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1.
Nat Commun ; 10(1): 3583, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395865

RESUMO

The majority of common variants associated with common diseases, as well as an unknown proportion of causal mutations for rare diseases, fall in noncoding regions of the genome. Although catalogs of noncoding regulatory elements are steadily improving, we have a limited understanding of the functional effects of mutations within them. Here, we perform saturation mutagenesis in conjunction with massively parallel reporter assays on 20 disease-associated gene promoters and enhancers, generating functional measurements for over 30,000 single nucleotide substitutions and deletions. We find that the density of putative transcription factor binding sites varies widely between regulatory elements, as does the extent to which evolutionary conservation or integrative scores predict functional effects. These data provide a powerful resource for interpreting the pathogenicity of clinically observed mutations in these disease-associated regulatory elements, and comprise a rich dataset for the further development of algorithms that aim to predict the regulatory effects of noncoding mutations.

2.
Hum Mutat ; 40(9): 1280-1291, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31106481

RESUMO

The integrative analysis of high-throughput reporter assays, machine learning, and profiles of epigenomic chromatin state in a broad array of cells and tissues has the potential to significantly improve our understanding of noncoding regulatory element function and its contribution to human disease. Here, we report results from the CAGI 5 regulation saturation challenge where participants were asked to predict the impact of nucleotide substitution at every base pair within five disease-associated human enhancers and nine disease-associated promoters. A library of mutations covering all bases was generated by saturation mutagenesis and altered activity was assessed in a massively parallel reporter assay (MPRA) in relevant cell lines. Reporter expression was measured relative to plasmid DNA to determine the impact of variants. The challenge was to predict the functional effects of variants on reporter expression. Comparative analysis of the full range of submitted prediction results identifies the most successful models of transcription factor binding sites, machine learning algorithms, and ways to choose among or incorporate diverse datatypes and cell-types for training computational models. These results have the potential to improve the design of future studies on more diverse sets of regulatory elements and aid the interpretation of disease-associated genetic variation.

3.
J Inherit Metab Dis ; 42(5): 993-997, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30945312

RESUMO

The translocon-associated protein (TRAP) complex facilitates the translocation of proteins across the endoplasmic reticulum membrane and associates with the oligosaccharyl transferase (OST) complex to maintain proper glycosylation of nascent polypeptides. Pathogenic variants in either complex cause a group of rare genetic disorders termed, congenital disorders of glycosylation (CDG). We report an individual who presented with severe intellectual and developmental disabilities and sensorineural deafness with an unsolved type I CDG, and sought to identify the underlying genetic basis. Exome sequencing identified a novel homozygous variant c.278_281delAGGA [p.Glu93Valfs*7] in the signal sequence receptor 3 (SSR3) subunit of the TRAP complex. Biochemical studies in patient fibroblasts showed the variant destabilized the TRAP complex with a complete loss of SSR3 protein and partial loss of SSR1 and SSR4. Importantly, all subunit levels were corrected by expression of wild-type SSR3. Abnormal glycosylation status in fibroblasts was confirmed using two markers proteins, GP130 and ICAM1. Our findings confirm mutations in SSR3 cause a novel CDG. A novel frameshift variant in the translocon associated protein, SSR3, disrupts the stability of the TRAP complex and causes a novel Congenital Disorder of Glycosylation.

