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Complex Genetic Loci, 2nd Edition
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Complex Genetic Loci, 2nd Edition

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 October 2020) | Viewed by 21916

Special Issue Editor

Dr. Santiago Rodriguez

E-Mail Website
Guest Editor
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
Interests: population genetics; genetic epidemiology; molecular genetics; medical education
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

After the success of the first edition of the Special Issue on Complex Genetic Loci in 2018, we are glad to announce a new edition on the same topic.

The study of genetic variation is key to understand genes, genetics, and genomics. In previous decades, genetic analyses have been successful in many areas. One of these areas is the understanding of the influence of genetics on complex traits, i.e., phenotypes that are not a direct reflection of genotypes. Current genetic studies are mainly focussed on binary genetic variants such as single nucleotide polymorphisms (SNPs) and mutations. However, genomes contain many other types of genetic variants. The use of complex genetic loci in genetic studies is currently underexplored compared to binary genetic variants. It is of interest to understand their role in the design and interpretation of genetic analyses in the post-GWAS era.

In this Special Issue, as in the previous edition, we welcome reviews, new methodologies, and original articles covering aspects of complex loci relevant to genes, genetics, and genomics. These include but are not limited to copy number variants (telomere length variation, mitochondrial DNA copy number, etc.), repeat polymorphisms (microsatellites, minisatellites, etc.), insertion-deletion variants, chromosomal abnormalities (irregular karyotype, structural modifications of chromosomes, etc.), and transposable elements (LINEs, SINES, etc.). This Special Issue has a special emphasis on the relationship between complex loci and complex traits, although studies relating complex loci to Mendelian traits are also welcome.

Dr. Santiago Rodriguez
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • genetic variation
  • complex loci
  • copy number variants (CNV)
  • telomere length
  • microsatellites
  • minisatellites
  • transposable elements
  • chromosomal abnormalities
  • complex traits
  • Mendelian traits
  • post-GWAS era

Published Papers (6 papers)

