Clinical interpretation of copy number variants in the human genome

Abstract

Molecular methods, by which copy number variants (CNVs) detection is available, have been gradually introduced into routine diagnostics over the last 15 years. Despite this, some CNVs continue to be a huge challenge when it comes to clinical interpretation. CNVs are an important source of normal and pathogenic variants, but, in many cases, their impact on human health depends on factors that are not yet known. Therefore, perception of their clinical consequences can change over time, as our knowledge grows. This review summarises guidelines that facilitate correct classification of identified changes and discusses difficulties with the interpretation of rare, small CNVs.

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Using Linkage Maps as a Tool To Determine Patterns of Chromosome Synteny in the Genus Salvelinus

Next generation sequencing techniques have revolutionized the collection of genome and transcriptome data from non-model organisms. This manuscript details the application of restriction site associated DNA sequencing (RADseq) to generate a marker dense genetic map for Brook trout (Salvelinus fontinalis). The consensus map was constructed from three full-sib families totaling 176 F₁ individuals. The map consisted of 42 linkage groups with a total female map size of 2502.5 cM, and a total male map size of 1863.8 cM. Synteny was confirmed with Atlantic salmon for 38 linkage groups, with Rainbow trout for 37 linkage groups, Arctic char for 36 linkage groups, and with a previously published Brook trout linkage map for 39 linkage groups. Comparative mapping confirmed the presence of eight metacentric and 34 acrocentric chromosomes in Brook trout. Six metacentric chromosomes seem to be conserved with Arctic char suggesting there have been at least two species specific fusion and fission events within the genus Salvelinus.  In addition, the sex marker (sdY; sexually dimorphic on the Y chromosome) was mapped to Brook trout BC35, which is homologous with Atlantic salmon Ssa09qa, Rainbow trout Omy25, and Arctic char AC04q. Ultimately, this linkage map will be a useful resource for studies on the genome organization of Salvelinus, and facilitates comparisons of the Salvelinus genome with Salmo and Oncorhynchus.

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First Draft Genome Sequence of the Pathogenic Fungus Lomentospora prolificans (formerly Scedosporium prolificans)

Here we describe the sequencing and assembly of the pathogenic fungus Lomentospora prolificans using a combination of short, highly accurate Illumina reads and additional coverage in very long Oxford Nanopore reads. The resulting assembly is highly contiguous, containing a total of 37,627,092 bp with over 98% of the sequence in just 26 scaffolds. Annotation identified 8,896 protein-coding genes. Pulsed-field gel analysis suggests that this organism contains at least 7 and possibly 11 chromosomes, the two longest of which have sizes corresponding closely to the sizes of the longest scaffolds, at 6.6 and 5.7 Mb.

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Preliminary paleoecological insights from the Pliocene avifauna of Kanapoi, Kenya: Implications for the ecology of Australopithecus anamensis

Publication date: Available online 29 September 2017
Source:Journal of Human Evolution
Author(s): Daniel J. Field
Fossil bird remains from the Pliocene hominin-bearing locality of Kanapoi comprise >100 elements representing at least 10 avian families, including previously undescribed elements referred to the 'giant' Pliocene marabou stork Leptoptilos cf. falconeri. The taxonomic composition of the Kanapoi fossil avifauna reveals an assemblage with a substantial aquatic component, corroborating geological evidence of this locality's close proximity to a large, slow-moving body of water. Both the taxonomic composition and relative abundance of avian higher-level clades at Kanapoi stand in stark contrast to the avifauna from the slightly older (∼4.4 Ma vs. 4.2 Ma) hominin-bearing Lower Aramis Member of Ethiopia, which has been interpreted as representing a mesic woodland paleoenvironment far from water. In general, the taxonomic composition of the Kanapoi avifauna resembles that from the Miocene hominoid-bearing locality of Lothagam (though Kanapoi is more diverse), and the aquatic character of the Kanapoi avifauna supports the idea that the environmental conditions experienced by Australopithecus anamensis at Kanapoi were markedly different from those experienced by Ardipithecus ramidus at Aramis. Additionally, the relative abundance of marabou stork (Leptoptilos) remains at Kanapoi may suggest a longstanding commensal relationship between total-clade humans and facultatively scavenging marabous. Additional avian remains from nearby fossil localities (e.g., the Nachukui Formation), ranging in age from 3.26 to 0.8 Ma, reveal the long-term persistence of an aquatic avifauna in the region.



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Extant ape dental topography and its implications for reconstructing the emergence of early Homo

Publication date: November 2017
Source:Journal of Human Evolution, Volume 112
Author(s): Michael A. Berthaume, Kes Schroer
Dental topography reflects diet accurately in several extant and extinct mammalian clades. However, dental topographic dietary reconstructions have high success rates only when closely related taxa are compared. Given the dietary breadth that exists among extant apes and likely existed among fossil hominins, dental topographic values from many species and subspecies of great apes are necessary for making dietary inferences about the hominin fossil record. Here, we present the results of one metric of dental topography, Dirichlet normal energy (DNE), for seven groups of great apes (Pongo pygmaeus pygmaeus, Pan paniscus, Pan troglodytes troglodytes and schweinfurthii, Gorilla gorilla gorilla, Gorilla beringei graueri and beringei). Dirichlet normal energy was inadequate at differentiating folivores from frugivores, but was adequate at predicting which groups had more fibrous diets among sympatric African apes. Character displacement analyses confirmed there is substantial dental topographic and relative molar size (M1:M2 ratio; length, width, and area) divergence in sympatric apes when compared to their allopatric counterparts, but character displacement is only present in relative molar size when DNE is also considered. Presence of character displacement is likely due to indirect competition over similar food resources. Assuming similar ecological conditions in the Plio-Pleistocene, the derived masticatory apparatuses of the robust australopiths and early Homo may be due to indirect competition over dietary resources between the taxa, causing dietary niche partitioning. Our results imply that dental topography cannot be used to predict dietary categories in fossil hominins without consideration of ecological factors, such as dietary and geographic overlap. In addition, our results may open new avenues for understanding the community compositions of early hominins and the formation of specific ecological niches among hominin taxa.



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Hippopotamidae (Cetartiodactyla, Hippopotamoidea) from Kanapoi, Kenya, and the taxonomic status of the late early Pliocene hippopotamids from the Turkana Basin

Publication date: Available online 29 September 2017
Source:Journal of Human Evolution
Author(s): Jean-Renaud Boisserie
New hippopotamid specimens recently collected at Kanapoi (ca. 4 Ma) are similar to the taxon previously recognized in this site and referred to aff. Hippopotamus protamphibius. Their examination provided the opportunity to reassess the taxonomic status of this taxon. It appears different from the late Miocene hippopotamids from the Turkana Basin (prominently Archaeopotamus harvardi), but also differs from the late Pliocene–early Pleistocene aff. Hip. protamphibius, which is smaller and displays more advanced features (notably canine expansion and orbit elevation). In contrast, the Kanapoi material appears very similar to the material from the Hadar Formation (3.4 Ma–2.9 Ma). However, the current confusion surrounding the taxonomic status of the Hadar specimens, previously attributed to various taxa that may be identical, does not allow attribution of a specific name to the Kanapoi material for now and, while waiting for the revision of Hadar hippopotamid diversity, it is referred here to aff. Hippopotamus cf. sp. Hadar. This contribution allows recognizing that a large hippopotamid, possibly a transitional form between the late Miocene species and Plio-Pleistocene species, was distributed from Afar to Turkana between 4.2 Ma and 2.95 Ma. The marked endemism of hippopotamids in the Pleistocene rift basins therefore initiated after 2.9 Ma.



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Effect of patients' functional status on satisfaction with outcomes 12-months after elective spine surgery for lumbar degenerative disease

Comprehensive assessment of quality of care includes patient-reported outcomes, safety of care delivered, and patient satisfaction. The impact of the patient-reported ODI (baseline and 12-month) scores on satisfaction with outcomes following spine surgery is not well documented.

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The Emerging Role of Epigenetic Modifiers in Repair of DNA Damage Associated with Chronic Inflammatory Diseases

Publication date: Available online 28 September 2017
Source:Mutation Research/Reviews in Mutation Research
Author(s): Ning Ding, Ashley R. Maiuri, Heather M. O'Hagan
At sites of chronic inflammation epithelial cells are exposed to high levels of reactive oxygen species (ROS), which can contribute to the initiation and development of many different human cancers. Aberrant epigenetic alterations that cause transcriptional silencing of tumor suppressor genes are also implicated in many diseases associated with inflammation, including cancer. However, it is not clear how altered epigenetic gene silencing is initiated during chronic inflammation. The high level of ROS at sites of inflammation is known to induce oxidative DNA damage in surrounding epithelial cells. Furthermore, DNA damage is known to trigger several responses, including recruitment of DNA repair proteins, transcriptional repression, chromatin modifications and other cell signaling events. Recruitment of epigenetic modifiers to chromatin in response to DNA damage results in transient covalent modifications to chromatin such as histone ubiquitination, acetylation and methylation and DNA methylation. DNA damage also alters non-coding RNA expression. All of these alterations have the potential to alter gene expression at sites of damage. Typically, these modifications and gene transcription are restored back to normal once the repair of the DNA damage is completed. However, chronic inflammation may induce sustained DNA damage and DNA damage responses that result in these transient covalent chromatin modifications becoming mitotically stable epigenetic alterations. Understanding how epigenetic alterations are initiated during chronic inflammation will allow us to develop pharmaceutical strategies to prevent or treat chronic inflammation-induced cancer. This review will focus on types of DNA damage and epigenetic alterations associated with chronic inflammatory diseases, the types of DNA damage and transient covalent chromatin modifications induced by inflammation and oxidative DNA damage and how these modifications may result in epigenetic alterations.



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Efficient genetic manipulation in the developing brain of tree shrew using in utero electroporation and virus infection

Publication date: Available online 28 September 2017
Source:Journal of Genetics and Genomics
Author(s): Dan Xu, Yuangang Zhu, Zhiheng Xu




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Issue Information

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Temporal trends in 137Cs concentrations in the bark, sapwood, heartwood, and whole wood of four tree species in Japanese forests from 2011 to 2016

Publication date: November 2017
Source:Journal of Environmental Radioactivity, Volumes 178–179
Author(s): Shinta Ohashi, Katsushi Kuroda, Tsutomu Takano, Youki Suzuki, Takeshi Fujiwara, Hisashi Abe, Akira Kagawa, Masaki Sugiyama, Yoshitaka Kubojima, Chunhua Zhang, Koichi Yamamoto
To understand the changes in radiocesium (¹³⁷Cs) concentrations in stem woods after the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident, we investigated ¹³⁷Cs concentrations in the bark, sapwood, heartwood, and whole wood of four major tree species at multiple sites with different levels of radiocesium deposition from the FDNPP accident since 2011 (since 2012 at some sites): Japanese cedar at four sites, hinoki cypress and Japanese konara oak at two sites, and Japanese red pine at one site. Our previous report on ¹³⁷Cs concentrations in bark and whole wood samples collected from 2011 to 2015 suggested that temporal variations were different among sites even within the same species. In the present study, we provided data on bark and whole wood samples in 2016 and separately measured ¹³⁷Cs concentrations in sapwood and heartwood samples from 2011 to 2016; we further discussed temporal trends in ¹³⁷Cs concentrations in each part of tree stems, particularly those in ¹³⁷Cs distributions between sapwood and heartwood, in relation to their species and site dependencies. Temporal trends in bark and whole wood samples collected from 2011 to 2016 were consistent with those reported in samples collected from 2011 to 2015. Temporal variations in ¹³⁷Cs concentrations in barks showed either a decreasing trend or no clear trend, implying that ¹³⁷Cs deposition in barks is inhomogeneous and that decontamination is relatively slow in some cases. Temporal trends in ¹³⁷Cs concentrations in sapwood, heartwood, and whole wood were different among species and also among sites within the same species. Relatively common trends within the same species, which were increasing, were observed in cedar heartwood, and in oak sapwood and whole wood. On the other hand, the ratio of ¹³⁷Cs concentration in heartwood to that in sapwood (fresh weight basis) was commonly increased to more than 2 in cedar, although distinct temporal trends were not found in the other species, for which the ratio was around 1 in cypress and pine and below 0.5 in oak, suggesting that ¹³⁷Cs transfer from sapwood to heartwood shows species dependency. Consequently, the species dependency of ¹³⁷Cs transfer within the tree appears easily, while that from the environment to the trees can be masked by various factors. Thus, prediction of ¹³⁷Cs concentrations in stem wood should be carried out carefully as it still requires investigations at multiple sites with a larger sample size and an understanding of the species-specific ¹³⁷Cs transfer mechanism.



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7Be, 210Pb and 40K depositions over 11 years in Málaga

Publication date: November 2017
Source:Journal of Environmental Radioactivity, Volumes 178–179
Author(s): C. Dueñas, E. Gordo, E. Liger, M. Cabello, S. Cañete, M. Pérez, P. de la Torre-Luque
The monthly bulk depositional fluxes of three natural radionuclides (⁷Be, ²¹⁰Pb and ⁴⁰K) were measured at a Mediterranean coastal station (Málaga) over an 11-year period from 2005 to 2015. The mean annual depositional fluxes of ⁷Be, ²¹⁰Pb and ⁴⁰K were 1215, 144 and 67 Bq m⁻² year⁻¹ respectively, showing a clear seasonal trend with minimum values recorded during summer and maximum values in winter. The rainfall regime with dry summers allows estimating the dry deposition. Assuming constant dry deposition through each year, ⁷Be, ²¹⁰Pb and ⁴⁰K would account for 12.5, 26.5 and 33% of the bulk fallout respectively which indicates that deposition for ²¹⁰Pb and ⁴⁰K are significantly higher than ⁷Be. The precipitation-normalized enrichment factor alpha used to explain seasonal variations in the depositional fluxes of radionuclides with respect the rainfall, indicates higher depositional fluxes during spring and summer than expected from the amount of rainfall. Despite their different origin, ²¹⁰Pb and ⁷Be monthly depositional fluxes have strong correlation. The atmospheric deposition fluxes of ⁷Be, ²¹⁰Pb and ⁴⁰K were controlled mainly by the amount of rainfall (r = 0.89, 0.91 and 0.66 respectively). Moreover, principal component analysis was applied to the datasets and deposition of radionuclides and rainfall in the same component highlighting the importance of the washout mechanism. The mean depositional velocity of aerosols evaluated using ⁷Be and ²¹⁰Pb are similar and are compared to other published values.



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