4.
Am J Hum Genet ; 104(1): 35-44, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30554721

RESUMO

Baratela-Scott syndrome (BSS) is a rare, autosomal-recessive disorder characterized by short stature, facial dysmorphisms, developmental delay, and skeletal dysplasia caused by pathogenic variants in XYLT1. We report clinical and molecular investigation of 10 families (12 individuals) with BSS. Standard sequencing methods identified biallelic pathogenic variants in XYLT1 in only two families. Of the remaining cohort, two probands had no variants and six probands had only a single variant, including four with a heterozygous 3.1 Mb 16p13 deletion encompassing XYLT1 and two with a heterozygous truncating variant. Bisulfite sequencing revealed aberrant hypermethylation in exon 1 of XYLT1, always in trans with the sequence variant or deletion when present; both alleles were methylated in those with no identified variant. Expression of the methylated XYLT1 allele was severely reduced in fibroblasts from two probands. Southern blot studies combined with repeat expansion analysis of genome sequence data showed that the hypermethylation is associated with expansion of a GGC repeat in the XYLT1 promoter region that is not present in the reference genome, confirming that BSS is a trinucleotide repeat expansion disorder. The hypermethylated allele accounts for 50% of disease alleles in our cohort and is not present in 130 control subjects. Our study highlights the importance of investigating non-sequence-based alterations, including epigenetic changes, to identify the missing heritability in genetic disorders.


Assuntos
Anormalidades Múltiplas/genética , Metilação de DNA/genética , Epigênese Genética/genética , Éxons/genética , Mutação , Pentosiltransferases/genética , Expansão das Repetições de Trinucleotídeos/genética , Alelos , Southern Blotting , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Sulfitos/metabolismo , Síndrome
5.
Am J Hum Genet ; 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30414627

RESUMO

Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy.

6.
Nucleic Acids Res ; 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30371827

RESUMO

Combined Annotation-Dependent Depletion (CADD) is a widely used measure of variant deleteriousness that can effectively prioritize causal variants in genetic analyses, particularly highly penetrant contributors to severe Mendelian disorders. CADD is an integrative annotation built from more than 60 genomic features, and can score human single nucleotide variants and short insertion and deletions anywhere in the reference assembly. CADD uses a machine learning model trained on a binary distinction between simulated de novo variants and variants that have arisen and become fixed in human populations since the split between humans and chimpanzees; the former are free of selective pressure and may thus include both neutral and deleterious alleles, while the latter are overwhelmingly neutral (or, at most, weakly deleterious) by virtue of having survived millions of years of purifying selection. Here we review the latest updates to CADD, including the most recent version, 1.4, which supports the human genome build GRCh38. We also present updates to our website that include simplified variant lookup, extended documentation, an Application Program Interface and improved mechanisms for integrating CADD scores into other tools or applications. CADD scores, software and documentation are available at https://cadd.gs.washington.edu.

7.
JIMD Rep ; 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30117111

RESUMO

Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations. Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. We also present data on three affected females that are young adults and have a somewhat milder, stable disease. Our findings expand both the molecular and clinical knowledge of previously published data but also widen the phenotypic spectrum of DPAGT1-CDG.

9.
Nat Genet ; 50(6): 874-882, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29785012

RESUMO

Determining the pathogenicity of genetic variants is a critical challenge, and functional assessment is often the only option. Experimentally characterizing millions of possible missense variants in thousands of clinically important genes requires generalizable, scalable assays. We describe variant abundance by massively parallel sequencing (VAMP-seq), which measures the effects of thousands of missense variants of a protein on intracellular abundance simultaneously. We apply VAMP-seq to quantify the abundance of 7,801 single-amino-acid variants of PTEN and TPMT, proteins in which functional variants are clinically actionable. We identify 1,138 PTEN and 777 TPMT variants that result in low protein abundance, and may be pathogenic or alter drug metabolism, respectively. We observe selection for low-abundance PTEN variants in cancer, and show that p.Pro38Ser, which accounts for ~10% of PTEN missense variants in melanoma, functions via a dominant-negative mechanism. Finally, we demonstrate that VAMP-seq is applicable to other genes, highlighting its generalizability.

10.
Hum Mutat ; 39(6): 811-815, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29524275

RESUMO

Isolated hand syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover two novel variants, chr11 g.46896373C>G; p.D1403H and chr11 g.46893078G>T; p.Q1564K, in LRP4 in a child with isolated bilateral syndactyly of the third and fourth fingers. Each variant was inherited from a different parent and neither parent was affected. Variants in LRP4 have been previously associated with syndactyly in Cenani-Lenz syndactyly syndrome and Sclerosteosis 2, but have not been reported in individuals with isolated syndactyly. LRP4 inhibits LRP6/LRP5-mediated activation of canonical Wnt signaling and mediates sclerostin-dependent inhibition of bone formation. p.D1403H and p.Q1564K are located within the fourth ß-propeller of the extracellular protein domain that has yet to be associated with human disease. Functional analyses of p.D1403H and p.Q1564K show that they significantly decrease LRP4's inhibition of Wnt signaling. These results suggest that variants in the fourth ß-propeller of the extracellular protein domain may cause a phenotype distinct from previously characterized LRP4 variants.

11.
Am J Med Genet A ; 173(11): 2906-2911, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28856833

RESUMO

Transport of activated nucleotide-sugars into the Golgi is critical for proper glycosylation and mutations in these transporters cause a group of rare genetic disorders termed congenital disorders of glycosylation. We performed exome sequencing on an individual with a profound neurological presentation and identified rare compound heterozygous mutations, p.Thr156Arg and p.Glu196Lys, in the CMP-sialic acid transporter, SLC35A1. Patient primary fibroblasts and serum showed a considerable decrease in the amount of N- and O-glycans terminating in sialic acid. Direct measurement of CMP-sialic acid transport into the Golgi showed a substantial decrease in overall rate of transport. Here we report the identification of the third patient with CMP-sialic acid transporter deficiency, who presented with severe neurological phenotype, but without hematological abnormalities.


Assuntos
Encefalopatias/genética , Complexo de Golgi/genética , Ácido N-Acetilneuramínico/metabolismo , Proteínas de Transporte de Nucleotídeos/genética , Animais , Encefalopatias/fisiopatologia , Células CHO , Criança , Cricetinae , Cricetulus , Feminino , Citometria de Fluxo , Humanos , Mutação , Ácido N-Acetilneuramínico/genética , Sequenciamento Completo do Exoma
12.
Sci Rep ; 7: 44585, 2017 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-28327635

RESUMO

Near the end of the Pleistocene epoch, populations of the woolly mammoth (Mammuthus primigenius) were distributed across parts of three continents, from western Europe and northern Asia through Beringia to the Atlantic seaboard of North America. Nonetheless, questions about the connectivity and temporal continuity of mammoth populations and species remain unanswered. We use a combination of targeted enrichment and high-throughput sequencing to assemble and interpret a data set of 143 mammoth mitochondrial genomes, sampled from fossils recovered from across their Holarctic range. Our dataset includes 54 previously unpublished mitochondrial genomes and significantly increases the coverage of the Eurasian range of the species. The resulting global phylogeny confirms that the Late Pleistocene mammoth population comprised three distinct mitochondrial lineages that began to diverge ~1.0-2.0 million years ago (Ma). We also find that mammoth mitochondrial lineages were strongly geographically partitioned throughout the Pleistocene. In combination, our genetic results and the pattern of morphological variation in time and space suggest that male-mediated gene flow, rather than large-scale dispersals, was important in the Pleistocene evolutionary history of mammoths.


Assuntos
Distribuição Animal , Evolução Biológica , DNA Mitocondrial/genética , Genoma Mitocondrial , Mamutes/genética , Filogenia , Animais , Ásia , Europa (Continente) , Extinção Biológica , Feminino , Fósseis , Fluxo Gênico , Masculino , Mamutes/classificação , América do Norte , Filogeografia , Análise de Sequência de DNA
13.
Mitochondrion ; 34: 84-90, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28216230

RESUMO

We report the clinical, biochemical, and molecular findings in two brothers with encephalopathy and multi-systemic disease. Abnormal transferrin glycoforms were suggestive of a type I congenital disorder of glycosylation (CDG). While exome sequencing was negative for CDG related candidate genes, the testing revealed compound heterozygous mutations in the mitochondrial elongation factor G gene (GFM1). One of the mutations had been reported previously while the second, novel variant was found deep in intron 6, activating a cryptic splice site. Functional studies demonstrated decreased GFM1 protein levels, suggested disrupted assembly of mitochondrial complexes III and V and decreased activities of mitochondrial complexes I and IV, all indicating combined OXPHOS deficiency.


Assuntos
Anormalidades Congênitas/genética , Anormalidades Congênitas/patologia , Expressão Gênica , Proteínas Mitocondriais/biossíntese , Proteínas Mitocondriais/genética , Fosforilação Oxidativa , Fator G para Elongação de Peptídeos/biossíntese , Fator G para Elongação de Peptídeos/genética , Sítios de Splice de RNA , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Masculino
14.
Genome Res ; 27(1): 38-52, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27831498

RESUMO

Candidate enhancers can be identified on the basis of chromatin modifications, the binding of chromatin modifiers and transcription factors and cofactors, or chromatin accessibility. However, validating such candidates as bona fide enhancers requires functional characterization, typically achieved through reporter assays that test whether a sequence can increase expression of a transcriptional reporter via a minimal promoter. A longstanding concern is that reporter assays are mainly implemented on episomes, which are thought to lack physiological chromatin. However, the magnitude and determinants of differences in cis-regulation for regulatory sequences residing in episomes versus chromosomes remain almost completely unknown. To address this systematically, we developed and applied a novel lentivirus-based massively parallel reporter assay (lentiMPRA) to directly compare the functional activities of 2236 candidate liver enhancers in an episomal versus a chromosomally integrated context. We find that the activities of chromosomally integrated sequences are substantially different from the activities of the identical sequences assayed on episomes, and furthermore are correlated with different subsets of ENCODE annotations. The results of chromosomally based reporter assays are also more reproducible and more strongly predictable by both ENCODE annotations and sequence-based models. With a linear model that combines chromatin annotations and sequence information, we achieve a Pearson's R2 of 0.362 for predicting the results of chromosomally integrated reporter assays. This level of prediction is better than with either chromatin annotations or sequence information alone and also outperforms predictive models of episomal assays. Our results have broad implications for how cis-regulatory elements are identified, prioritized and functionally validated.


Assuntos
Cromatina/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica/genética , Plasmídeos/genética , Montagem e Desmontagem da Cromatina/genética , Cromossomos/genética , Genes Reporter , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Regiões Promotoras Genéticas , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição
15.
Blood Adv ; 1(13): 824-834, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-29296726

RESUMO

Hemophilia A and B are rare, X-linked bleeding disorders. My Life, Our Future (MLOF) is a collaborative project established to genotype and study hemophilia. Patients were enrolled at US hemophilia treatment centers (HTCs). Genotyping was performed centrally using next-generation sequencing (NGS) with an approach that detected common F8 gene inversions simultaneously with F8 and F9 gene sequencing followed by confirmation using standard genotyping methods. Sixty-nine HTCs enrolled the first 3000 patients in under 3 years. Clinically reportable DNA variants were detected in 98.1% (2357/2401) of hemophilia A and 99.3% (595/599) of hemophilia B patients. Of the 924 unique variants found, 285 were novel. Predicted gene-disrupting variants were common in severe disease; missense variants predominated in mild-moderate disease. Novel DNA variants accounted for ∼30% of variants found and were detected continuously throughout the project, indicating that additional variation likely remains undiscovered. The NGS approach detected >1 reportable variants in 36 patients (10 females), a finding with potential clinical implications. NGS also detected incidental variants unlikely to cause disease, including 11 variants previously reported in hemophilia. Although these genes are thought to be conserved, our findings support caution in interpretation of new variants. In summary, MLOF has contributed significantly toward variant annotation in the F8 and F9 genes. In the near future, investigators will be able to access MLOF data and repository samples for research to advance our understanding of hemophilia.