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Research

Jump to: Review

16 pages, 2429 KiB  
Article
TYK2 Variants in B-Acute Lymphoblastic Leukaemia
by Edgar Turrubiartes-Martínez, Irene Bodega-Mayor, Pablo Delgado-Wicke, Francisca Molina-Jiménez, Diana Casique-Aguirre, Martín González-Andrade, Inmaculada Rapado, Mireia Camós, Cristina Díaz-de-Heredia, Eva Barragán, Manuel Ramírez-Orellana, Beatriz Aguado, Ángela Figuera, Joaquín Martínez-López and Elena Fernández-Ruiz
Genes 2020, 11(12), 1434; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11121434 - 28 Nov 2020
Cited by 4 | Viewed by 2850
Abstract
B-cell precursor acute lymphoblastic leukaemia (B-ALL) is a malignancy of lymphoid progenitor cells with altered genes including the Janus kinase (JAK) gene family. Among them, tyrosine kinase 2 (TYK2) is involved in signal transduction of cytokines such as interferon (IFN) α/β through IFN−α/β [...] Read more.
B-cell precursor acute lymphoblastic leukaemia (B-ALL) is a malignancy of lymphoid progenitor cells with altered genes including the Janus kinase (JAK) gene family. Among them, tyrosine kinase 2 (TYK2) is involved in signal transduction of cytokines such as interferon (IFN) α/β through IFN−α/β receptor alpha chain (IFNAR1). To search for disease-associated TYK2 variants, bone marrow samples from 62 B-ALL patients at diagnosis were analysed by next-generation sequencing. TYK2 variants were found in 16 patients (25.8%): one patient had a novel mutation at the four-point-one, ezrin, radixin, moesin (FERM) domain (S431G) and two patients had the rare variants rs150601734 or rs55882956 (R425H or R832W). To functionally characterise them, they were generated by direct mutagenesis, cloned in expression vectors, and transfected in TYK2-deficient cells. Under high-IFNα doses, the three variants were competent to phosphorylate STAT1/2. While R425H and R832W induced STAT1/2-target genes measured by qPCR, S431G behaved as the kinase-dead form of the protein. None of these variants phosphorylated STAT3 in in vitro kinase assays. Molecular dynamics simulation showed that TYK2/IFNAR1 interaction is not affected by these variants. Finally, qPCR analysis revealed diminished expression of TYK2 in B-ALL patients at diagnosis compared to that in healthy donors, further stressing the tumour immune surveillance role of TYK2. Full article
(This article belongs to the Special Issue Complex Genetic Loci, 2nd Edition)
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11 pages, 1027 KiB  
Article
Variation in the Caprine Keratin-Associated Protein 27-1 Gene is Associated with Cashmere Fiber Diameter
by Mengli Zhao, Huitong Zhou, Yuzhu Luo, Jiqing Wang, Jiang Hu, Xiu Liu, Shaobin Li, Zhiyun Hao, Xiayang Jin, Yize Song, Xinmiao Wu, Liyan Hu and Jon G. H. Hickford
Genes 2020, 11(8), 934; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11080934 - 13 Aug 2020
Cited by 11 | Viewed by 2196
Abstract
Variation in some caprine keratin-associated protein (KAP) genes has been associated with cashmere fiber traits, but many KAP genes remain unidentified in goats. In this study, we confirm the identification of a KAP27-1 gene (KRTAP27-1) and describe its effect on cashmere [...] Read more.
Variation in some caprine keratin-associated protein (KAP) genes has been associated with cashmere fiber traits, but many KAP genes remain unidentified in goats. In this study, we confirm the identification of a KAP27-1 gene (KRTAP27-1) and describe its effect on cashmere traits in 248 Longdong cashmere goats. A polymerase chain reaction–single strand conformation polymorphism (PCR-SSCP) analysis was used to screen for sequence variation in this gene, and three sequence variants (named A to C) were found. These sequences have the highest similarity (77% identity) to a human KRTAP27-1 sequence, while sharing some homology with a predicted caprine KRTAP27-1 sequence ENSCHIG00000023347 in the goat genome construct (ARS1:CM004562.1) at chromosome 1 position 3,966,193–3,973,677 in the forward strand. There were two single nucleotide polymorphisms (SNPs) detected in the coding sequence, including one nonsynonymous SNP (c.413C/T; p.Ala138Val) and one synonymous SNP (c.495C/T). The C variant differed from A and B at c.413C/T, having cytosine in its nucleotide sequence, while the B variant differed from A and C at c.495C/T, having thymine in its nucleotide sequence. Goats of the genotypes AB and BB produced cashmere fibers of higher mean fiber diameter (MFD) than goats of genotype AA, but no difference in MFD was detected between the AB and BB goats. These results suggest that B is associated with increased MFD. Expression of the caprine KRTAP27-1 sequence was predominantly detected in the skin tissue of goats but not or only weakly detected in other tissues, including longissimus dorsi muscle, heart, kidney, liver, lung and spleen. Full article
(This article belongs to the Special Issue Complex Genetic Loci, 2nd Edition)
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10 pages, 2182 KiB  
Article
Genetic Variation in Complex Traits in Transgenic α-Synuclein Strains of Caenorhabditis elegans
by Yiru A. Wang, Lisa van Sluijs, Yu Nie, Mark G. Sterken, Simon C. Harvey and Jan E. Kammenga
Genes 2020, 11(7), 778; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11070778 - 11 Jul 2020
Cited by 2 | Viewed by 2925
Abstract
Different genetic backgrounds can modify the effect of mutated genes. Human α-synuclein (SNCA) gene encodes α-synuclein, and its oligomeric complexes accumulate with age and mediate the disruption of cellular homeostasis, resulting in the neuronal death that is characteristic of Parkinson’s Disease. [...] Read more.
Different genetic backgrounds can modify the effect of mutated genes. Human α-synuclein (SNCA) gene encodes α-synuclein, and its oligomeric complexes accumulate with age and mediate the disruption of cellular homeostasis, resulting in the neuronal death that is characteristic of Parkinson’s Disease. Polymorphic variants modulate this complex pathologic mechanism. Previously, we constructed five transgenic introgression lines of a Caenorhabditis elegans model of α-synuclein using genetic backgrounds that are genetically diverse from the canonical wild-type Bristol N2. A gene expression analysis revealed that the α-synuclein transgene differentially affects genome-wide transcription due to background modifiers. To further investigate how complex traits are affected in these transgenic lines, we measured the α-synuclein transgene expression, the overall accumulation of the fusion protein of α-synuclein and yellow fluorescent protein (YFP), the lysosome-related organelles, and the body size. By using quantitative PCR (qPCR), we demonstrated stable and similar expression levels of the α-synuclein transgene in different genetic backgrounds. Strikingly, we observed that the levels of the a-synuclein:YFP fusion protein vary in different genetic backgrounds by using the COPAS™ biosorter. The quantification of the Nile Red staining assay demonstrates that α-synuclein also affects lysosome-related organelles and body size. Our results show that the same α-synuclein introgression in different C. elegans backgrounds can produces differing effects on complex traits due to background modifiers. Full article
(This article belongs to the Special Issue Complex Genetic Loci, 2nd Edition)
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13 pages, 3192 KiB  
Article
Identification of the Ovine Keratin-Associated Protein 2-1 Gene and Its Sequence Variation in Four Chinese Sheep Breeds
by Jianqing Wang, Huitong Zhou, Jon G. H. Hickford, Yuzhu Luo, Hua Gong, Jiang Hu, Xiu Liu, Shaobin Li, Yize Song, Na Ke, Lirong Qiao and Jiqing Wang
Genes 2020, 11(6), 604; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11060604 - 29 May 2020
Cited by 5 | Viewed by 1850
Abstract
Keratin-associated proteins are important components of wool fibers. The gene encoding the high-sulfur keratin-associated protein 2-1 has been described in humans, but it has not been described in sheep. A basic local alignment search tool nucleotide search of the Ovine Genome Assembly version [...] Read more.
Keratin-associated proteins are important components of wool fibers. The gene encoding the high-sulfur keratin-associated protein 2-1 has been described in humans, but it has not been described in sheep. A basic local alignment search tool nucleotide search of the Ovine Genome Assembly version 4.0 using a human keratin-associated protein 2-1 gene sequence revealed a 399-base pair open reading frame, which was clustered among nine previously identified keratin-associated protein genes on chromosome 11. Polymerase chain reaction–single strand conformation polymorphism analysis revealed four different banding patterns, with these representing four different sequences (A–D) in Chinese sheep breeds. These sequences had the highest similarity to human keratin-associated protein 2-1 gene, suggesting that they represent variants of ovine keratin-associated protein 2-1 gene. Nine single nucleotide variations were detected in the gene, including one non-synonymous nucleotide substitution. Differences in variant frequencies between fine-wool sheep breeds and coarse-wool sheep breeds were detected. The gene was found to be expressed in various tissues, with the highest expression level in skin, and moderate expression levels in heart and lung tissue. These results reveal that the ovine keratin-associated protein 2-1 gene is variable and suggest the gene might affect variation in mean fiber diameter. Full article
(This article belongs to the Special Issue Complex Genetic Loci, 2nd Edition)
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Review

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19 pages, 1548 KiB  
Review
The Y Chromosome: A Complex Locus for Genetic Analyses of Complex Human Traits
by Katherine Parker, A. Mesut Erzurumluoglu and Santiago Rodriguez
Genes 2020, 11(11), 1273; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111273 - 29 Oct 2020
Cited by 9 | Viewed by 6455
Abstract
The Human Y chromosome (ChrY) has been demonstrated to be a powerful tool for phylogenetics, population genetics, genetic genealogy and forensics. However, the importance of ChrY genetic variation in relation to human complex traits is less clear. In this review, we summarise existing [...] Read more.
The Human Y chromosome (ChrY) has been demonstrated to be a powerful tool for phylogenetics, population genetics, genetic genealogy and forensics. However, the importance of ChrY genetic variation in relation to human complex traits is less clear. In this review, we summarise existing evidence about the inherent complexities of ChrY variation and their use in association studies of human complex traits. We present and discuss the specific particularities of ChrY genetic variation, including Y chromosomal haplogroups, that need to be considered in the design and interpretation of genetic epidemiological studies involving ChrY. Full article
(This article belongs to the Special Issue Complex Genetic Loci, 2nd Edition)
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15 pages, 787 KiB  
Review
A Systematic Review of Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders
by Sana Amanat, Teresa Requena and Jose Antonio Lopez-Escamez
Genes 2020, 11(9), 987; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11090987 - 25 Aug 2020
Cited by 32 | Viewed by 5117
Abstract
Exome sequencing has been commonly used to characterize rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) and searching for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has [...] Read more.
Exome sequencing has been commonly used to characterize rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) and searching for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to the heritability of complex clinical traits. We conducted a systematic review to find evidence supporting the use of EP strategies in the search for rare variants in genetic studies of complex diseases and highlight the contribution of rare variations to the genetic structure of polygenic conditions. After assessing the quality of the retrieved records, we selected 19 genetic studies considering EPs to demonstrate genetic association. All studies successfully identified several rare or de novo variants, and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach for patients with an early onset of a disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss. Full article
(This article belongs to the Special Issue Complex Genetic Loci, 2nd Edition)
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