplogroup Q3-L275. 47 Q3-L275 samples and 1 Q1a-M346 outgroup. Constructed with the Phylomurka software using MP criteria, from the alignment obtained with read depth > = 2, base quality > = 15 and mapping quality > = 10, call rate = 60%. (XLSX 279 kb

Expanding the allelic spectrum of ELOVL4‐related autosomal recessive neuro‐ichthyosis

Background Very long-chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt-like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single-nucleotide variants. Methods We performed clinical exome sequencing on probands from four unrelated families with neuro-ichthyosis. Results We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three. Conclusion Our study expands the allelic spectrum of ELOVL4-related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation

Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders.

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'

The Effect of Extrinsic Staining on 3D Printed Provisional Crowns

Objectives: The aim of this study was to evaluate the color stability of 3D printed resin disks using spectral reflectance data obtained at different time periods after immersion in staining solution. Methods: Forty identical round disk specimens measuring 10 mm in diameter and 2 mm in thickness were fabricated using CAD/CAM 3D printing resin (shade B1). Half of the specimens (n=20) were polished using an acrylic bur and medium pumice. The other half was left unpolished (n=20). Each group of disks was then immersed in one of the following immersion solutions : artificial saliva, black tea, carrot juice, and red wine. Color difference ΔE was evaluated using a spectral reflectance instrument known as spectrophotometer at baseline, day 1, week 1, week 2 and week 3, against a white background. Results: Color difference ΔE was measured using CIELAB formula. The mean ΔE values of each group were calculated. The greatest difference in color was observed in the unpolished and polished disks immersed in red wine. Polished disks showed less color difference when compared to unpolished disks. Significant differences in ΔE were detected between polished and non-polished disks immersed in red wine at week 1 (p = 0.0159), week 2 (p = 0.0079) and week 3 (p = 0.0079) and in carrot juice at week 3 (p = 0.0317). Conclusion: Immersion in different staining solutions caused detectable color difference in the tested materials which was relative to the immersion duration and the staining solution used. v The color of the 3D printing resins is influenced by the surface finishing, which may result in visually perceptible color differences. The color stability of 3D printing material should be improved to manufacture oral appliances which provide long-term esthetics

Long-term outcomes of (Gore) fistula plug versus ligation of intersphincteric fistula tract for anal fistula

