Journal of Human Genetics最新文献

A search for the modern descendants of the Neolithic population has been conducted using two datasets of Y-chromosome polymorphisms: literature data on the ancient population of Northeast Eurasia and our own data on 256 whole genomes of 11 indigenous peoples of the Russian Far East (Aleuts, Chukchi, Evens, Evenks, Itelmens, Koryaks, Nanais, Negidals, Nivkhs, Orochi, and Ulchi). Y-SNP analysis revealed that both Kyordyughen I (4200 YBP) and Kyordyughen II (4600 YВР) samples of the Yakutian Late Neolithic belong to the haplogroup N-L708 and lie on its two branches that diverged at 6200 YBP. A quarter (67 of 256) of the analysed samples, including Chukchi, Evens, Evenks, Itelmens, Koryaks, Nanais, Nivkhs, Orochi, and Ulchi, belong to the haplogroup N-L708 and are, to various extents, genetically related to the Neolithic Yakutian individuals. The most direct descendants of the famous Kyordyughen warrior (Kyordyughen I) are the indigenous peoples of Kamchatka and Chukotka (Chukchi, Koryaks, Evens). The divergence time of their Y-lineages (4300 ± 1000 YВР) is consistent with the radiocarbon dates for Kyordyughen I. Literary data on Y-STR polymorphism suggest that descendants of the Kyordyughen warrior dispersed far across North Asia. Ancient N-L708 carriers started to expand from Transbaikalia across Northeast Eurasia at ~7000 YBP. About 4000-3000 YВР, the lineages close to the Kyordyughen samples arrived in today's Krasnoyarsk territory, Yakutia, Mongolia and Chukotka. Our findings are in good agreement with archaeological data and the autosomal genome-based modelling of the Kyordyughen warrior's origin.

Loeys-Dietz syndrome (LDS), an autosomal dominant connective tissue disorder, was initially considered "atypical" Marfan syndrome (MFS). MFS is caused by mutations in FBN1 encoding fibrillin 1, which binds to transforming growth factor β (TGF-β) to inhibit it from binding to TGF-β receptors. In contrast, LDS is caused by mutations in TGF-β-related genes, including TGFBR2. Some clinical symptoms of LDS, including cardiovascular and skeletal complications, are similar to those observed in MFS; however, arterial tortuosity and widespread aortic aneurysm, hypertelorism, and cleft palate or bifida uvula are specific to LDS. Therefore, the role and difference of the TGF-β signaling pathway in LDS remains unclear. To elucidate the pathological mechanisms of LDS and the phenotypical differences between MFS and LDS, an LDS zebrafish model was established by knocking down tgfbr2b using an antisense morpholino oligonucleotide (tgfbr2b morphant), and the phenotype and expression of genes and proteins related to the TGF-β signaling pathway were investigated. tgfbr2b morphants presented with a dysmorphic face, bent body, and cardiovascular abnormalities, some of which were similar to those observed in patients with LDS. The TGF-β1 gene and protein expression, as well as the genes related to the BMP signaling pathway, were upregulated, and the smad1/5/9 protein exhibited enhanced phosphorylation. These results suggest that dysregulation of BMP signaling during development plays an essential role in the craniofacial dysmorphism and cardiac abnormalities observed in the LDS zebrafish model. Our study clarified the differences of pathological mechanism between MFS and LDS.

Congenital diarrhea/enteropathy due to inherited biallelic defects in the newly discovered gene PERCC1 has been reported in only a few patients thus far. We utilized whole-exome sequencing (WES) to identify a novel PERCC1 stop-gain variant (c.188C>G, p.Ser63*). Literature review identified 16 additional patients - 13 with large biallelic deletions involving the PERCC1 gene and three with a homozygous single-nucleotide (stop-gain) variant (c.390C>G, p.Tyr130*). Median [range] age at onset of diarrhea in patients with available data (including ours) is 9.5 [1-21] days. Chronic intractable diarrhea often results in growth failure, meriting the utilization of parenteral nutrition (PN), especially during the first few years of life. Discontinuation of PN has been reported in six patients at an age of 8 [4-17] years. Our report highlights the role of WES in identifying PERCC1 variants in patients with congenital diarrhea/enteropathy. Thus far, PERCC1 variants have primarily been identified through targeted testing or whole-genome sequencing.

Biallelic variants in FRA10AC1, encoding a component of the spliceosomal C complex that is crucial for functional mRNA processing, have been recently associated with a neurodevelopmental disorder characterized by developmental delay, variable dysmorphic facies, growth retardation, and corpus callosum abnormalities. Skeletal and congenital heart defects were observed in some patients. To date, only 10 patients from 6 unrelated families with FRA10AC1 variants have been reported in the literature. Herein, we describe a new patient harboring a loss-of-function variant in FRA10AC1. Our patient presented with global developmental delay, hypotonia, dysmorphic facies, hyperactivity, and severe intellectual disability. He had no seizures. Unusual findings noted in the patient were fused kidneys and bilateral cone dystrophy. Brain MRI showed a hypoplastic corpus callosum, delayed myelination, and a small cyst in the caudate nucleus. Exome sequencing revealed a novel homozygous variant in the donor splice site of exon 7 of the FRA10AC1 (c.465+1G>A) as the likely cause of the patient's phenotype. Thorough investigations of the exome data did not reveal any additional potential pathogenic variants to justify the patient's renal and ocular phenotypes. The identified c.465+1G>A was confirmed by studying the patient's mRNA to result in exon skipping and early protein truncation, p.(Trp127CysfsTer8). Our study increases the number of patients and variants associated with FRA10AC1-related disorder and contributes to increasing our understanding of FRA10AC1 role in neurodevelopmental disorders. In addition, it reinforces kidney and ocular anomalies as part of this multisystem disorder.

