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Genes, Volume 8, Issue 6 (June 2017)

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Cover Story MYC is a key regulator of cell type progression, apoptosis and cellular transformation; however, it [...] Read more.
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Research

Jump to: Review, Other

Open AccessArticle Fine Mapping and Transcriptome Analysis Reveal Candidate Genes Associated with Hybrid Lethality in Cabbage (Brassica Oleracea)
Genes 2017, 8(6), 147; doi:10.3390/genes8060147
Received: 4 April 2017 / Revised: 8 May 2017 / Accepted: 15 May 2017 / Published: 5 June 2017
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Abstract
Hybrid lethality is a deleterious phenotype that is vital to species evolution. We previously reported hybrid lethality in cabbage (Brassica oleracea) and performed preliminary mapping of related genes. In the present study, the fine mapping of hybrid lethal genes revealed that
[...] Read more.
Hybrid lethality is a deleterious phenotype that is vital to species evolution. We previously reported hybrid lethality in cabbage (Brassica oleracea) and performed preliminary mapping of related genes. In the present study, the fine mapping of hybrid lethal genes revealed that BoHL1 was located on chromosome C1 between BoHLTO124 and BoHLTO130, with an interval of 101 kb. BoHL2 was confirmed to be between insertion-deletion (InDels) markers HL234 and HL235 on C4, with a marker interval of 70 kb. Twenty-eight and nine annotated genes were found within the two intervals of BoHL1 and BoHL2, respectively. We also applied RNA-Seq to analyze hybrid lethality in cabbage. In the region of BoHL1, seven differentially expressed genes (DEGs) and five resistance (R)-related genes (two in common, i.e., Bo1g153320 and Bo1g153380) were found, whereas in the region of BoHL2, two DEGs and four R-related genes (two in common, i.e., Bo4g173780 and Bo4g173810) were found. Along with studies in which R genes were frequently involved in hybrid lethality in other plants, these interesting R-DEGs may be good candidates associated with hybrid lethality. We also used SNP/InDel analyses and quantitative real-time PCR to confirm the results. This work provides new insight into the mechanisms of hybrid lethality in cabbage. Full article
(This article belongs to the Special Issue Evolution and Biodiversity of the Plant Genome Architecture)
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Open AccessArticle Reticulate Evolution of the Rock Lizards: Meiotic Chromosome Dynamics and Spermatogenesis in Diploid and Triploid Males of the Genus Darevskia
Genes 2017, 8(6), 149; doi:10.3390/genes8060149
Received: 28 March 2017 / Revised: 10 May 2017 / Accepted: 18 May 2017 / Published: 24 May 2017
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Abstract
Knowing whether triploid hybrids resulting from natural hybridization of parthenogenetic and bisexual species are fertile is crucial for understanding the mechanisms of reticulate evolution in rock lizards. Here, using males of the bisexual diploid rock lizard species Darevskia raddei nairensis and Darevskia valentini
[...] Read more.
Knowing whether triploid hybrids resulting from natural hybridization of parthenogenetic and bisexual species are fertile is crucial for understanding the mechanisms of reticulate evolution in rock lizards. Here, using males of the bisexual diploid rock lizard species Darevskia raddei nairensis and Darevskia valentini and a triploid hybrid male Darevskia unisexualis × Darevskia valentini, we performed karyotyping and comparative immunocytochemistry of chromosome synapsis and investigated the distribution of RAD51 and MLH1 foci in spread spermatocyte nuclei in meiotic prophase I. Three chromosome sets were found to occur in cell nuclei in the D. unisexualis × D. valentini hybrid, two originating from a parthenogenetic D. unisexualis female and one from the D. valentini male. Despite this distorted chromosome synapsis and incomplete double-strand breaks repair in meiotic prophase I, the number of mismatch repair foci in the triploid hybrid was enough to pass through both meiotic divisions. The defects in synapsis and repair did not arrest meiosis or spermatogenesis. Numerous abnormal mature spermatids were observed in the testes of the studied hybrid. Full article
(This article belongs to the Special Issue Chromosomal Evolution)
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Open AccessArticle DNA Methylation Profiling of Human Prefrontal Cortex Neurons in Heroin Users Shows Significant Difference between Genomic Contexts of Hyper- and Hypomethylation and a Younger Epigenetic Age
Genes 2017, 8(6), 152; doi:10.3390/genes8060152
Received: 14 February 2017 / Revised: 21 April 2017 / Accepted: 25 May 2017 / Published: 30 May 2017
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Abstract
We employed Illumina 450 K Infinium microarrays to profile DNA methylation (DNAm) in neuronal nuclei separated by fluorescence-activated sorting from the postmortem orbitofrontal cortex (OFC) of heroin users who died from heroin overdose (N = 37), suicide completers (N = 22)
[...] Read more.
