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1.
Theor Appl Genet ; 135(3): 755-776, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34283259

RESUMO

KEY MESSAGE: We present a comprehensive survey of cytogenetic and genomic diversity of the GGAtAt genepool of wheat, thereby unlocking these plant genetic resources for wheat improvement. Wheat yields are stagnating around the world and new sources of genes for resistance or tolerances to abiotic traits are required. In this context, the tetraploid wheat wild relatives are among the key candidates for wheat improvement. Despite its potential huge value for wheat breeding, the tetraploid GGAtAt genepool is largely neglected. Understanding the population structure, native distribution range, intraspecific variation of the entire tetraploid GGAtAt genepool and its domestication history would further its use for wheat improvement. The paper provides the first comprehensive survey of genomic and cytogenetic diversity sampling the full breadth and depth of the tetraploid GGAtAt genepool. According to the results obtained, the extant GGAtAt genepool consists of three distinct lineages. We provide detailed insights into the cytogenetic composition of GGAtAt wheats, revealed group- and population-specific markers and show that chromosomal rearrangements play an important role in intraspecific diversity of T. araraticum. The origin and domestication history of the GGAtAt lineages is discussed in the context of state-of-the-art archaeobotanical finds. We shed new light on the complex evolutionary history of the GGAtAt wheat genepool and provide the basis for an increased use of the GGAtAt wheat genepool for wheat improvement. The findings have implications for our understanding of the origins of agriculture in southwest Asia.


Assuntos
Domesticação , Triticum , Variação Genética , Fenótipo , Melhoramento Vegetal , Tetraploidia , Triticum/genética
3.
Genes (Basel) ; 12(6)2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071867

RESUMO

Hereditary nonsyndromic sensorineural hearing loss is a disease in which hearing loss occurs due to damage to the organ of the inner ear, the auditory nerve, or the center in the brain that is responsible for the perception of sound, characterized by wide locus and allelic heterogeneity and different types of inheritance. Given the diversity of population of the Russian Federation, it seems necessary to study the ethnic characteristics of the molecular causes of the disease. The aim is to study the molecular and genetic causes of hereditary sensorineural hearing loss in Chuvash, the fifth largest ethnic group in Russia. DNA samples of 26 patients from 21 unrelated Chuvash families from the Republic of Chuvashia, in whom the diagnosis of hereditary sensorineural hearing loss had been established, were analyzed using a combination of targeted Sanger sequencing, multiplex ligase-dependent probe amplification, and whole exome sequencing. The homozygous variant NM_133261.3(GIPC3):c.245A>G (p.Asn82Ser) is the major molecular cause of hereditary sensorineural hearing loss in 23% of Chuvash patients (OMIM #601869). Its frequency was 25% in patients and 1.1% in healthy Chuvash population. Genotyping of the NM_133261.3(GIPC3):c.245A>G (p.Asn82Ser) variant in five neighboring populations from the Volga-Ural region (Russian, Udmurt, Mary, Tatar, Bushkir) found no evidence that this variant is common in those populations.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Perda Auditiva Neurossensorial/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Frequência do Gene , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Federação Russa
4.
Eur J Hum Genet ; 29(6): 965-976, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33767456

RESUMO

Congenital autosomal recessive cataract with unknown genetic etiology is one of the most common Mendelian diseases among the Turkic-speaking Yakut population (Eastern Siberia, Russia). To identify the genetic cause of congenital cataract spread in this population, we performed whole-exome sequencing (Illumina NextSeq 500) in one Yakut family with three affected siblings whose parents had preserved vision. We have revealed the novel homozygous c.1621C>T transition leading to premature stop codon p.(Gln541*) in exon 8 of the FYCO1 gene (NM_024513.4). Subsequent screening of c.1621C>T p.(Gln541*) revealed this variant in a homozygous state in 25 out of 29 Yakut families with congenital cataract (86%). Among 424 healthy individuals from seven populations of Eastern Siberia (Russians, Yakuts, Evenks, Evens, Dolgans, Chukchi, and Yukaghirs), the highest carrier frequency of c.1621C>T p.(Gln541*) was found in the Yakut population (7.9%). DNA samples of 25 homozygous for c.1621C>T p.(Gln541*) patients with congenital cataract and 114 unaffected unrelated individuals without this variant were used for a haplotype analysis based on the genotyping of six STR markers (D3S3512, D3S3685, D3S3582, D3S3561, D3S1289, and D3S3698). The structure of the identified haplotypes indicates a common origin for all of the studied mutant chromosomes bearing c.1621C>T p.(Gln541*). The age of the с.1621C>T p.(Gln541*) founder haplotype was estimated to be approximately 260 ± 65 years (10 generations). These findings characterize Eastern Siberia as the region of the world with the most extensive accumulation of the unique variant c.1621C>T p.(Gln541*) in the FYCO1 gene as a result of the founder effect.