16.
JCI Insight ; 1(9)2016 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-27631024

RESUMO

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Malformações do Desenvolvimento Cortical/genética , Mosaicismo , Malformações Vasculares/genética , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Mutação , Fenótipo , Distribuição Tecidual
17.
Am J Med Genet A ; 170(12): 3165-3171, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27480077

RESUMO

Increasing numbers of congenital disorders of glycosylation (CDG) have been reported recently resulting in an expansion of the phenotypes associated with this group of disorders. SRD5A3 codes for polyprenol reductase which converts polyprenol to dolichol. This is a major pathway for dolichol biosynthesis for N-glycosylation, O-mannosylation, C-mannosylation, and GPI anchor synthesis. We present the features of five individuals (three children and two adults) with mutations in SRD5A3 focusing on the variable eye and skin involvement. We compare that to 13 affected individuals from the literature including five adults allowing us to delineate the features that may develop over time with this disorder including kyphosis, retinitis pigmentosa, and cataracts. © 2016 Wiley Periodicals, Inc.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Defeitos Congênitos da Glicosilação/genética , Olho/fisiopatologia , Proteínas de Membrana/genética , Pele/fisiopatologia , Adulto , Criança , Defeitos Congênitos da Glicosilação/fisiopatologia , Dolicol/metabolismo , Feminino , Glicosilação , Homozigoto , Humanos , Masculino , Mutação , Fenótipo , Tretinoína/análogos & derivados , Tretinoína/metabolismo
18.
Hum Genet ; 135(5): 525-40, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27023906

RESUMO

Ehlers-Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes B3GALT6, GORAB, ZNF469, B3GAT3, ALDH18A1, FKBP14, PYCR1, CHST14 and SPARC with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive COL1A1 variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene, AEBP1. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose ATP6V1E1 and ATP6V0D2 (two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome.


Assuntos
Doenças do Tecido Conjuntivo/genética , Heterogeneidade Genética , Marcadores Genéticos/genética , Anormalidades da Pele/genética , Sequência de Aminoácidos , Estudos de Coortes , Doenças do Tecido Conjuntivo/patologia , Exoma/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Homologia de Sequência de Aminoácidos
19.
Hum Mutat ; 37(7): 653-60, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26931382

RESUMO

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a ß1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Manosiltransferases/genética , Mutação , Polissacarídeos/metabolismo , Biomarcadores/metabolismo , Defeitos Congênitos da Glicosilação/metabolismo , Feminino , Genes Letais , Glicosilação , Humanos , Masculino , Análise de Sequência de DNA , Análise de Sobrevida
20.
Nature ; 530(7591): 429-33, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26886800

RESUMO

It has been shown that Neanderthals contributed genetically to modern humans outside Africa 47,000-65,000 years ago. Here we analyse the genomes of a Neanderthal and a Denisovan from the Altai Mountains in Siberia together with the sequences of chromosome 21 of two Neanderthals from Spain and Croatia. We find that a population that diverged early from other modern humans in Africa contributed genetically to the ancestors of Neanderthals from the Altai Mountains roughly 100,000 years ago. By contrast, we do not detect such a genetic contribution in the Denisovan or the two European Neanderthals. We conclude that in addition to later interbreeding events, the ancestors of Neanderthals from the Altai Mountains and early modern humans met and interbred, possibly in the Near East, many thousands of years earlier than previously thought.


Assuntos
Fluxo Gênico/genética , Homem de Neandertal/genética , Altitude , Animais , Teorema de Bayes , Cromossomos Humanos Par 21/genética , Croácia/etnologia , Genoma Humano/genética , Genômica , Haplótipos/genética , Heterozigoto , Humanos , Hibridização Genética/genética , Filogenia , Densidade Demográfica , Sibéria , Espanha/etnologia , Fatores de Tempo
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