We employed Illumina 450 K Infinium microarrays to profile DNA methylation (DNAm) in neuronal nuclei separated by fluorescence-activated sorting from the postmortem orbitofrontal cortex (OFC) of heroin users who died from heroin overdose (N = 37), suicide completers (N = 22) with no evidence of heroin use and from control subjects who did not abuse illicit drugs and died of non-suicide causes (N = 28). We identified 1298 differentially methylated CpG sites (DMSs) between heroin users and controls, and 454 DMSs between suicide completers and controls (p < 0.001). DMSs and corresponding genes (DMGs) in heroin users showed significant differences in the preferential context of hyper and hypo DM. HyperDMSs were enriched in gene bodies and exons but depleted in promoters, whereas hypoDMSs were enriched in promoters and enhancers. In addition, hyperDMGs showed preference for genes expressed specifically by glutamatergic as opposed to GABAergic neurons and enrichment for axonogenesis- and synaptic-related gene ontology categories, whereas hypoDMGs were enriched for transcription factor activity- and gene expression regulation-related terms. Finally, we found that the DNAm-based “epigenetic age” of neurons from heroin users was younger than that in controls. Suicide-related results were more difficult to interpret. Collectively, these findings suggest that the observed DNAm differences could represent functionally significant marks of heroin-associated plasticity in the OFC. Full article
(This article belongs to the Special Issue Role of Epigenetic Gene Regulation in Brain Function)
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Open AccessArticle HiSeeker: Detecting High-Order SNP Interactions Based on Pairwise SNP Combinations
Genes 2017, 8(6), 153; doi:10.3390/genes8060153
Received: 31 March 2017 / Revised: 6 May 2017 / Accepted: 25 May 2017 / Published: 31 May 2017
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Abstract
Detecting single nucleotide polymorphisms’ (SNPs) interaction is one of the most popular approaches for explaining the missing heritability of common complex diseases in genome-wide association studies. Many methods have been proposed for SNP interaction detection, but most of them only focus on pairwise
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Detecting single nucleotide polymorphisms’ (SNPs) interaction is one of the most popular approaches for explaining the missing heritability of common complex diseases in genome-wide association studies. Many methods have been proposed for SNP interaction detection, but most of them only focus on pairwise interactions and ignore high-order ones, which may also contribute to complex traits. Existing methods for high-order interaction detection can hardly handle genome-wide data and suffer from low detection power, due to the exponential growth of search space. In this paper, we proposed a flexible two-stage approach (called HiSeeker) to detect high-order interactions. In the screening stage, HiSeeker employs the chi-squared test and logistic regression model to efficiently obtain candidate pairwise combinations, which have intermediate or significant associations with the phenotype for interaction detection. In the search stage, two different strategies (exhaustive search and ant colony optimization-based search) are utilized to detect high-order interactions from candidate combinations. The experimental results on simulated datasets demonstrate that HiSeeker can more efficiently and effectively detect high-order interactions than related representative algorithms. On two real case-control datasets, HiSeeker also detects several significant high-order interactions, whose individual SNPs and pairwise interactions have no strong main effects or pairwise interaction effects, and these high-order interactions can hardly be identified by related algorithms. Full article
(This article belongs to the Section Human Genetics and Genomics)
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Open AccessArticle Genome-Wide Identification and Characterization of Salinity Stress-Responsive miRNAs in Wild Emmer Wheat (Triticum turgidum ssp. dicoccoides)
Genes 2017, 8(6), 156; doi:10.3390/genes8060156
Received: 21 April 2017 / Revised: 26 May 2017 / Accepted: 26 May 2017 / Published: 6 June 2017
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Abstract
MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs which regulate diverse molecular and biochemical processes at a post-transcriptional level in plants. As the ancestor of domesticated wheat, wild emmer wheat (Triticum turgidum ssp. dicoccoides) has great genetic potential for
[...] Read more.
MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs which regulate diverse molecular and biochemical processes at a post-transcriptional level in plants. As the ancestor of domesticated wheat, wild emmer wheat (Triticum turgidum ssp. dicoccoides) has great genetic potential for wheat improvement. However, little is known about miRNAs and their functions on salinity stress in wild emmer. To obtain more information on miRNAs in wild emmer, we systematically investigated and characterized the salinity-responsive miRNAs using deep sequencing technology. A total of 88 conserved and 124 novel miRNAs were identified, of which 50 were proven to be salinity-responsive miRNAs, with 32 significantly up-regulated and 18 down-regulated. miR172b and miR1120a, as well as mi393a, were the most significantly differently expressed. Targets of these miRNAs were computationally predicted, then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the targets of salinity-responsive miRNAs were enriched in transcription factors and stress-related proteins. Finally, we investigated the expression profiles of seven miRNAs ranging between salt-tolerant and sensitive genotypes, and found that they played critical roles in salinity tolerance in wild emmer. Our results systematically identified the salinity-responsive miRNAs in wild emmer, not only enriching the miRNA resource but also laying the foundation for further study on the biological functions and evolution of miRNAs in wild wheat and beyond. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessArticle Comparative Analysis of Genome Wide DNA Methylation Profiles for the Genic Male Sterile Cabbage Line 01-20S and Its Maintainer Line
Genes 2017, 8(6), 159; doi:10.3390/genes8060159
Received: 20 April 2017 / Revised: 21 May 2017 / Accepted: 2 June 2017 / Published: 16 June 2017
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Abstract
Methylation modifications play an important role in multiple biological processes. Several studies have reported altered methylation patterns in male sterile plants such as rice and wheat, but little is known about the global methylation profiles and their possible roles in the cabbage (
[...] Read more.
Methylation modifications play an important role in multiple biological processes. Several studies have reported altered methylation patterns in male sterile plants such as rice and wheat, but little is known about the global methylation profiles and their possible roles in the cabbage (Brassica oleracea) male sterile line. In this study, single-base-resolution bisulfite sequencing (BS-Seq) was adopted to identify the pattern and degree of cytosine methylation in the male sterile line 01-20S and its near-isogenic fertile line 01-20F. Similar methylation patterns were profiled, with some changes observed in local positions. In total, 505 differentially methylated genomic regions (DMRs) and 106 DMR-associated genes were detected. Nine genes related to pollen development were discovered and further validated by a quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Among these, four were downregulated in 01-20S. In particular, Bol039180 (an invertase/pectin methylesterase inhibitor family protein) is likely involved in pectin degradation, and might play an important role in the pollen separation defects of 01-20S. This study facilitates a better understanding of DNA methylation alterations and their possible roles in genic male sterility in cabbages. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessArticle Haplotypes of the Ovine Adiponectin Gene and Their Association with Growth and Carcass Traits in New Zealand Romney Lambs
Genes 2017, 8(6), 160; doi:10.3390/genes8060160
Received: 21 April 2017 / Revised: 26 May 2017 / Accepted: 3 June 2017 / Published: 12 June 2017
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Abstract
Adiponectin plays an important role in energy homeostasis and metabolism in mammalian adipose tissue. In this study, the relationship between adiponectin gene (ADIPOQ) haplotypes and variation in growth and carcass traits in New Zealand (NZ) Romney lambs was investigated using General
[...] Read more.
Adiponectin plays an important role in energy homeostasis and metabolism in mammalian adipose tissue. In this study, the relationship between adiponectin gene (ADIPOQ) haplotypes and variation in growth and carcass traits in New Zealand (NZ) Romney lambs was investigated using General Linear Models (GLMs). Eight haplotypes were found in these lambs and they were composed of the four previously reported promoter fragment sequences (A1D1) and three previously reported intron 2–exon 3 sequences (A3C3). The frequencies of the haplotypes ranged from 0.07% to 45.91%. The presence of A1A3 was associated with a decreased pre-weaning growth rate (p = 0.037), and decreased leg lean-meat yield (p = 0.001), loin lean-meat yield (p = 0.018) and total lean-meat yield (p = 0.004). The presence of A1C3 was associated with increased carcass fat depth over the 12th rib (V-GR; p = 0.001) and a decreased proportion of loin lean-meat yield (p = 0.045). The presence of B1A3 was associated with an increased proportion of leg lean-meat yield (p = 0.016) and proportion of shoulder lean-meat yield (p = 0.030). No associations were found with birth weight, tailing weight and weaning weight. These results suggest that ovine ADIPOQ may have value as a genetic marker for NZ Romney sheep breeding. Full article
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Open AccessCommunication Using Small RNA-seq Data to Detect siRNA Duplexes Induced by Plant Viruses
Genes 2017, 8(6), 163; doi:10.3390/genes8060163
Received: 20 April 2017 / Revised: 26 May 2017 / Accepted: 12 June 2017 / Published: 16 June 2017
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Abstract
Small interfering RNA (siRNA) duplexes are short (usually 21 to 24 bp) double-stranded RNAs (dsRNAs) with several overhanging nucleotides at both 5′- and 3′-ends. It has been found that siRNA duplexes bind the RNA-induced silencing complex (RISC) and cleave the sense strands with
[...] Read more.