Assuntos
Catarata/genética , Efeito Fundador , Proteínas Associadas aos Microtúbulos/genética , Catarata/patologia , Criança , Códon de Terminação , Frequência do Gene , Genes Recessivos , Homozigoto , Humanos , Povos Indígenas/genética , Mutação , Sibéria
5.
Clin Genet ; 99(5): 673-683, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33463715

RESUMO

A young boy with multifocal epilepsy with infantile spasms and hypsarrhythmia with minimal organic lesions of brain structures underwent DNA diagnosis using whole-exome sequencing. A heterozygous amino-acid substitution p.L519R in a PHACTR1 gene was identified. PHACTR1 belongs to a protein family of G-actin binding protein phosphatase 1 (PP1) cofactors and was not previously associated with a human disease. The missense single nucleotide variant in the proband was shown to occur de novo in the paternal allele. The mutation was shown in vitro to reduce the affinity of PHACTR1 for G-actin, and to increase its propensity to form complexes with the catalytic subunit of PP1. These properties are associated with altered subcellular localization of PHACTR1 and increased ability to induce cytoskeletal rearrangements. Although the molecular role of the PHACTR1 in neuronal excitability and differentiation remains to be defined, PHACTR1 has been previously shown to be involved in Slack channelopathy pathogenesis, consistent with our findings. We conclude that this activating mutation in PHACTR1 causes a severe type of sporadic multifocal epilepsy in the patient.


Assuntos
Epilepsia/genética , Proteínas dos Microfilamentos/genética , Mutação , Espasmos Infantis/genética , Actinas/metabolismo , Animais , Pré-Escolar , Humanos , Lactente , Masculino , Camundongos , Células NIH 3T3 , Sequenciamento do Exoma
6.
J Neuromuscul Dis ; 8(2): 273-285, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33337382

RESUMO

A family of five male siblings (three survivors at 48, 53 and 58 years old; two deceased at 8 months old and 2.5 years old) demonstrating significant phenotypic variability ranging from intermediate to the myosclerotic like Bethlem myopathy is presented. Whole-exome sequencing (WES) identified a new homozygous missense mutation chr21:47402679 T > C in the canonical splice donor site of the second intron (c.227 + 2T>C) in the COL6A1 gene. mRNA analysis confirmed skipping of exon 2 encoding 925 amino-acids in 94-95% of resulting transcripts. Three sibs presented with intermediate phenotype of collagen VI-related dystrophies (48, 53 and 2.5 years old) while the fourth sibling (58 years old) was classified as Bethlem myopathy with spine rigidity. The two older siblings with the moderate progressive phenotype (48 and 53 years old) lost their ability to maintain a vertical posture caused by pronounced contractures of large joints, but continued to ambulate throughout life on fully bent legs without auxiliary means of support. Immunofluorescence analysis of dermal fibroblasts demonstrated that no type VI collagen was secreted in any of the siblings' cells, regardless of clinical manifestations severity while fibroblast proliferation and colony formation ability was decreased. The detailed genetic and long term clinical data contribute to broadening the genotypic and phenotypic spectrum of COL6A1 related disease.


Assuntos
Colágeno Tipo VI , Contratura/genética , Distrofias Musculares/congênito , Variação Biológica da População , Éxons , Genótipo , Humanos , Lactente , Íntrons , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/genética , Mutação , Mutação de Sentido Incorreto , Fenótipo
7.
Orphanet J Rare Dis ; 15(1): 207, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32791987

RESUMO

BACKGROUND: Mutations in CRYAA, which encodes the α-crystallin protein, are associated with a spectrum of congenital cataract-microcornea syndromes. RESULTS: In this study, we performed clinical examination and subsequent genetic analysis in two unrelated sporadic cases of different geographical origins presenting with a complex phenotype of ocular malformation. Both cases manifested bilateral microphthalmia and severe anterior segment dysgenesis, primarily characterized by congenital aphakia, microcornea, and iris hypoplasia/aniridia. NGS-based analysis revealed two novel single nucleotide variants occurring de novo and affecting the translation termination codon of the CRYAA gene, c.520T > C and c.521A > C. Both variants are predicted to elongate the C-terminal protein domain by one-third of the original length. CONCLUSIONS: Our report not only expands the mutational spectrum of CRYAA but also identifies the genetic cause of the unusual ocular phenotype described in this report.


Assuntos
Catarata , Cristalinas , Anormalidades do Olho , Cristalinas/genética , Anormalidades do Olho/genética , Humanos , Mutação/genética , Nucleotídeos , Linhagem , Fenótipo
8.
J Pediatr Genet ; 8(2): 58-62, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31061747

RESUMO

Ataxia with oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive, PNKP -related disorder delineated in 2015 in Portugal. We diagnosed AOA4 by next generation sequencing (NGS) followed by Sanger's sequencing in three boys from two unrelated Belarusian families. In both families, one of the heterozygous PNKP mutations was c.1123G>T, common in Portuguese patients; biallelic mutations, c.1270_1283dup14 and c.1029+2T>C, respectively, were novel. These are the first reported AOA4 Slavic cases and the first with a "Portuguese" PNKP mutation outside Portugal. Distinction in two brothers was microcephaly but their disease was not severe in contrast to PNKP -related "microcephaly, seizures, and developmental delay" and reported cases with features of both phenotypes.

9.
J Hum Genet ; 63(8): 919-922, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29760529

RESUMO

Intellectual disability is the most common developmental disorder caused by chromosomal aberrations as well as single-nucleotide variants (SNVs) and small insertions/deletions (indels). Here we report identification of a novel, probably pathogenic mutation in the WHSC1 gene in a patient case with phenotype overlapping the features of Wolf-Hirschhorn syndrome. Deletions involving WHSC1 (Wolf-Hirschhorn syndrome candidate 1 gene) were described earlier in patients with Wolf-Hirschhorn syndrome. However, to our knowledge, single-point mutations in WHSC1 associated with any intellectual deficiency syndromes have not been reported. Using whole exome sequencing, we found a de novo nonsense mutation in WHSC1 (c.3412C>T, p.Arg1138Ter, NM_001042424.2) in patient with syndromic intellectual disability. This finding is challenging regarding a possible causative role of WHSC1 in intellectual disability syndromes, specifically Wolf-Hirschhorn syndrome. From the clinical standpoint, our finding suggests that next-generation sequencing along with chromosome microarray analysis (CMA) might be useful in genetic testing for patients with intellectual disability and dysmorphic features.


Assuntos
Códon sem Sentido/genética , Predisposição Genética para Doença , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Síndrome de Wolf-Hirschhorn/genética , Sequência de Aminoácidos , Sequência de Bases , Feminino , Histona-Lisina N-Metiltransferase/química , Humanos , Lactente , Masculino , Linhagem , Proteínas Repressoras/química
10.
BMC Med Genomics ; 11(Suppl 1): 8, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29504900

RESUMO

BACKGROUND: Primary microcephaly represents an example of clinically and genetically heterogeneous condition. Here we describe a case of primary microcephaly from the Karachay-Cherkess Republic, which was initially diagnosed with Seckel syndrome. CASE PRESENTATION: Clinical exome sequencing of the proband revealed a novel homozygous single nucleotide deletion in ASPM gene, c.1386delC, resulting in preterm termination codon. Population screening reveals allele frequency to be less than 0.005. Mutations in this gene were not previously associated with Seckel syndrome. CONCLUSIONS: Our case represents an additional support for the clinical continuum between Seckel Syndrome and primary microcephaly.


