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Recent Advances in Human Genetics

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 10 June 2024 | Viewed by 10961

Special Issue Editor


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Guest Editor
Director, W. Montague Cobb Research Laboratory, Howard University, Washington, DC 20059, USA
Interests: human genomics; human diversity and microevolution; epigenomic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Next-generation sequencing (NGS) technologies such as whole exome sequencing (WES) and whole genome sequencing (WGS) have played an important role in the genetic testing of human genetics in the whole world. Interpreting the millions of human genetic variants identified by high-throughput sequencing presents one of the greatest scientific challenges of our time. Variants can be classified by their location in genomic DNA, as well as their evolutionary, physico–chemical, structural, and functional properties, and their impact on transcripts, proteins, and molecular interactions.

This Special Issue aims to provide a comprehensive overview of human genetics studies on genome/exome or targeted sequencing panels. In this Special Issue, we welcome all papers, including original research, systematic reviews, and meta-analyses. We also welcome basic research on humans and/or animals.

Prof. Dr. Fatimah L. C. Jackson
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • human genomics
  • mutation
  • sequencing
  • variants
  • human microevolution
  • epigenomic
  • human diversity

Published Papers (6 papers)

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Research

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12 pages, 2009 KiB  
Article
Evaluating the Transition from Targeted to Exome Sequencing: A Guide for Clinical Laboratories
by Kevin Yauy, Charles Van Goethem, Henri Pégeot, David Baux, Thomas Guignard, Corinne Thèze, Olivier Ardouin, Anne-Françoise Roux, Michel Koenig, Anne Bergougnoux and Mireille Cossée
Int. J. Mol. Sci. 2023, 24(8), 7330; https://doi.org/10.3390/ijms24087330 - 15 Apr 2023
Viewed by 1573
Abstract
The transition from targeted to exome or genome sequencing in clinical contexts requires quality standards, such as targeted sequencing, in order to be fully adopted. However, no clear recommendations or methodology have emerged for evaluating this technological evolution. We developed a structured method [...] Read more.
The transition from targeted to exome or genome sequencing in clinical contexts requires quality standards, such as targeted sequencing, in order to be fully adopted. However, no clear recommendations or methodology have emerged for evaluating this technological evolution. We developed a structured method based on four run-specific sequencing metrics and seven sample-specific sequencing metrics for evaluating the performance of exome sequencing strategies to replace targeted strategies. The indicators include quality metrics and coverage performance on gene panels and OMIM morbid genes. We applied this general strategy to three different exome kits and compared them with a myopathy-targeted sequencing method. After having achieved 80 million reads, all-tested exome kits generated data suitable for clinical diagnosis. However, significant differences in the coverage and PCR duplicates were observed between the kits. These are two main criteria to consider for the initial implementation with high-quality assurance. This study aims to assist molecular diagnostic laboratories in adopting and evaluating exome sequencing kits in a diagnostic context compared to the strategy used previously. A similar strategy could be used to implement whole-genome sequencing for diagnostic purposes. Full article
(This article belongs to the Special Issue Recent Advances in Human Genetics)
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14 pages, 2716 KiB  
Article
Accurate Prediction of Transcriptional Activity of Single Missense Variants in HIV Tat with Deep Learning
by Houssemeddine Derbel, Christopher J. Giacoletto, Ronald Benjamin, Gordon Chen, Martin R. Schiller and Qian Liu
Int. J. Mol. Sci. 2023, 24(7), 6138; https://doi.org/10.3390/ijms24076138 - 24 Mar 2023
Cited by 1 | Viewed by 1669
Abstract
Tat is an essential gene for increasing the transcription of all HIV genes, and affects HIV replication, HIV exit from latency, and AIDS progression. The Tat gene frequently mutates in vivo and produces variants with diverse activities, contributing to HIV viral heterogeneity as [...] Read more.
Tat is an essential gene for increasing the transcription of all HIV genes, and affects HIV replication, HIV exit from latency, and AIDS progression. The Tat gene frequently mutates in vivo and produces variants with diverse activities, contributing to HIV viral heterogeneity as well as drug-resistant clones. Thus, identifying the transcriptional activities of Tat variants will help to better understand AIDS pathology and treatment. We recently reported the missense mutation landscape of all single amino acid Tat variants. In these experiments, a fraction of double missense alleles exhibited intragenic epistasis. However, it is too time-consuming and costly to determine the effect of the variants for all double mutant alleles through experiments. Therefore, we propose a combined GigaAssay/deep learning approach. As a first step to determine activity landscapes for complex variants, we evaluated a deep learning framework using previously reported GigaAssay experiments to predict how transcription activity is affected by Tat variants with single missense substitutions. Our approach achieved a 0.94 Pearson correlation coefficient when comparing the predicted to experimental activities. This hybrid approach can be extensible to more complex Tat alleles for a better understanding of the genetic control of HIV genome transcription. Full article
(This article belongs to the Special Issue Recent Advances in Human Genetics)
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Review

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22 pages, 2312 KiB  
Review
Exploring the Role of Enhancer-Mediated Transcriptional Regulation in Precision Biology
by Xueyan Wang, Danli Liu, Jing Luo, Dashuai Kong and Yubo Zhang
Int. J. Mol. Sci. 2023, 24(13), 10843; https://doi.org/10.3390/ijms241310843 - 29 Jun 2023
Cited by 1 | Viewed by 1392
Abstract
The emergence of precision biology has been driven by the development of advanced technologies and techniques in high-resolution biological research systems. Enhancer-mediated transcriptional regulation, a complex network of gene expression and regulation in eukaryotes, has attracted significant attention as a promising avenue for [...] Read more.
The emergence of precision biology has been driven by the development of advanced technologies and techniques in high-resolution biological research systems. Enhancer-mediated transcriptional regulation, a complex network of gene expression and regulation in eukaryotes, has attracted significant attention as a promising avenue for investigating the underlying mechanisms of biological processes and diseases. To address biological problems with precision, large amounts of data, functional information, and research on the mechanisms of action of biological molecules is required to address biological problems with precision. Enhancers, including typical enhancers and super enhancers, play a crucial role in gene expression and regulation within this network. The identification and targeting of disease-associated enhancers hold the potential to advance precision medicine. In this review, we present the concepts, progress, importance, and challenges in precision biology, transcription regulation, and enhancers. Furthermore, we propose a model of transcriptional regulation for multi-enhancers and provide examples of their mechanisms in mammalian cells, thereby enhancing our understanding of how enhancers achieve precise regulation of gene expression in life processes. Precision biology holds promise in providing new tools and platforms for discovering insights into gene expression and disease occurrence, ultimately benefiting individuals and society as a whole. Full article
(This article belongs to the Special Issue Recent Advances in Human Genetics)
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16 pages, 1038 KiB  
Review
Narrative Review: Update on the Molecular Diagnosis of Fragile X Syndrome
by Cristian-Gabriel Ciobanu, Irina Nucă, Roxana Popescu, Lucian-Mihai Antoci, Lavinia Caba, Anca Viorica Ivanov, Karina-Alexandra Cojocaru, Cristina Rusu, Cosmin-Teodor Mihai and Monica-Cristina Pânzaru
Int. J. Mol. Sci. 2023, 24(11), 9206; https://doi.org/10.3390/ijms24119206 - 24 May 2023
Cited by 1 | Viewed by 3124
Abstract
The diagnosis and management of fragile X syndrome (FXS) have significantly improved in the last three decades, although the current diagnostic techniques are not yet able to precisely identify the number of repeats, methylation status, level of mosaicism, and/or the presence of AGG [...] Read more.
The diagnosis and management of fragile X syndrome (FXS) have significantly improved in the last three decades, although the current diagnostic techniques are not yet able to precisely identify the number of repeats, methylation status, level of mosaicism, and/or the presence of AGG interruptions. A high number of repeats (>200) in the fragile X messenger ribonucleoprotein 1 gene (FMR1) results in hypermethylation of promoter and gene silencing. The actual molecular diagnosis is performed using a Southern blot, TP-PCR (Triplet-Repeat PCR), MS-PCR (Methylation-Specific PCR), and MS-MLPA (Methylation-Specific MLPA) with some limitations, with multiple assays being necessary to completely characterise a patient with FXS. The actual gold standard diagnosis uses Southern blot; however, it cannot accurately characterise all cases. Optical genome mapping is a new technology that has also been developed to approach the diagnosis of fragile X syndrome. Long-range sequencing represented by PacBio and Oxford Nanopore has the potential to replace the actual diagnosis and offers a complete characterization of molecular profiles in a single test. The new technologies have improved the diagnosis of fragile X syndrome and revealed unknown aberrations, but they are a long way from being used routinely in clinical practice. Full article
(This article belongs to the Special Issue Recent Advances in Human Genetics)
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Other

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11 pages, 620 KiB  
Brief Report
The Rationale of Complement Blockade of the MCPggaac Haplotype following Atypical Hemolytic Uremic Syndrome of Three Southeastern European Countries with a Literature Review
by Daniel Turudic, Danka Pokrajac, Velibor Tasic, Dino Kasumovic, Zoltan Prohaszka and Danko Milosevic
Int. J. Mol. Sci. 2023, 24(17), 13041; https://doi.org/10.3390/ijms241713041 - 22 Aug 2023
Viewed by 984
Abstract
We present eight cases of the homozygous MCPggaac haplotype, which is considered to increase the likelihood and severity of atypical hemolytic uremic syndrome (aHUS), especially in combination with additional risk aHUS mutations. Complement blockade (CBT) was applied at a median age of 92 [...] Read more.
We present eight cases of the homozygous MCPggaac haplotype, which is considered to increase the likelihood and severity of atypical hemolytic uremic syndrome (aHUS), especially in combination with additional risk aHUS mutations. Complement blockade (CBT) was applied at a median age of 92 months (IQR 36–252 months). The median number of relapses before CBT initiation (Eculizumab) was two. Relapses occurred within an average of 22.16 months (median 17.5, minimum 8 months, and maximum 48 months) from the first subsequent onset of the disease (6/8 patients). All cases were treated with PI/PEX, and rarely with renal replacement therapy (RRT). When complement blockade was applied, children had no further disease relapses. Children with MCPggaac haplotype with/without additional gene mutations can achieve remission through renal replacement therapy without an immediate need for complement blockade. If relapse of aHUS occurs soon after disease onset or relapses are repeated frequently, a permanent complement blockade is required. However, the duration of such a blockade remains uncertain. If complement inhibition is not applied within 4–5 relapses, proteinuria and chronic renal failure will eventually occur. Full article
(This article belongs to the Special Issue Recent Advances in Human Genetics)
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6 pages, 509 KiB  
Commentary
Synonymous Variants of Uncertain Silence
by Christopher J. Giacoletto, Jerome I. Rotter, Wayne W. Grody and Martin R. Schiller
Int. J. Mol. Sci. 2023, 24(13), 10556; https://doi.org/10.3390/ijms241310556 - 23 Jun 2023
Viewed by 1402
Abstract
Synonymous variants, traditionally regarded as silent mutations due to their lack of impact on protein sequence, structure and function, have been the subject of increasing scrutiny. This commentary explores the emerging evidence challenging the notion of synonymous variants as functionally inert. Analysis of [...] Read more.
Synonymous variants, traditionally regarded as silent mutations due to their lack of impact on protein sequence, structure and function, have been the subject of increasing scrutiny. This commentary explores the emerging evidence challenging the notion of synonymous variants as functionally inert. Analysis of the activity of 70 synonymous variants in the HIV Tat transcription factor revealed that 50% of the variants exhibited significant deviations from wild-type activity. Our analysis supports previous work and raises important questions about the broader impact of non-silent synonymous variants in human genes. Considering the potential functional implications, the authors propose classifying such variants as “synonymous variants of uncertain silence” (sVUS), highlighting the need for cautious interpretation and further investigations in clinical and genetic testing settings. Full article
(This article belongs to the Special Issue Recent Advances in Human Genetics)
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