Small interfering RNA (siRNA) duplexes are short (usually 21 to 24 bp) double-stranded RNAs (dsRNAs) with several overhanging nucleotides at both 5′- and 3′-ends. It has been found that siRNA duplexes bind the RNA-induced silencing complex (RISC) and cleave the sense strands with endonucleases. In this study, for the first time, we detected siRNA duplexes induced by plant viruses on a large scale using next-generation sequencing (NGS) data. In addition, we used the detected 21 nucleotide (nt) siRNA duplexes with 2 nt overhangs to construct a dataset for future data mining. The analytical results of the features in the detected siRNA duplexes were consistent with those from previous studies. The investigation of siRNA duplexes is useful for a better understanding of the RNA interference (RNAi) mechanism. It can also help to improve the virus detection based on the small RNA sequencing (sRNA-seq) technologies and to rationally design siRNAs for RNAi experiments. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessArticle An ‛Aukward’ Tale: A Genetic Approach to Discover the Whereabouts of the Last Great Auks
Genes 2017, 8(6), 164; doi:10.3390/genes8060164
Received: 30 May 2017 / Accepted: 9 June 2017 / Published: 15 June 2017
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Abstract
One hundred and seventy-three years ago, the last two Great Auks, Pinguinus impennis, ever reliably seen were killed. Their internal organs can be found in the collections of the Natural History Museum of Denmark, but the location of their skins has remained
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One hundred and seventy-three years ago, the last two Great Auks, Pinguinus impennis, ever reliably seen were killed. Their internal organs can be found in the collections of the Natural History Museum of Denmark, but the location of their skins has remained a mystery. In 1999, Great Auk expert Errol Fuller proposed a list of five potential candidate skins in museums around the world. Here we take a palaeogenomic approach to test which—if any—of Fuller’s candidate skins likely belong to either of the two birds. Using mitochondrial genomes from the five candidate birds (housed in museums in Bremen, Brussels, Kiel, Los Angeles, and Oldenburg) and the organs of the last two known individuals, we partially solve the mystery that has been on Great Auk scholars’ minds for generations and make new suggestions as to the whereabouts of the still-missing skin from these two birds. Full article
(This article belongs to the Special Issue Novel and Neglected Areas of Ancient DNA Research)
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Open AccessArticle Endogenous Retroviral Insertions Indicate a Secondary Introduction of Domestic Sheep Lineages to the Caucasus and Central Asia between the Bronze and Iron Age
Genes 2017, 8(6), 165; doi:10.3390/genes8060165
Received: 12 May 2017 / Revised: 29 May 2017 / Accepted: 13 June 2017 / Published: 20 June 2017
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Abstract
Sheep were one of the first livestock species domesticated by humans. After initial domestication in the Middle East they were spread across Eurasia. The modern distribution of endogenous Jaagsiekte sheep retrovirus insertions in domestic sheep breeds suggests that over the course of millennia,
[...] Read more.
Sheep were one of the first livestock species domesticated by humans. After initial domestication in the Middle East they were spread across Eurasia. The modern distribution of endogenous Jaagsiekte sheep retrovirus insertions in domestic sheep breeds suggests that over the course of millennia, successive introductions of improved lineages and selection for wool quality occurred in the Mediterranean region and most of Asia. Here we present a novel ancient DNA approach using data of endogenous retroviral insertions in Bronze and Iron Age domestic sheep from the Caucasus and Pamir mountain areas. Our findings support a secondary introduction of wool sheep from the Middle East between the Late Bronze Age and Iron Age into most areas of Eurasia. Full article
(This article belongs to the Special Issue Novel and Neglected Areas of Ancient DNA Research)
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Open AccessArticle A Comparative Study of the Structural Dynamics of Four Terminal Uridylyl Transferases
Genes 2017, 8(6), 166; doi:10.3390/genes8060166
Received: 22 March 2017 / Revised: 22 May 2017 / Accepted: 7 June 2017 / Published: 20 June 2017
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Abstract
African trypanosomiasis occurs in 36 countries in sub-Saharan Africa with 10,000 reported cases annually. No definitive remedy is currently available and if left untreated, the disease becomes fatal. Structural and biochemical studies of trypanosomal terminal uridylyl transferases (TUTases) demonstrated their functional role in
[...] Read more.