Assuntos
Anormalidades Múltiplas/patologia , Nanismo/patologia , Microcefalia/complicações , Anormalidades Múltiplas/etiologia , Idoso , Nanismo/etiologia , Fácies , Feminino , Humanos , Masculino , Microcefalia/etiologia , Microcefalia/patologia , Pessoa de Meia-Idade , Mutação , Proteínas do Tecido Nervoso/genética , Linhagem , Prognóstico , Síndrome
11.
J Invest Dermatol ; 136(6): 1097-1105, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26902920

RESUMO

Hypotrichosis is an abnormal condition characterized by decreased hair density and various defects in hair structure and growth patterns. In particular, in woolly hair, hypotrichosis is characterized by a tightly curled structure and abnormal growth. In this study, we present a detailed comparative examination of individuals affected by autosomal-recessive hypotrichosis (ARH), which distinguishes two types of ARH. Earlier, we demonstrated that exon 4 deletion in the lipase H gene caused an ARH (hypotrichosis 7; MIM: 604379) in populations of the Volga-Ural region of Russia. Screening for this mutation in all affected individuals revealed its presence only in the group with the hypotrichosis 7 phenotype. Other patients formed a separate group of woolly hair-associated ARH, with a homozygous missense mutation c.712G>T (p.Val238Leu) in a highly conserved position of type I keratin KRT25 (K25). Haplotype analysis indicated a founder effect. An expression study in the HaCaT cell line demonstrated a deleterious effect of the p.Val238Leu mutation on the formation of keratin intermediate filaments. Hence, we have identified a previously unreported missense mutation in the KRT25 gene causing ARH with woolly hair.


Assuntos
Alopecia/congênito , Predisposição Genética para Doença/epidemiologia , Queratinas Específicas do Cabelo/genética , Mutação de Sentido Incorreto , Alopecia/etnologia , Alopecia/genética , Análise Mutacional de DNA , Éxons/genética , Feminino , Genes Recessivos , Cabelo/anormalidades , Doenças do Cabelo , Folículo Piloso/patologia , Haplótipos/genética , Humanos , Masculino , Linhagem , Fenótipo , Federação Russa , Estudos de Amostragem , Deleção de Sequência
12.
Mol Genet Genomics ; 283(6): 551-63, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20407790

RESUMO

Molecular markers based on retrotransposon insertions are widely used for various applications including phylogenetic analysis. Multiple cases were described where retrotransposon-based markers, namely sequence-specific amplification polymorphism (SSAP), were superior to other marker types in resolving the phylogenetic relationships due to their higher variability and informativeness. However, the patterns of evolutionary relationships revealed by SSAP may be dependent on the underlying retrotransposon activity in different periods of time. Hence, the proper choice of retrotransposon family is essential for obtaining significant results. We compared the phylogenetic trees for a diverse set of diploid A-genome wheat species (Triticum boeoticum, T. urartu and T. monococcum) based on two unrelated retrotransposon families, BARE-1 and Jeli. BARE-1 belongs to Copia class and has a uniform distribution between common wheat (T. aestivum) genomes of different origin (A, B and D), indicating similar activity in the respective diploid genome donors. Gypsy-class family Jeli was found by us to be an A-genome retrotransposon with >70% copies residing in A genome of hexaploid common wheat, suggesting a burst of transposition in the history of A-genome progenitors. The results indicate that a higher Jeli transpositional activity was associated with T. urartu versus T. boeoticum speciation, while BARE-1 produced more polymorphic insertions during subsequent intraspecific diversification; as an outcome, each retrotransposon provides more informative markers at the corresponding level of phylogenetic relationships. We conclude that multiple retroelement families should be analyzed for an image of evolutionary relationships to be solid and comprehensive.


Assuntos
Evolução Molecular , Genes de Plantas , Marcadores Genéticos , Retroelementos/genética , Triticum/genética , Mapeamento Cromossômico , Diploide , Genes de Plantas/genética , Variação Genética , Genoma de Planta , Filogenia , Sequências Repetidas Terminais/genética
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