The Facioscapulohumeral muscular dystrophy region on 4qter and the homologous locus on 10qter evolved independently under different evolutionary pressure

BACKGROUND: The homologous 4q and 10q subtelomeric regions include two distinctive polymorphic arrays of 3.3 kb repeats, named D4Z4. An additional BlnI restriction site on the 10q-type sequence allows to distinguish the chromosomal origin of the repeats. Reduction in the number of D4Z4 repeats below a threshold of 10 at the 4q locus is tightly linked to Facioscapulohumeral Muscular Dystrophy (FSHD), while similar contractions at 10q locus, are not pathogenic. Sequence variations due to the presence of BlnI-sensitive repeats (10q-type) on chromosome 4 or viceversa of BlnI-resistant repeats (4q-type) on chromosome 10 are observed in both alleles. RESULTS: We analysed DNA samples from 116 healthy subiects and 114 FSHD patients and determined the size distributions of polymorphic 4q and 10q alleles, the frequency and the D4Z4 repeat assortment of variant alleles, and finally the telomeric sequences both in standard and variant alleles. We observed the same frequency and types of variant alleles in FSHD patients and controls, but we found marked differences between the repeat arrays of the 4q and 10q chromosomes. In particular we detected 10q alleles completely replaced by the 4q subtelomeric region, consisting in the whole set of 4q-type repeats and the distal telomeric markers. However the reciprocal event, 10q-type subtelomeric region on chromosome 4, was never observed. At 4q locus we always identified hybrid alleles containing a mixture of 4q and 10q-type repeats. CONCLUSION: The different size distribution and different structure of 10q variant alleles as compared with 4q suggests that these loci evolved in a different manner, since the 4q locus is linked to FSHD, while no inheritable disease is associated with mutations in 10qter genomic region. Hybrid alleles on chromosome 4 always retain a minimum number of 4q type repeats, as they are probably essential for maintaining the structural and functional properties of this subtelomeric region. In addition we found: i) several instances of variant alleles that could be misinterpreted and interfere with a correct diagnosis of FSHD; ii) the presence of borderline alleles in the range of 30–40 kb that carried a qA type telomere and were not associated with the disease

A Gene Catalogue of the Euchromatic Male-Specific Region of the Horse Y Chromosome: Comparison with Human and Other Mammals

Studies of the Y chromosome in primates, rodents and carnivores provide compelling evidence that the male specific region of Y (MSY) contains functional genes, many of which have specialized roles in spermatogenesis and male-fertility. Little similarity, however, has been found between the gene content and sequence of MSY in different species. This hinders the discovery of species-specific male fertility genes and limits our understanding about MSY evolution in mammals. Here, a detailed MSY gene catalogue was developed for the horse – an odd-toed ungulate. Using direct cDNA selection from horse testis, and sequence analysis of Y-specific BAC clones, 37 horse MSY genes/transcripts were identified. The genes were mapped to the MSY BAC contig map, characterized for copy number, analyzed for transcriptional profiles by RT-PCR, examined for the presence of ORFs, and compared to other mammalian orthologs. We demonstrate that the horse MSY harbors 20 X-degenerate genes with known orthologs in other eutherian species. The remaining 17 genes are acquired or novel and have so far been identified only in the horse or donkey Y chromosomes. Notably, 3 transcripts were found in the heterochromatic part of the Y. We show that despite substantial differences between the sequence, gene content and organization of horse and other mammalian Y chromosomes, the functions of MSY genes are predominantly related to testis and spermatogenesis. Altogether, 10 multicopy genes with testis-specific expression were identified in the horse MSY, and considered likely candidate genes for stallion fertility. The findings establish an important foundation for the study of Y-linked genetic factors governing fertility in stallions, and improve our knowledge about the evolutionary processes that have shaped Y chromosomes in different mammalian lineages

South-to-north migration preceded the advent of intensive farming in the Maya region

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: The aligned sequences have been deposited in the European Nucleotide Archive database under accession code PRJEB49391. The processed genotype data used in analysis are available online on the Nature Communications website as Supplementary Data 9.The genetic prehistory of human populations in Central America is largely unexplored leaving an important gap in our knowledge of the global expansion of humans. We report genome-wide ancient DNA data for a transect of twenty individuals from two Belize rock-shelters dating between 9,600-3,700 calibrated radiocarbon years before present (cal. BP). The oldest individuals (9,600-7,300 cal. BP) descend from an Early Holocene Native American lineage with only distant relatedness to present-day Mesoamericans, including Mayan-speaking populations. After ~5,600 cal. BP a previously unknown human dispersal from the south made a major demographic impact on the region, contributing more than 50% of the ancestry of all later individuals. This new ancestry derived from a source related to present-day Chibchan speakers living from Costa Rica to Colombia. Its arrival corresponds to the first clear evidence for forest clearing and maize horticulture in what later became the Maya region.Alphawood FoundationNational Science Foundation (NSF)National Institutes of Health (NIH)John Templeton FoundationPaul G. Allen Family Foundatio

Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy

American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation

The following are the recommendations of the American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee, which was convened to assist health care professionals in making decisions regarding cytogenetic diagnostic testing and counseling for mental retardation (MR) and developmental delay (DD). This document reviews available evidence concerning the value of conventional and molecular cytogenetic testing for the identification of chromosomal anomalies that play a role in the etiology of MR/DD, and, based on this evidence, specific recommendations for each method of testing are provided