African trypanosomiasis occurs in 36 countries in sub-Saharan Africa with 10,000 reported cases annually. No definitive remedy is currently available and if left untreated, the disease becomes fatal. Structural and biochemical studies of trypanosomal terminal uridylyl transferases (TUTases) demonstrated their functional role in extensive uridylate insertion/deletion of RNA. Trypanosoma brucei RNA Editing TUTase 1 (TbRET1) is involved in guide RNA 3’ end uridylation and maturation, while TbRET2 is responsible for U-insertion at RNA editing sites. Two additional TUTases called TbMEAT1 and TbTUT4 have also been reported to share similar function. TbRET1 and TbRET2 are essential enzymes for the parasite viability making them potential drug targets. For this study, we clustered molecular dynamics (MD) trajectories of four TUTases based on active site shape measured by Pocket Volume Measurer (POVME) program. Among the four TUTases, TbRET1 exhibited the largest average pocket volume, while TbMEAT1’s and TbTUT4’s active sites displayed the most flexibility. A side pocket was also identified within the active site in all TUTases with TbRET1 having the most pronounced. Our results indicate that TbRET1’s larger side pocket can be exploited to achieve selective inhibitor design as FTMap identifies it as a druggable pocket. Full article
(This article belongs to the Special Issue RNA Editing)
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Open AccessArticle Assessing Genetic Diversity and Population Differentiation of Colored Calla Lily (Zantedeschia Hybrid) for an Efficient Breeding Program
Genes 2017, 8(6), 168; doi:10.3390/genes8060168
Received: 20 April 2017 / Revised: 13 June 2017 / Accepted: 14 June 2017 / Published: 21 June 2017
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Abstract
Plastome-genome incompatibility (PGI) is prevalent in several plants including the Zantedeschia species, a worldwide commercial flower crop native to South Africa. Generally, hybrids suffering from PGI appear less vigorous and more susceptible than normal plants. Previous reports revealed that the PGI level in
[...] Read more.
Plastome-genome incompatibility (PGI) is prevalent in several plants including the Zantedeschia species, a worldwide commercial flower crop native to South Africa. Generally, hybrids suffering from PGI appear less vigorous and more susceptible than normal plants. Previous reports revealed that the PGI level in interspecific hybrids is correlated with the relatedness of the parental species in the genus Zantedeschia. To provide a basis for utilizing and improving resources in breeding programs, a total of 117 accessions of colored calla lily (Zantedeschia hybrid), collected from New Zealand, the Netherlands and the United States, were genotyped using 31 transferable expressed sequence tags-simple sequence repeats (EST-SSR) markers from the white calla lily (Zantedeschia aethiopica). A moderately high level of genetic diversity was observed, with 111 alleles in total, an observed/expected heterozygosity (Ho/He) of 0.453/0.478, and polymorphism information content (PIC) of 0.26. Genetic distance and STRUCTURE-based analysis further clustered all accessions into four subgroups (G-Ia, G-Ib, G-IIa and G-IIb), which mostly consisted of Zantedeschia pentlandii, Zantedeschia elliotiana, Zantedeschia albomaculata and Zantedeschia rehmannii, respectively. Significant genetic differentiation was observed between all inferred subgroup pairs, with the Fst ranging from 0.142 to 0.281. Finally, the accessions assigned into G-IIb (Z. rehmannii) were recommended as top priority parents in efficient Zantedeschia breeding program designs. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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Open AccessArticle Identifying Bird Remains Using Ancient DNA Barcoding
Genes 2017, 8(6), 169; doi:10.3390/genes8060169
Received: 29 May 2017 / Revised: 11 June 2017 / Accepted: 15 June 2017 / Published: 21 June 2017
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Abstract
Bird remains that are difficult to identify taxonomically using morphological methods, are common in the palaeontological record. Other types of challenging avian material include artefacts and food items from endangered taxa, as well as remains from aircraft strikes. We here present a DNA-based
[...] Read more.
Bird remains that are difficult to identify taxonomically using morphological methods, are common in the palaeontological record. Other types of challenging avian material include artefacts and food items from endangered taxa, as well as remains from aircraft strikes. We here present a DNA-based method that enables taxonomic identification of bird remains, even from material where the DNA is heavily degraded. The method is based on the amplification and sequencing of two short variable parts of the 16S region in the mitochondrial genome. To demonstrate the applicability of this approach, we evaluated the method on a set of Holocene and Late Pleistocene postcranial bird bones from several palaeontological and archaeological sites in Europe with good success. Full article
(This article belongs to the Special Issue Novel and Neglected Areas of Ancient DNA Research)

Review

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Open AccessReview CpG and Non-CpG Methylation in Epigenetic Gene Regulation and Brain Function
Genes 2017, 8(6), 148; doi:10.3390/genes8060148
Received: 16 February 2017 / Revised: 18 April 2017 / Accepted: 19 May 2017 / Published: 23 May 2017
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Abstract
DNA methylation is a major epigenetic mark with important roles in genetic regulation. Methylated cytosines are found primarily at CpG dinucleotides, but are also found at non-CpG sites (CpA, CpT, and CpC). The general functions of CpG and non-CpG methylation include gene silencing
[...] Read more.