White matter hyperintensities (WMH) are common findings on brain magnetic resonance imaging (MRI) in older adults and are associated with an increased risk of dementia and stroke. Although large-scale European genome-wide association studies (GWAS) have identified more than 20 loci associated with WMH, the genetic architecture of WMH in Asian populations has not been fully elucidated. Here, we conducted a GWAS comprising 1001 Japanese individuals from the National Center for Geriatrics and Gerontology (NCGG) Biobank, followed by a meta-analysis with GWAS data from 9479 individuals in the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD), identifying three novel loci significantly associated with WMH volume (P < 5 × 10^-8). A subsequent trans-ethnic meta-analysis with UK Biobank data revealed twelve genome-wide significance loci, including one novel locus. Cis-expression quantitative trait locus (cis-eQTL) analyses using blood RNA-Seq data implicated 39 genes, especially showing downregulation of ACOX1 at a chromosome 17 locus. Protein QTL (pQTL) analyses using plasma proteomics data further demonstrated associations between these loci and increased levels of immune and inflammatory proteins. These findings provide new insights into the genetic architecture of WHH in the Japanese population and highlight immune and inflammatory pathways in the pathogenesis of age-related neurological diseases.

The double homeobox 4 gene (DUX4) and its centromeric paralogue, DUX4C, reside in the subtelomeric region of chromosome 4 and have been implicated in facioscapulohumeral muscular dystrophy (FSHD) and cancers. However, the high sequence similarity between these genes, together with the widespread presence of DUX4-like paralogues across the human genome, has hindered accurate genotyping and expression profiling using short-read sequencing. To elucidate the genetic architecture and potential disease-associated functions of DUX4 and DUX4C, we first identified two distinct DUX4C haplotypes with expression quantitative trait effects-DUX4C-4qα and DUX4C-4qβ. We then integrated them with known DUX4 haplotypes to generate a reference genome, D4Ref-T2T, using long-read sequencing. Haplotype analysis indicated strong linkage disequilibrium between DUX4C and DUX4 haplotypes (r² = 0.86). We further characterized full-length DUX4C mRNA isoforms and established a corresponding transcriptome reference. Applying these resources to breast tumor, FSHD, and lymphoblastoid cell line datasets revealed that DUX4 is expressed in both breast tumor and FSHD tissues, whereas DUX4C shows expression only in breast tumors. Differential gene expression and Gene Ontology enrichment analyses further suggested that DUX4C expression is associated with activation of pathways involved in leukocyte differentiation, chemotaxis, and cell migration.

Press releases on genomic research play an important role in Japan. Not only do journalists use them as major sources of news stories, but the public also accesses them directly across various media platforms. Given the unique characteristics of genomic information, including ethical implications, it is essential to report research results in a responsible and comprehensive manner. To support individuals involved in communicating such results, we developed a press release guide for genomic research in collaboration with diverse stakeholders, including members of the public. This guide outlines 12 key items for scientific research press releases, five of which are tailored to genomic research: protect personal information; avoid detrimental behavior change; consider individuals involved; avoid prejudice or discrimination; and avoid "genetic determinism." For each item, supplementary explanations and guidance are presented in the form of "Note" and "For Media." Additionally, fresh insights gained through the discussions with the diverse stakeholders are incorporated into a new section titled "From a different viewpoint." Genomic research is increasingly integrated into clinical practice and society, which indicates that reports on genomic studies directly affect a broader audience. Furthermore, enhancing the reporting quality of genomic research is critical because of the distinctive characteristics of genomic information. Our guide provides practical support for those disseminating genomic research results and will be valuable in promoting communication among stakeholders with different roles and expectations.

Sarcoidosis is a heterogenous inflammatory disease with complex genetic susceptibilities. Multi-ethnic genome-wide association studies have validated the association of sarcoidosis susceptibilities with single nucleotide variants on interleukin 23 receptor gene (IL23R), which is highly expressed in adrenal gland and testis, but not in skeletal muscle. Here we report concomitant ectopic expression of a canonical IL23R transcript and alternative polyadenylation of intron 6 of IL23R, leading to novel aberrant transcripts containing two retrotransposons, LINE1 (L1PA16) and THE1A, in the 3' untranslated region (IL23R^L1-THE1A), in sarcoid myopathy (SM) compared with non-SM disease controls. RT-qPCR confirmed the expression of both transcripts in an additional sample set, including 14 SM and 29 non-SM. We also observed expression of both transcripts in T cells by single-nucleus RNA-sequencing. These findings should serve as an additional resource for investigating the role of IL23R transcript variants in the genetic background of sarcoidosis susceptibility and other inflammatory diseases.