Endogenous retroviruses (ERVs) have contributed to more than 8% of the human genome. The majority of these elements lack function due to accumulated mutations or internal recombination resulting in a ...solitary (solo) LTR, although members of one group of human ERVs (HERVs), HERV-K, were recently active with members that remain nearly intact, a subset of which is present as insertionally polymorphic loci that include approximately full-length (2-LTR) and solo-LTR alleles in addition to the unoccupied site. Several 2-LTR insertions have intact reading frames in some or all genes that are expressed as functional proteins. These properties reflect the activity of HERV-K and suggest the existence of additional unique loci within humans. We sought to determine the extent to which other polymorphic insertions are present in humans, using sequenced genomes from the 1000 Genomes Project anda subset of the Human Genome Diversity Project panel. We report analysis of a total of 36 nonreference polymorphic HERV-K proviruses, including 19 newly reported loci, with insertion frequencies ranging from <0.0005 to >0.75 that varied by population. Targeted screening of individual loci identified three new unfixed 2-LTR proviruses within our set, including an intact provirus present at Xq21.33 in some individuals, with the potential for retained infectivity.
Africa is inferred to be the continent of origin for all modern human populations, but the details of human prehistory and evolution in Africa remain largely obscure owing to the complex histories of ...hundreds of distinct populations. We present data for more than 580,000 SNPs for several hunter-gatherer populations: the Hadza and Sandawe of Tanzania, and the not equalKhomani Bushmen of South Africa, including speakers of the nearly extinct N
Summary
Background The discovery of somatostatin (SST) and the synthesis of a variety of analogues constituted a major therapeutic advance in the treatment of gastroenteropancreatic neuroendocrine ...(carcinoid) tumours (GEP‐NETs). They currently provide the most efficient treatment to achieve symptomatic relief and have recently been demonstrated to inhibit tumour growth.
Aim To review 35 years of experience regarding the clinical application and efficacy of SST analogues.
Methods The PubMed database (1972–2009) was searched using somatostatin as a search term with combinations of terms including ‘treatment’; ‘neuroendocrine’; ‘carcinoid’; ‘tumor’; ‘octreotide’; ‘lanreotide’ and ‘pasireotide’.
Results In a review of 15 studies including 481 patients, the slow‐release formulations Sandostatin LAR and Somatuline SR/Autogel achieved symptomatic relief in 74.2% (61.9–92.8%) and 67.5% (40.0–100%), biochemical response in 51.4% (31.5–100%) and 39.0% (17.9–58%), and tumour response in 69.8% (47.0–87.5%) and 64.4% (48.0–87.0%) respectively. Novel SST analogues like SOM230 (pasireotide) that exhibit pan SST receptor activity and analogues with high affinity to specific somatostatin receptor (sstr) subtypes may further advance the field, but efficacy studies are lacking.
Conclusion As more precise understanding of NET cell biology evolves and molecular biological tools advance, more accurate identification of individual tumours sstr profile will probably facilitate a more precise delineation of SST analogue treatment.
Aliment Pharmacol Ther 31, 169–188
Current monoanalyte blood-based biomarkers for the diagnosis and follow-up of neuroendocrine tumors (NETs) do not achieve satisfactory metrics of sensitivity and specificity. We report the ...sensitivity and selectivity of the PCR-based test, the NETest, to detect tumors with reference to other benign and malignant gastrointestinal diseases.
A total of 179 cases (gastrointestinal tumors: n=81; pancreatic disease: n=98) were prospectively collected and assessed using the NETest or chromogranin A (CgA) to determine metrics for detecting small intestinal and pancreatic NETs.
For intestinal carcinoids, the accuracy of the NETest was 93% (all NETs positive and 3 (12%) colorectal tumors were positive). CgA was positive in 80%, but 29% (n=7) of colorectal cancers were CgA positive. For pancreatic disease, the NETest accuracy was 94% (96% NETs positive, 2 (6%) of intraductal papillary mucinous neoplasms (IPMNs) were positive). The accuracy of CgA was 56% (29% of pancreatic NETs were CgA positive). Overall, the NETest was significantly more sensitive than CgA for the detection of small intestinal (area under the curve 0.98 vs. 0.75 P<0.0001) and pancreatic NETs (0.94 vs. 0.52, P<0.0001). NETest scores were elevated (P<0.05) in extensive disease and were more accurate (76-80%) than CgA levels (20-32%). The metrics of the multianalyte NETest met the performance criteria proposed by the National Institutes of Health for biomarkers, whereas CgA measurement did not.
This study demonstrates that a blood-based multianalyte NET gene transcript measurement of well-differentiated small intestinal and pancreatic neuroendocrine tumor disease is sensitive and specific and outperforms the current monoanalyte diagnostic strategy of plasma CgA measurement.