Background: The surgical treatment of anal fistula is complex due to the possibility of fecal incontinence. Fistulotomy and cutting Setons have the same incidence of fecal incontinence depending on the complexity of the fistula. Sphincter-preserving procedures such as anal fistula plug and ligation of intersphincteric fistula tract procedure may result in more recurrence requiring repeated operations. The aim of this study was to evaluate and compare the outcomes of treating fistula in Ano utilizing two methods: Fistula plug (Gore Bio-A) and ligation of intersphincteric tract (LIFT). Methods: Fifty four patients (33 males; 21 female, median ages 42 [range 32–47] years) with high anal inter-transphenteric fistula were treated with LIFT and fistula plug procedures from September 2011 until August 2016 by a single surgeon and were retrospectively evaluated. All were followed for a median of 23.9 (range 4–54) months with clinical examination. Twenty one patients underwent fistula plug and 33 patients underwent LIFT procedure (4 patients of the LIFT group underwent LIFT and rectal mucosa advancement flap). The healing rate and complications were evaluated clinically and through telephone calls. Results: The mean operative time for the Plug was 25 ± 17 min and for the LIFT was 40 ± 20 min (p = 0.017) and the mean hospital stay was 2.4 ± 1.1 and 1.9 ± 0.3 (p = 0.01) respectively. The early complications of the plug and LIFT procedures included; anal pain (33.3%, 66.6%, p = 0.13), perianal discharge (77.8%, 91%, p = 0.62), anal pruritus (38.9%, 50.0%, p = 0.71) and bleeding per rectum (16.7%, 33.3%, p = 0.39) respectively. The overall mean follow-up was 20.9 ± 16.8 months, p = 0.68. There was no statistically significant difference between the two groups (21.9 ± 7.5 months, 19.9 ± 16.1 months, p = 0.682). The healing rate was 76.2% (16/21 patients) in the fistula plug group and 81.1% (27/33 patients) in the LIFT group (p = 0.73). Patients who had LIFT procedure and a mucosal advancement flap had 100% healing rate (4 out of 4 patients). No incontinence of stool or feces and no fistula plug expulsion were seen in our patients. The healing time ranged from 1 to 6 months after surgery. There was no post-operative perianal abscess, cellulitis or pain. Conclusions: LIFT and anal plug are safe procedures for patients with primary and recurrent anal fistula. Both techniques showed excellent results in terms of healing and complication rate. None of our patients had incontinence after 5 years follow-up. The best success rate in our patients was seen after LIFT procedure with mucosal advancement flap. Larger and controlled randomized trials are needed for better assessment of treatment options. Resumo: Introdução: O tratamento cirúrgico da fístula anal é complexo devido à possibilidade de incontinência fecal. A fistulotomia e o seton de corte têm a mesma incidência da incontinência fecal, dependendo da complexidade da fístula. Procedimentos de preservação do esfíncter, como o tampão da fístula anal e o procedimento LIFT (ligadura do trato da fístula interesfincteriana), podem resultar em mais recorrência, exigindo cirurgias repetidas. O objetivo deste estudo foi avaliar e comparar os desfechos do tratamento da fístula anal utilizando dois métodos: Tampão de fístula (Gore Bio-A) e Ligadura do Trato Interesfincteriano (LIFT). Métodos: Cinquenta e quatro pacientes (33 homens; 21 mulheres, com mediana de idade de 42 [variação 32-47] anos) foram tratados com LIFT e procedimentos com tampão de fístula de setembro de 2011 até agosto de 2016 por um único cirurgião e foram avaliados retrospectivamente. Todos foram acompanhados por uma mediana de 23,9 (variação de 4 a 54) meses com exame clínico. Vinte e um pacientes foram submetidos a tampão de fístula e 33 pacientes foram submetidos ao procedimento LIFT (4 pacientes do grupo LIFT foram submetidos a LIFT e retalho de avanço da mucosa retal). A taxa de cicatrização e as complicações foram avaliadas clinicamente e por meio de ligações telefônicas. Resultados: O tempo cirúrgico médio para o Tampão foi de 25 ± 17 minutos e para o LIFT foi de 40 ± 20 minutos (p = 0,017) e o tempo médio de internação foi de 2,4 ± 1,1 e 1,9 ± 0,3 (p = 0,01), respectivamente. As primeiras complicações dos procedimentos de tampão e LIFT incluíram: dor anal (33,3%, 66,6%, p = 0,13), secreção perianal (77,8%, 91%, p = 0,62), prurido anal (38,9%, 50,0%, p = 0,71) e sangramento pelo reto (16,7%, 33,3 %, p = 0,39) respectivamente. A média geral de acompanhamento foi de 20,9 ± 16,8 meses, p = 0,68. Não houve diferença estatisticamente significativa entre os dois grupos (21,9 ± 7,5 meses, 19,9 ± 16,1 meses, p = 0,682). A taxa de cicatrização foi de 76,2% (16/21 pacientes) no grupo com tampão de fístula e 81,1% (27/33 pacientes) no grupo LIFT (p = 0,73). Pacientes submetidos ao procedimento LIFT e um retalho de avanço da mucosa tiveram 100% de taxa de cura (4 de 4 pacientes). Nenhuma incontinência fecal e nenhuma expulsão do tampão da fístula foram observadas em nossos pacientes. O tempo de cicatrização variou de 1 a 6 meses após a cirurgia. Não houve abscesso perianal, celulite ou dor no pós-operatório. Conclusões: LIFT e tampão anal são procedimentos seguros para pacientes com fístula anal primária e recorrente. Ambas as técnicas apresentaram excelentes resultados em termos de cicatrização e taxa de complicações. Nenhum de nossos pacientes teve incontinência após 5 anos de acompanhamento. A melhor taxa de sucesso em nossos pacientes foi observada após o procedimento LIFT com retalho de avanço da mucosa. Ensaios clínicos randomizados de maior porte e controlados são necessários para melhor avaliação das opções de tratamento. Keywords: Anal fistula, Ligation of intersphincteric fistula tract, Fistula plug, Palavras-chave: Fístula anal, Ligadura do trato de fístula interesfincteriana, Tampão de fístul

Biallelic missense variants in COG3 cause a congenital disorder of glycosylation with impairment of retrograde vesicular trafficking

Biallelic variants in genes for seven out of eight subunits of the conserved oligomeric Golgi complex (COG) are known to cause recessive congenital disorders of glycosylation (CDG) with variable clinical manifestations. COG3 encodes a constituent subunit of the COG complex that has not been associated with disease traits in humans. Herein, we report two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families that co-segregated with COG3–CDG presentations. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings. Biochemical analysis of serum transferrin from one family showed the loss of a single sialic acid. Western blotting on patient-derived fibroblasts revealed reduced COG3 and COG4. Further experiments showed delayed retrograde vesicular recycling in patient cells. This report adds to the knowledge of the COG–CDG network by providing collective evidence for a COG3–CDG rare disease trait and implicating a likely pathology of the disorder as the perturbation of Golgi trafficking

Additional file 3: Table S2. of Phylogeography of human Y-chromosome haplogroup Q3-L275 from an academic/citizen science collaboration

Genotypes of the individual samples. (XLSX 36 kb

Additional file 4: Data S1. of Phylogeography of human Y-chromosome haplogroup Q3-L275 from an academic/citizen science collaboration

VCF and BED files for the sequenced Y-chromosomes. (RAR 12315 kb