DNA methylation is a major epigenetic mark with important roles in genetic regulation. Methylated cytosines are found primarily at CpG dinucleotides, but are also found at non-CpG sites (CpA, CpT, and CpC). The general functions of CpG and non-CpG methylation include gene silencing or activation depending on the methylated regions. CpG and non-CpG methylation are found throughout the whole genome, including repetitive sequences, enhancers, promoters, and gene bodies. Interestingly, however, non-CpG methylation is restricted to specific cell types, such as pluripotent stem cells, oocytes, neurons, and glial cells. Thus, accumulation of methylation at non-CpG sites and CpG sites in neurons seems to be involved in development and disease etiology. Here, we provide an overview of CpG and non-CpG methylation and their roles in neurological diseases. Full article
(This article belongs to the Special Issue Role of Epigenetic Gene Regulation in Brain Function)
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Open AccessReview Maternal Factors that Induce Epigenetic Changes Contribute to Neurological Disorders in Offspring
Genes 2017, 8(6), 150; doi:10.3390/genes8060150
Received: 17 March 2017 / Revised: 6 May 2017 / Accepted: 19 May 2017 / Published: 24 May 2017
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Abstract
It is well established that the regulation of epigenetic factors, including chromatic reorganization, histone modifications, DNA methylation, and miRNA regulation, is critical for the normal development and functioning of the human brain. There are a number of maternal factors influencing epigenetic pathways such
[...] Read more.
It is well established that the regulation of epigenetic factors, including chromatic reorganization, histone modifications, DNA methylation, and miRNA regulation, is critical for the normal development and functioning of the human brain. There are a number of maternal factors influencing epigenetic pathways such as lifestyle, including diet, alcohol consumption, and smoking, as well as age and infections (viral or bacterial). Genetic and metabolic alterations such as obesity, gestational diabetes mellitus (GDM), and thyroidism alter epigenetic mechanisms, thereby contributing to neurodevelopmental disorders (NDs) such as embryonic neural tube defects (NTDs), autism, Down’s syndrome, Rett syndrome, and later onset of neuropsychological deficits. This review comprehensively describes the recent findings in the epigenetic landscape contributing to altered molecular profiles resulting in NDs. Furthermore, we will discuss potential avenues for future research to identify diagnostic markers and therapeutic epi-drugs to reverse these abnormalities in the brain as epigenetic marks are plastic and reversible in nature. Full article
(This article belongs to the Special Issue Role of Epigenetic Gene Regulation in Brain Function)
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Open AccessReview MYC Deregulation in Primary Human Cancers
Genes 2017, 8(6), 151; doi:10.3390/genes8060151
Received: 23 March 2017 / Revised: 19 May 2017 / Accepted: 19 May 2017 / Published: 25 May 2017
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Abstract
MYC regulates a complex biological program by transcriptionally activating and repressing its numerous target genes. As such, MYC is a master regulator of many processes, including cell cycle entry, ribosome biogenesis, and metabolism. In cancer, the activity of the MYC transcriptional network is
[...] Read more.
MYC regulates a complex biological program by transcriptionally activating and repressing its numerous target genes. As such, MYC is a master regulator of many processes, including cell cycle entry, ribosome biogenesis, and metabolism. In cancer, the activity of the MYC transcriptional network is frequently deregulated, contributing to the initiation and maintenance of disease. Deregulation often leads to constitutive overexpression of MYC, which can be achieved through gross genetic abnormalities, including copy number alterations, chromosomal translocations, increased enhancer activity, or through aberrant signal transduction leading to increased MYC transcription or increased MYC mRNA and protein stability. Herein, we summarize the frequency and modes of MYC deregulation and describe both well-established and more recent findings in a variety of cancer types. Notably, these studies have highlighted that with an increased appreciation for the basic mechanisms deregulating MYC in cancer, new therapeutic vulnerabilities can be discovered and potentially exploited for the inhibition of this potent oncogene in cancer. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview R Loops in the Regulation of Antibody Gene Diversification
Genes 2017, 8(6), 154; doi:10.3390/genes8060154
Received: 28 March 2017 / Revised: 24 May 2017 / Accepted: 31 May 2017 / Published: 2 June 2017
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Abstract
For nearly three decades, R loops have been closely linked with class switch recombination (CSR), the process that generates antibody isotypes and that occurs via a complex cascade initiated by transcription-coupled mutagenesis in switch recombination sequences. R loops form during transcription of switch
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For nearly three decades, R loops have been closely linked with class switch recombination (CSR), the process that generates antibody isotypes and that occurs via a complex cascade initiated by transcription-coupled mutagenesis in switch recombination sequences. R loops form during transcription of switch recombination sequences in vitro and in vivo, and there is solid evidence that R loops are required for efficient class switching. The classical model of R loops posits that they boost mutation rates by generating stable and long tracts of single-stranded DNA that serve as the substrate for activation induced deaminase (AID), the enzyme that initiates the CSR reaction cascade by co-transcriptionally mutating ssDNA in switch recombination sequences. Though logical and compelling, this model has not been supported by in vivo evidence. Indeed, several reports suggest that R loops may not be involved in recruiting AID activity to switch regions, meaning that R loops probably serve other unanticipated roles in CSR. Here, I review the key findings in this field to date and propose hypotheses that could help towards elucidating the precise function of R loops in CSR. Full article
(This article belongs to the Special Issue R-loop Biology in Eukaryotes)
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Open AccessReview New Insights in the Cytogenetic Practice: Karyotypic Chaos, Non-Clonal Chromosomal Alterations and Chromosomal Instability in Human Cancer and Therapy Response
Genes 2017, 8(6), 155; doi:10.3390/genes8060155
Received: 15 April 2017 / Revised: 26 May 2017 / Accepted: 31 May 2017 / Published: 3 June 2017
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Abstract
Recently, non-clonal chromosomal alterations previously unappreciated are being proposed to be included in cytogenetic practice. The aim of this inclusion is to obtain a greater understanding of chromosomal instability (CIN) and tumor heterogeneity and their role in cancer evolution and therapy response. Although
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Recently, non-clonal chromosomal alterations previously unappreciated are being proposed to be included in cytogenetic practice. The aim of this inclusion is to obtain a greater understanding of chromosomal instability (CIN) and tumor heterogeneity and their role in cancer evolution and therapy response. Although several genetic assays have allowed the evaluation of the variation in a population of cancer cells, these assays do not provide information at the level of individual cells, therefore limiting the information of the genomic diversity within tumors (heterogeneity). The karyotype is one of the few available cytogenetic techniques that allow us not only to identify the chromosomal alterations present within a single cell, but also allows us to profile both clonal (CCA) and non-clonal chromosomal alterations (NCCAs). A greater understanding of CIN and tumor heterogeneity in cancer could not only improve existing therapeutic regimens but could also be used as targets for the design of new therapeutic approaches. In this review we indicate the importance and significance of karyotypic chaos, NCCAs and CIN in the prognosis of human cancers. Full article
(This article belongs to the Section Clinical Genomics in Genetic Diseases and Cancer)
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Open AccessReview Ataxin-2: From RNA Control to Human Health and Disease
Genes 2017, 8(6), 157; doi:10.3390/genes8060157
Received: 1 March 2017 / Revised: 23 May 2017 / Accepted: 31 May 2017 / Published: 5 June 2017
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Abstract
RNA-binding proteins play fundamental roles in the regulation of molecular processes critical to cellular and organismal homeostasis. Recent studies have identified the RNA-binding protein Ataxin-2 as a genetic determinant or risk factor for various diseases including spinocerebellar ataxia type II (SCA2) and amyotrophic
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RNA-binding proteins play fundamental roles in the regulation of molecular processes critical to cellular and organismal homeostasis. Recent studies have identified the RNA-binding protein Ataxin-2 as a genetic determinant or risk factor for various diseases including spinocerebellar ataxia type II (SCA2) and amyotrophic lateral sclerosis (ALS), amongst others. Here, we first discuss the increasingly wide-ranging molecular functions of Ataxin-2, from the regulation of RNA stability and translation to the repression of deleterious accumulation of the RNA-DNA hybrid-harbouring R-loop structures. We also highlight the broader physiological roles of Ataxin-2 such as in the regulation of cellular metabolism and circadian rhythms. Finally, we discuss insight from clinically focused studies to shed light on the impact of molecular and physiological roles of Ataxin-2 in various human diseases. We anticipate that deciphering the fundamental functions of Ataxin-2 will uncover unique approaches to help cure or control debilitating and lethal human diseases. Full article
(This article belongs to the Special Issue R-loop Biology in Eukaryotes)
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Open AccessReview The Dual Roles of MYC in Genomic Instability and Cancer Chemoresistance
Genes 2017, 8(6), 158; doi:10.3390/genes8060158
Received: 28 February 2017 / Revised: 31 May 2017 / Accepted: 1 June 2017 / Published: 7 June 2017
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Abstract
Cancer is associated with genomic instability and aging. Genomic instability stimulates tumorigenesis, whereas deregulation of oncogenes accelerates DNA replication and increases genomic instability. It is therefore reasonable to assume a positive feedback loop between genomic instability and oncogenic stress. Consistent with this premise,
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Cancer is associated with genomic instability and aging. Genomic instability stimulates tumorigenesis, whereas deregulation of oncogenes accelerates DNA replication and increases genomic instability. It is therefore reasonable to assume a positive feedback loop between genomic instability and oncogenic stress. Consistent with this premise, overexpression of the MYC transcription factor increases the phosphorylation of serine 139 in histone H2AX (member X of the core histone H2A family), which forms so-called γH2AX, the most widely recognized surrogate biomarker of double-stranded DNA breaks (DSBs). Paradoxically, oncogenic MYC can also promote the resistance of cancer cells to chemotherapeutic DNA-damaging agents such as cisplatin, clearly implying an antagonistic role of MYC in genomic instability. In this review, we summarize the underlying mechanisms of the conflicting functions of MYC in genomic instability and discuss when and how the oncoprotein exerts the contradictory roles in induction of DSBs and protection of cancer-cell genomes. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview Splice-Switching Therapy for Spinal Muscular Atrophy
Genes 2017, 8(6), 161; doi:10.3390/genes8060161
Received: 21 April 2017 / Revised: 26 May 2017 / Accepted: 2 June 2017 / Published: 12 June 2017
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Abstract
Spinal muscular atrophy (SMA) is a genetic disorder with severity ranging from premature death in infants to restricted motor function in adult life. Despite the genetic cause of this disease being known for over twenty years, only recently has a therapy been approved
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Spinal muscular atrophy (SMA) is a genetic disorder with severity ranging from premature death in infants to restricted motor function in adult life. Despite the genetic cause of this disease being known for over twenty years, only recently has a therapy been approved to treat the most severe form of this disease. Here we discuss the genetic basis of SMA and the subsequent studies that led to the utilization of splice switching oligonucleotides to enhance production of SMN protein, which is absent in patients, through a mechanism of exon inclusion into the mature mRNA. Whilst approval of oligonucleotide-based therapies for SMA should be celebrated, we also discuss some of the limitations of this approach and alternate genetic strategies that are currently underway in clinical trials. Full article
(This article belongs to the Special Issue Therapeutic Alternative Splicing: Mechanisms and Applications)
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Open AccessReview Effects of Type 1 Diabetes Risk Alleles on Immune Cell Gene Expression
Genes 2017, 8(6), 167; doi:10.3390/genes8060167
Received: 2 March 2017 / Revised: 17 May 2017 / Accepted: 14 June 2017 / Published: 21 June 2017
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Abstract
Genetic studies have identified 61 variants associated with the risk of developing Type 1 Diabetes (T1D). The functions of most of the non-HLA (Human Leukocyte Antigen) genetic variants remain unknown. We found that only 16 of these risk variants could potentially be linked
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Genetic studies have identified 61 variants associated with the risk of developing Type 1 Diabetes (T1D). The functions of most of the non-HLA (Human Leukocyte Antigen) genetic variants remain unknown. We found that only 16 of these risk variants could potentially be linked to a protein-coding change. Therefore, we investigated whether these variants affected susceptibility by regulating changes in gene expression. To do so, we examined whole transcriptome profiles of 600 samples from the Type 1 Diabetes Genetics Consortium (T1DGC). These comprised four different immune cell types (Epstein-Barr virus (EBV)-transformed B cells, either basal or after stimulation; and cluster of differentiation (CD)4+ and CD8+ T cells). Many of the T1D-associated risk variants regulated expression of either neighboring (cis-) or distant (trans-) genes. In brief, 24 of the non-HLA T1D variants affected the expression of 31 nearby genes (cis) while 25 affected 38 distant genes (trans). The effects were highly significant (False Discovery Rate p < 0.001). In addition, we searched in public databases for expression effects of T1D single nucleotide polymorphisms (SNPs) in other immune cell types such as CD14+ monocytes, lipopolysaccharide (LPS) stimulated monocytes, and CD19+ B cells. In this paper, we review the (expression quantitative trait loci (eQTLs) associated with each of the 60 T1D variants and provide a summary of the genes impacted by T1D risk alleles in various immune cells. We then review the methodological steps involved in analyzing the function of genome wide association studies (GWAS)-identified variants, with emphasis on those affecting gene expression. We also discuss recent advancements in the methodologies and their advantages. We conclude by suggesting future study designs that will aid in the study of T1D risk variants. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Open AccessErratum Erratum: Michael A. Picker; et al.; H-NS, Its Family Members and Their Regulation of Virulence Genes in Shigella Species. Genes 2016, 7, 112
Genes 2017, 8(6), 162; doi:10.3390/genes8060162
Received: 14 June 2017 / Revised: 14 June 2017 / Accepted: 14 June 2017 / Published: 15 June 2017
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Abstract
The authors wish to make the following change to their paper [1]. [...]
Full article
(This article belongs to the Special Issue Virulence Gene Regulation in Bacteria)

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