The transfer of mitochondrial genetic material into the nuclear genomes of eukaryotes is a well-established phenomenon that has been previously limited to the study of static reference genomes. The ...recent advancement of high throughput sequencing has enabled an expanded exploration into the diversity of polymorphic nuclear mitochondrial insertions (NumtS) within human populations. We have developed an approach to discover and genotype novel Numt insertions using whole genome, paired-end sequencing data. We have applied this method to a thousand individuals in 20 populations from the 1000 Genomes Project and other datasets and identified 141 new sites of Numt insertions, extending our current knowledge of existing NumtS by almost 20%. We find that recent Numt insertions are derived from throughout the mitochondrial genome, including the D-loop, and have integration biases that differ in some respects from previous studies on older, fixed NumtS in the reference genome. We determined the complete inserted sequence for a subset of these events and have identified a number of nearly full-length mitochondrial genome insertions into nuclear chromosomes. We further define their age and origin of insertion and present an analysis of their potential impact to ongoing studies of mitochondrial heteroplasmy and disease.
There is growing interest among nutritionists in feeding reduced protein diets to broiler chickens. Although nearly a century of research has been conducted providing biochemical insights on the ...impact of reduced protein diets for broilers, practical limitation still exists. The present review was written to provide insights on further reducing dietary protein in broilers. To construct this review, eighty-nine peer reviewed manuscripts in the area of amino acid nutrition in poultry were critiqued. Hence, nutritional research areas of low protein diets, threonine, glycine, valine, isoleucine, leucine, phenylalanine, histidine, and glutamine have been assessed and combined in this text, thus providing concepts into reduced protein diets for broilers. In addition, linkages between the cited work and least cost formation ingredient and nutrient matrix considerations are provided. In conclusion, practical applications in feeding reduced protein diets to broilers are advancing, but more work is warranted.
Europe has played a major role in dog evolution, harbouring the oldest uncontested Palaeolithic remains and having been the centre of modern dog breed creation. Here we sequence the genomes of an ...Early and End Neolithic dog from Germany, including a sample associated with an early European farming community. Both dogs demonstrate continuity with each other and predominantly share ancestry with modern European dogs, contradicting a previously suggested Late Neolithic population replacement. We find no genetic evidence to support the recent hypothesis proposing dual origins of dog domestication. By calibrating the mutation rate using our oldest dog, we narrow the timing of dog domestication to 20,000-40,000 years ago. Interestingly, we do not observe the extreme copy number expansion of the AMY2B gene characteristic of modern dogs that has previously been proposed as an adaptation to a starch-rich diet driven by the widespread adoption of agriculture in the Neolithic.
Domesticated from gray wolves between 10 and 40 kya in Eurasia, dogs display a vast array of phenotypes that differ from their ancestors, yet mirror other domesticated animal species, a phenomenon ...known as the domestication syndrome. Here, we use signatures persisting in dog genomes to identify genes and pathways possibly altered by the selective pressures of domestication.
Whole-genome SNP analyses of 43 globally distributed village dogs and 10 wolves differentiated signatures resulting from domestication rather than breed formation. We identified 246 candidate domestication regions containing 10.8 Mb of genome sequence and 429 genes. The regions share haplotypes with ancient dogs, suggesting that the detected signals are not the result of recent selection. Gene enrichments highlight numerous genes linked to neural crest and central nervous system development as well as neurological function. Read depth analysis suggests that copy number variation played a minor role in dog domestication.
Our results identify genes that act early in embryogenesis and can confer phenotypes distinguishing domesticated dogs from wolves, such as tameness, smaller jaws, floppy ears, and diminished craniofacial development as the targets of selection during domestication. These differences reflect the phenotypes of the domestication syndrome, which can be explained by alterations in the migration or activity of neural crest cells during development. We propose that initial selection during early dog domestication was for behavior, a trait influenced by genes which act in the neural crest, which secondarily gave rise to the phenotypes of modern dogs.
The Out-of-Africa (OOA) dispersal ∼50,000 y ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of ...mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from seven geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia, and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.
Despite their importance in gene innovation and phenotypic variation, duplicated regions have remained largely intractable owing to difficulties in accurately resolving their structure, copy number ...and sequence content. We present an algorithm (mrFAST) to comprehensively map next-generation sequence reads, which allows for the prediction of absolute copy-number variation of duplicated segments and genes. We examine three human genomes and experimentally validate genome-wide copy number differences. We estimate that, on average, 73-87 genes vary in copy number between any two individuals and find that these genic differences overwhelmingly correspond to segmental duplications (odds ratio = 135; P < 2.2 x 10(-16)). Our method can distinguish between different copies of highly identical genes, providing a more accurate assessment of gene content and insight into functional constraint without the limitations of array-based technology.
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