Refined physical map of the human PAX2/HOX11/NFKB2 cancer gene region at 10q24 and relocalization of the HPV6AI1 viral integration site to 14q13.3-q21.1

BACKGROUND: Chromosome band 10q24 is a gene-rich domain and host to a number of cancer, developmental, and neurological genes. Recurring translocations, deletions and mutations involving this chromosome band have been observed in different human cancers and other disease conditions, but the precise identification of breakpoint sites, and detailed characterization of the genetic basis and mechanisms which underlie many of these rearrangements has yet to be resolved. Towards this end it is vital to establish a definitive genetic map of this region, which to date has shown considerable volatility through time in published works of scientific journals, within different builds of the same international genomic database, and across the differently constructed databases. RESULTS: Using a combination of chromosome and interphase fluorescent in situ hybridization (FISH), BAC end-sequencing and genomic database analysis we present a physical map showing that the order and chromosomal orientation of selected genes within 10q24 is CEN-CYP2C9-PAX2-HOX11-NFKB2-TEL. Our analysis has resolved the orientation of an otherwise dynamically evolving assembly of larger contigs upstream of this region, and in so doing verifies the order and orientation of a further 9 cancer-related genes and GOT1. This study further shows that the previously reported human papillomavirus type 6a DNA integration site HPV6AI1 does not map to 10q24, but that it maps at the interface of chromosome bands 14q13.3-q21.1. CONCLUSIONS: This revised map will allow more precise localization of chromosome rearrangements involving chromosome band 10q24, and will serve as a useful baseline to better understand the molecular aetiology of chromosomal instability in this region. In particular, the relocation of HPV6AI1 is important to report because this HPV6a integration site, originally isolated from a tonsillar carcinoma, was shown to be rearranged in other HPV6a-related malignancies, including 2 of 25 genital condylomas, and 2 of 7 head and neck tumors tested. Our finding shifts the focus of this genomic interest from 10q24 to the chromosome 14 site

Life-Cycle and Genome of OtV5, a Large DNA Virus of the Pelagic Marine Unicellular Green Alga Ostreococcus tauri

Large DNA viruses are ubiquitous, infecting diverse organisms ranging from algae to man, and have probably evolved from an ancient common ancestor. In aquatic environments, such algal viruses control blooms and shape the evolution of biodiversity in phytoplankton, but little is known about their biological functions. We show that Ostreococcus tauri, the smallest known marine photosynthetic eukaryote, whose genome is completely characterized, is a host for large DNA viruses, and present an analysis of the life-cycle and 186,234 bp long linear genome of OtV5. OtV5 is a lytic phycodnavirus which unexpectedly does not degrade its host chromosomes before the host cell bursts. Analysis of its complete genome sequence confirmed that it lacks expected site-specific endonucleases, and revealed the presence of 16 genes whose predicted functions are novel to this group of viruses. OtV5 carries at least one predicted gene whose protein closely resembles its host counterpart and several other host-like sequences, suggesting that horizontal gene transfers between host and viral genomes may occur frequently on an evolutionary scale. Fifty seven percent of the 268 predicted proteins present no similarities with any known protein in Genbank, underlining the wealth of undiscovered biological diversity present in oceanic viruses, which are estimated to harbour 200Mt of carbon

Self-help interventions for depressive disorders and depressive symptoms: a systematic review

<p>Abstract</p> <p>Background</p> <p>Research suggests that depressive disorders exist on a continuum, with subthreshold symptoms causing considerable population burden and increasing individual risk of developing major depressive disorder. An alternative strategy to professional treatment of subthreshold depression is population promotion of effective self-help interventions that can be easily applied by an individual without professional guidance. The evidence for self-help interventions for depressive symptoms is reviewed in the present work, with the aim of identifying promising interventions that could inform future health promotion campaigns or stimulate further research.</p> <p>Methods</p> <p>A literature search for randomised controlled trials investigating self-help interventions for depressive disorders or depressive symptoms was performed using PubMed, PsycINFO and the Cochrane Database of Systematic Reviews. Reference lists and citations of included studies were also checked. Studies were grouped into those involving participants with depressive disorders or a high level of depressive symptoms, or non-clinically depressed participants not selected for depression. A number of exclusion criteria were applied, including trials with small sample sizes and where the intervention was adjunctive to antidepressants or psychotherapy.</p> <p>Results</p> <p>The majority of interventions searched had no relevant evidence to review. Of the 38 interventions reviewed, the ones with the best evidence of efficacy in depressive disorders were S-adenosylmethionine, St John's wort, bibliotherapy, computerised interventions, distraction, relaxation training, exercise, pleasant activities, sleep deprivation, and light therapy. A number of other interventions showed promise but had received less research attention. Research in non-clinical samples indicated immediate beneficial effects on depressed mood for distraction, exercise, humour, music, negative air ionisation, and singing; while potential for helpful longer-term effects was found for autogenic training, light therapy, omega 3 fatty acids, pets, and prayer. Many of the trials were poor quality and may not generalise to self-help without professional guidance.</p> <p>Conclusion</p> <p>A number of self-help interventions have promising evidence for reducing subthreshold depressive symptoms. Other forms of evidence such as expert consensus may be more appropriate for interventions that are not feasible to evaluate in randomised controlled trials. There needs to be evaluation of whether promotion to the public of effective self-help strategies for subthreshold depressive symptoms could delay or prevent onset of depressive illness, reduce functional impairment, and prevent progression to other undesirable outcomes such as harmful use of substances.</p

A next-generation liquid xenon observatory for dark matter and neutrino physics

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector