Search

The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture1. The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate2–4. Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans—including 278 individuals from England—alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France5,6.

Hepatitis B virus (HBV) has been infecting humans for millennia and remains a global health problem, but its past diversity and dispersal routes are largely unknown. We generated HBV genomic data from 137 Eurasians and Native Americans dated between ~10,500 and ~400 years ago. We date the most recent common ancestor of all HBV lineages to between ~20,000 and 12,000 years ago, with the virus present in European and South American hunter-gatherers during the early Holocene. After the European Neolithic transition, Mesolithic HBV strains were replaced by a lineage likely disseminated by early farmers that prevailed throughout western Eurasia for ~4000 years, declining around the end of the 2nd millennium BCE. The only remnant of this prehistoric HBV diversity is the rare genotype G, which appears to have reemerged during the HIV pandemic.

Hepatitis B virus (HBV) has been infecting humans for millennia and remains a global health problem, but its past diversity and dispersal routes are largely unknown. We generated HBV genomic data from 137 Eurasians and Native Americans dated between ~10,500 and ~400 years ago. We date the most recent common ancestor of all HBV lineages to between ~20,000 and 12,000 years ago, with the virus present in European and South American hunter-gatherers during the early Holocene. After the European Neolithic transition, Mesolithic HBV strains were replaced by a lineage likely disseminated by early farmers that prevailed throughout western Eurasia for ~4000 years, declining around the end of the 2nd millennium BCE. The only remnant of this prehistoric HBV diversity is the rare genotype G, which appears to have reemerged during the HIV pandemic., European Union (EU); Horizon 2020; European Research Council (ERC); Research and Innovation Program; PALEoRIDER; CoDisEASe; ARCHCAUCASUS; Seventh Framework Programme; Marie Curie Actions; Programme SASPRO; ERA.NET RUS Plus-S&T Programme; Institute of Archaeology of the Czech Academy of Sciences; Russian Foundation for Basic Research; German Research Foundation; French National Research Agency; Wenner-Gren Dissertation Fieldwork Grant; Ministry of Education and Science of the Republic of Kazakhstan; Max Planck Society; Slovak Academy of Sciences; Werner Siemens Stiftung; Paleobiochemistry; Award Praemium Academiae of the Czech Academy of Sciences

We report here the identification and characterization of a novel human leucocyte antigen (HLA)-DPB1 allele that was subsequently named HLA-DPB1*0302 by the WHO Nomenclature Committee. HLA-DPB1*0302 was identified in a single Sicilian individual by a combination of sequence-specific primers, reverse line sequence-specific oligonucleotide probing and DNA sequencing-based typing. The DPB1*0302 allele is most similar to the DPB1*3101 allele, differing by a single mismatch at nucleotide position 301 (T to G).

We report here the identification and characterization of a novel human leucocyte antigen (HLA)-DPB1 allele that was subsequently named HLA-DPB1*0302 by the WHO Nomenclature Committee. HLA-DPB1*0302 was identified in a single Sicilian individual by a combination of sequence-specific primers, reverse line sequence-specific oligonucleotide probing and DNA sequencing-based typing. The DPB1*0302 allele is most similar to the DPB1*3101 allele, differing by a single mismatch at nucleotide position 301 (T to G).

In this paper we confront a dangerous retrenchment that affects field archaeologist who dig the dead. Unchecked skeletal investigation, and cemetery archaeology, may be rendered impotent and unable to engage with the forefront of scientific practice. Archaeology has undergone, and continues to undergo, a process of professionalization and like other professions it operates away from the public gaze. At the same time Government policy – realised though research councils - requires measurable impact, openness and outreach. As a result public archaeology is progressively significant; however, as if to stifle this development the licence to remove human remains requires that all excavation projects must take place behind screens. So how are field projects to consolidate the necessity to engage with a community and the need or desire to use barriers? In 2010 archaeologists working at Oakington obtained permission to excavate the cemetery without screens. This paper outlines the results of a detailed investigation which looked at how the public engaged with the skeletons during excavation. As a result of this research it is our central argument that public perception is more than observation; it is the result of a complex mutable combination of ideas and emotions that evolve alongside a project. This knowledge is valuable and we believe it has the potential to inform professional practice for the benefit of archaeology as a whole. The excavation of human remains is one of the most pressing and contentious issues facing global archaeologies today. However, while there are numerous discussions of the ethics and politics of displaying the dead in museums, and many academic studies addressing the repatriation and reburial of human remains, there has been little consideration of the practice of digging up human remains itself (but see Kirk & Start 1999; Williams and Williams 2007). In this paper we will investigate the impact of digging the dead within a community and will use

A number of recent events inside and outside of the heritage sector have triggered a lively and largely constructive debate about the excavation, display and conservation of human remains in the UK (see Sayer 2009, 2010a; Moshenska 2009; Parker Pearson et al. 2011; Jenkins 2008, 2010; Giesen 2013). These events focus on two areas, the reburial of human remains prompted by requests to museums from the Pagan community, and independently of these requests the Ministry of Justice decided to revisit its conditions for the excavation of human remains (Parker Pearson et al. 2013). In the short term these issues seem to have been resolved through open consultation and campaigning by archaeologists. British archaeologists consider that they have public support; public-facing archaeology develops strong links within local communities, the portable antiquities scheme engages members of the public in the discovery of metal objects on a national scale, and TV and Radio programmes regularly include archaeology or excavation as their central theme. There are various ways to consume archaeology outside of a traditional museum environment; people can shift soil or sit back and read about it in numerous academic and popular books, in magazines and digitally on the internet. This chapter discusses this new digital environment by describing and analyzing three events in British burial archaeology which deliberately sought coverage online and within global media. These are: 1) the burial campaign which was instrumental in raising the profile of the reburial problem in England, 2) the discovery of a cow and woman buried in the same grave in a fifth and sixth century cemetery at Oakington, Cambridgeshire, 3) the investigation of King Richard III's final resting place in Leicester, Leics. One of us was instrumental in publicizing the first two events; neither of us was involved in the third. We will refer also to a recent case in East Anglia where negative media publicity came unsought by

In this paper we confront a dangerous retrenchment that affects field archaeologist who dig the dead. Unchecked skeletal investigation, and cemetery archaeology, may be rendered impotent and unable to engage with the forefront of scientific practice. Archaeology has undergone, and continues to undergo, a process of professionalization and like other professions it operates away from the public gaze. At the same time Government policy – realised though research councils - requires measurable impact, openness and outreach. As a result public archaeology is progressively significant; however, as if to stifle this development the licence to remove human remains requires that all excavation projects must take place behind screens. So how are field projects to consolidate the necessity to engage with a community and the need or desire to use barriers? In 2010 archaeologists working at Oakington obtained permission to excavate the cemetery without screens. This paper outlines the results of a detailed investigation which looked at how the public engaged with the skeletons during excavation. As a result of this research it is our central argument that public perception is more than observation; it is the result of a complex mutable combination of ideas and emotions that evolve alongside a project. This knowledge is valuable and we believe it has the potential to inform professional practice for the benefit of archaeology as a whole. The excavation of human remains is one of the most pressing and contentious issues facing global archaeologies today. However, while there are numerous discussions of the ethics and politics of displaying the dead in museums, and many academic studies addressing the repatriation and reburial of human remains, there has been little consideration of the practice of digging up human remains itself (but see Kirk & Start 1999; Williams and Williams 2007). In this paper we will investigate the impact of digging the dead within a community and will use

A number of recent events inside and outside of the heritage sector have triggered a lively and largely constructive debate about the excavation, display and conservation of human remains in the UK (see Sayer 2009, 2010a; Moshenska 2009; Parker Pearson et al. 2011; Jenkins 2008, 2010; Giesen 2013). These events focus on two areas, the reburial of human remains prompted by requests to museums from the Pagan community, and independently of these requests the Ministry of Justice decided to revisit its conditions for the excavation of human remains (Parker Pearson et al. 2013). In the short term these issues seem to have been resolved through open consultation and campaigning by archaeologists. British archaeologists consider that they have public support; public-facing archaeology develops strong links within local communities, the portable antiquities scheme engages members of the public in the discovery of metal objects on a national scale, and TV and Radio programmes regularly include archaeology or excavation as their central theme. There are various ways to consume archaeology outside of a traditional museum environment; people can shift soil or sit back and read about it in numerous academic and popular books, in magazines and digitally on the internet. This chapter discusses this new digital environment by describing and analyzing three events in British burial archaeology which deliberately sought coverage online and within global media. These are: 1) the burial campaign which was instrumental in raising the profile of the reburial problem in England, 2) the discovery of a cow and woman buried in the same grave in a fifth and sixth century cemetery at Oakington, Cambridgeshire, 3) the investigation of King Richard III's final resting place in Leicester, Leics. One of us was instrumental in publicizing the first two events; neither of us was involved in the third. We will refer also to a recent case in East Anglia where negative media publicity came unsought by

In this paper we confront a dangerous retrenchment that affects field archaeologist who dig the dead. Unchecked skeletal investigation, and cemetery archaeology, may be rendered impotent and unable to engage with the forefront of scientific practice. Archaeology has undergone, and continues to undergo, a process of professionalization and like other professions it operates away from the public gaze. At the same time Government policy – realised though research councils - requires measurable impact, openness and outreach. As a result public archaeology is progressively significant; however, as if to stifle this development the licence to remove human remains requires that all excavation projects must take place behind screens. So how are field projects to consolidate the necessity to engage with a community and the need or desire to use barriers? In 2010 archaeologists working at Oakington obtained permission to excavate the cemetery without screens. This paper outlines the results of a detailed investigation which looked at how the public engaged with the skeletons during excavation. As a result of this research it is our central argument that public perception is more than observation; it is the result of a complex mutable combination of ideas and emotions that evolve alongside a project. This knowledge is valuable and we believe it has the potential to inform professional practice for the benefit of archaeology as a whole. The excavation of human remains is one of the most pressing and contentious issues facing global archaeologies today. However, while there are numerous discussions of the ethics and politics of displaying the dead in museums, and many academic studies addressing the repatriation and reburial of human remains, there has been little consideration of the practice of digging up human remains itself (but see Kirk & Start 1999; Williams and Williams 2007). In this paper we will investigate the impact of digging the dead within a community and will use

A number of recent events inside and outside of the heritage sector have triggered a lively and largely constructive debate about the excavation, display and conservation of human remains in the UK (see Sayer 2009, 2010a; Moshenska 2009; Parker Pearson et al. 2011; Jenkins 2008, 2010; Giesen 2013). These events focus on two areas, the reburial of human remains prompted by requests to museums from the Pagan community, and independently of these requests the Ministry of Justice decided to revisit its conditions for the excavation of human remains (Parker Pearson et al. 2013). In the short term these issues seem to have been resolved through open consultation and campaigning by archaeologists. British archaeologists consider that they have public support; public-facing archaeology develops strong links within local communities, the portable antiquities scheme engages members of the public in the discovery of metal objects on a national scale, and TV and Radio programmes regularly include archaeology or excavation as their central theme. There are various ways to consume archaeology outside of a traditional museum environment; people can shift soil or sit back and read about it in numerous academic and popular books, in magazines and digitally on the internet. This chapter discusses this new digital environment by describing and analyzing three events in British burial archaeology which deliberately sought coverage online and within global media. These are: 1) the burial campaign which was instrumental in raising the profile of the reburial problem in England, 2) the discovery of a cow and woman buried in the same grave in a fifth and sixth century cemetery at Oakington, Cambridgeshire, 3) the investigation of King Richard III's final resting place in Leicester, Leics. One of us was instrumental in publicizing the first two events; neither of us was involved in the third. We will refer also to a recent case in East Anglia where negative media publicity came unsought by

In this paper we confront a dangerous retrenchment that affects field archaeologist who dig the dead. Unchecked skeletal investigation, and cemetery archaeology, may be rendered impotent and unable to engage with the forefront of scientific practice. Archaeology has undergone, and continues to undergo, a process of professionalization and like other professions it operates away from the public gaze. At the same time Government policy – realised though research councils - requires measurable impact, openness and outreach. As a result public archaeology is progressively significant; however, as if to stifle this development the licence to remove human remains requires that all excavation projects must take place behind screens. So how are field projects to consolidate the necessity to engage with a community and the need or desire to use barriers? In 2010 archaeologists working at Oakington obtained permission to excavate the cemetery without screens. This paper outlines the results of a detailed investigation which looked at how the public engaged with the skeletons during excavation. As a result of this research it is our central argument that public perception is more than observation; it is the result of a complex mutable combination of ideas and emotions that evolve alongside a project. This knowledge is valuable and we believe it has the potential to inform professional practice for the benefit of archaeology as a whole. The excavation of human remains is one of the most pressing and contentious issues facing global archaeologies today. However, while there are numerous discussions of the ethics and politics of displaying the dead in museums, and many academic studies addressing the repatriation and reburial of human remains, there has been little consideration of the practice of digging up human remains itself (but see Kirk & Start 1999; Williams and Williams 2007). In this paper we will investigate the impact of digging the dead within a community and will use

A number of recent events inside and outside of the heritage sector have triggered a lively and largely constructive debate about the excavation, display and conservation of human remains in the UK (see Sayer 2009, 2010a; Moshenska 2009; Parker Pearson et al. 2011; Jenkins 2008, 2010; Giesen 2013). These events focus on two areas, the reburial of human remains prompted by requests to museums from the Pagan community, and independently of these requests the Ministry of Justice decided to revisit its conditions for the excavation of human remains (Parker Pearson et al. 2013). In the short term these issues seem to have been resolved through open consultation and campaigning by archaeologists. British archaeologists consider that they have public support; public-facing archaeology develops strong links within local communities, the portable antiquities scheme engages members of the public in the discovery of metal objects on a national scale, and TV and Radio programmes regularly include archaeology or excavation as their central theme. There are various ways to consume archaeology outside of a traditional museum environment; people can shift soil or sit back and read about it in numerous academic and popular books, in magazines and digitally on the internet. This chapter discusses this new digital environment by describing and analyzing three events in British burial archaeology which deliberately sought coverage online and within global media. These are: 1) the burial campaign which was instrumental in raising the profile of the reburial problem in England, 2) the discovery of a cow and woman buried in the same grave in a fifth and sixth century cemetery at Oakington, Cambridgeshire, 3) the investigation of King Richard III's final resting place in Leicester, Leics. One of us was instrumental in publicizing the first two events; neither of us was involved in the third. We will refer also to a recent case in East Anglia where negative media publicity came unsought by

An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the dearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci in the MHC. However, the direct effects of any of the 150–200 genes that constitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is associated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitns (IDDM), systemic lupus erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency, myasthenia gravis and several other conditions. We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis co the central MHC between HLA-B and the tumour necrosis factor or complement genes. Here we consider which of the remaining 8.1-associated diseases are more closely associated with HLA-DR3 and/or DQ2. Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH. Hence these genes may act as a common co-factor in the diverse immunopathological conditions associated with the 8.1 AH.

No abstract available

An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the dearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci in the MHC. However, the direct effects of any of the 150–200 genes that constitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is associated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitns (IDDM), systemic lupus erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency, myasthenia gravis and several other conditions. We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis co the central MHC between HLA-B and the tumour necrosis factor or complement genes. Here we consider which of the remaining 8.1-associated diseases are more closely associated with HLA-DR3 and/or DQ2. Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH. Hence these genes may act as a common co-factor in the diverse immunopathological conditions associated with the 8.1 AH.

Objective: The identification of a vitamin D-responsive (VDRE) motif within the HLA-DRB1*15:01 promoter region provides an attractive explanation for the combined effects of HLA-DR inheritance and vitamin D exposure on multiple sclerosis (MS) risk. We therefore sought to incorporate HLA-DRB1 promoter variation, including the VDRE motif, in an assessment of HLA-DRB1-associated MS risk. Methods: We utilized 32 homozygous HLA cell lines (covering 17 DRB1 alleles) and 53 heterozygote MS samples (20 DRB1 alleles) for HLA-DRB1 promoter sequencing. The influence of HLA-DRB1 variation on MS risk was then assessed among 466 MS cases and 498 controls. Results: The majority of HLA*DRB1 alleles (including HLA-DRB1*15:01) express the functional VDRE motif, apart from HLA-DRB1*04, *07, and *09 alleles that comprise the HLA-DR53 serologic group. Allele-specific variation within functional X-box and Y-box motifs was also associated with serologically defined HLA-DR haplotypes. Incorporating these results in an analysis of MS risk, we identified a strong protective effect of HLA-DRB1*04, *07, and *09 (DR53) alleles (p = 10(-12)) and elevated risk associated with DRB1*15 and *16 (DR51) and *08 (DR8) alleles (p < 10(-18)). Conclusions: HLA-DRB1 groups corresponding to serologic HLA-DR profiles as well as promoter polymorphism haplotypes effectively stratified MS risk over an 11-fold range, suggesting functional relationships between risk-modifying HLA-DRB1 alleles. An independent contribution of VDRE motif variation to increase MS risk was not discernible, although vitamin D-dependent regulation of HLA-DR expression may still play an important role given that HLA-DRB1*04/*07/*09 (DR53) alleles that express the "nonresponsive" VDRE motif were associated with significantly reduced risk of MS.

Objective: The identification of a vitamin D-responsive (VDRE) motif within the HLA-DRB1*15:01 promoter region provides an attractive explanation for the combined effects of HLA-DR inheritance and vitamin D exposure on multiple sclerosis (MS) risk. We therefore sought to incorporate HLA-DRB1 promoter variation, including the VDRE motif, in an assessment of HLA-DRB1-associated MS risk. Methods: We utilized 32 homozygous HLA cell lines (covering 17 DRB1 alleles) and 53 heterozygote MS samples (20 DRB1 alleles) for HLA-DRB1 promoter sequencing. The influence of HLA-DRB1 variation on MS risk was then assessed among 466 MS cases and 498 controls. Results: The majority of HLA*DRB1 alleles (including HLA-DRB1*15:01) express the functional VDRE motif, apart from HLA-DRB1*04, *07, and *09 alleles that comprise the HLA-DR53 serologic group. Allele-specific variation within functional X-box and Y-box motifs was also associated with serologically defined HLA-DR haplotypes. Incorporating these results in an analysis of MS risk, we identified a strong protective effect of HLA-DRB1*04, *07, and *09 (DR53) alleles (p = 10(-12)) and elevated risk associated with DRB1*15 and *16 (DR51) and *08 (DR8) alleles (p < 10(-18)). Conclusions: HLA-DRB1 groups corresponding to serologic HLA-DR profiles as well as promoter polymorphism haplotypes effectively stratified MS risk over an 11-fold range, suggesting functional relationships between risk-modifying HLA-DRB1 alleles. An independent contribution of VDRE motif variation to increase MS risk was not discernible, although vitamin D-dependent regulation of HLA-DR expression may still play an important role given that HLA-DRB1*04/*07/*09 (DR53) alleles that express the "nonresponsive" VDRE motif were associated with significantly reduced risk of MS.

The effect of TNF polymorphisms on the time-to-onset of lipodystrophy was investigated in 191 Caucasian participants in the western Australian HIV cohort. Carriage of the TNF-α-238G/A polymorphism was found in 13.1% of the cohort, and was associated with an earlier onset of lipodystrophy. The presence of TNF-α-238G/A was associated with lipodystrophy progression in Cox proportional hazards regression analyses, without influencing the relative risk and significance of other predictive host and treatment-related variables.

Background: A number of international research groups have developed DNA quantitation assays in order to investigate the role of mitochondrial DNA depletion in anti-retroviral therapy-induced toxicities. Objectives: A collaborative study was undertaken to evaluate intra-assay precision and between laboratory concordance of measurements of mitochondrial DNA quantity, as a component of a comprehensive quality assurance project. Study design: Four laboratories were asked to measure and report mitochondrial DNA and nuclear DNA genome copy number, as well as mitochondrial DNA copy number/cell, for 17 coded aliquots of DNA derived from serial dilutions of pooled DNA from a lymphoblastoid cell line. Samples included masked replicates and five standards. All samples had similar mitochondrial DNA/nuclear DNA ratios. Precision within laboratories was assessed by determining the coefficient of variation of replicates. Concordance between laboratories was assessed by determining the average coefficient of variation of the mean replicate values for each sample. The effect of standardising the assay for these three measurements was also assessed for laboratories A, B and C. Results: Measurements of mitochondrial DNA and nuclear DNA content for replicate samples varied by an average of less than 6% (based on log10 values, 72% non-logged values), and measurements of mitochondrial DNA/cell for replicates varied by less than 12% (based on log10 values, 32% non-logged values), with no improvement of precision after standardisation. Standardisation did significantly improve the concordance of results for measurements of mitochondrial DNA content and mitochondrial DNA/cell. Non-standardised measurements of mitochondrial DNA content for the same sample set varied by 19% between laboratories (based on log10 values, 96% non-logged values), and after standardisation results varied by less than 3% (based on log10 values, 54% non-logged values). There was no significant improvement for concor

Background: HIV and ancestral retroviruses have evolved under intense selective pressure from HLA restricted immune responses, consistent with recent evidence of HLA Class I associated viral polymorphisms at a population level. The efficacy of an HIV vaccine will depend on the breadth and strength of HLA restricted immune responses it elicits, and the extent to which the infecting HIV sequence has escaped those responses. Methods: Full-length HIV genome sequencing and high resolution HLA typing is being undertaken on pre-ART samples in 249 sequential patients (pts) enrolled in the WA HIV Cohort Study since 1996. Analysis of the first 80 pts identified HLA associations in all coding regions. 1) The proportion of Class I associated polymorphic sites adapted to the relevant Class I allele present (non-consensus amino acid at sites with positive HLA associations or consensus amino acid at sites with negative associations) was calculated; and 2) an optimal vaccine was designed for this population using the population consensus at positive HLA associations and the second most common amino acid at negative associations. A simulation was done to determine the likely efficacy of different vaccine candidates assuming the target population had the same HLA diversity, and was exposed to the same viral diversity, as in our cohort. Results: 1) Pts with HIV sequences well adapted to HLA restricted immune responses had higher viral loads (mean 26,000 cps/ml in least adapted and 110,000 cps/ml in most adapted, p = 0.02); and 2) percentages of pts in the highest quartile for matches between the candidate vaccine and potential infecting viruses at residues likely to afford protection were: optimal 45%, our population consensus 35%, Clade B 28%, Clade C 14%, Clade A 25% and SIV 2% (p < 0.05). Similar results were obtained if the strength of HLA-restricted immune responses for these matches was estimated using the relevant data obtained in our HIV infected cohort. Conclusions:These data

Background: A number of international research groups have developed DNA quantitation assays in order to investigate the role of mitochondrial DNA depletion in anti-retroviral therapy-induced toxicities. Objectives: A collaborative study was undertaken to evaluate intra-assay precision and between laboratory concordance of measurements of mitochondrial DNA quantity, as a component of a comprehensive quality assurance project. Study design: Four laboratories were asked to measure and report mitochondrial DNA and nuclear DNA genome copy number, as well as mitochondrial DNA copy number/cell, for 17 coded aliquots of DNA derived from serial dilutions of pooled DNA from a lymphoblastoid cell line. Samples included masked replicates and five standards. All samples had similar mitochondrial DNA/nuclear DNA ratios. Precision within laboratories was assessed by determining the coefficient of variation of replicates. Concordance between laboratories was assessed by determining the average coefficient of variation of the mean replicate values for each sample. The effect of standardising the assay for these three measurements was also assessed for laboratories A, B and C. Results: Measurements of mitochondrial DNA and nuclear DNA content for replicate samples varied by an average of less than 6% (based on log10 values, 72% non-logged values), and measurements of mitochondrial DNA/cell for replicates varied by less than 12% (based on log10 values, 32% non-logged values), with no improvement of precision after standardisation. Standardisation did significantly improve the concordance of results for measurements of mitochondrial DNA content and mitochondrial DNA/cell. Non-standardised measurements of mitochondrial DNA content for the same sample set varied by 19% between laboratories (based on log10 values, 96% non-logged values), and after standardisation results varied by less than 3% (based on log10 values, 54% non-logged values). There was no significant improvement for concor

Background The use of abacavir a potent HIV—1 nucleosideanalogue reverse—transcriptase inhibitor is complicated by a potentially life-threatening hypersensitivity syndrome in about 5% of cases. Genetic factors influencing the immune response to abacavir might confer susceptibility. We aimed to find associations between MHC alleles and abacavir hypersensitivity in HIV—1-positive individuals treated with abacavir. Methods MHC region typing was done in the first 200 Western Australian HIV Cohort Study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases, and was excluded in 167 individuals with more than 6 weeks' exposure to the drug (abacavir tolerant). 15 individuals experienced some symptoms but did not meet criteria for abacavir hypersensitivity. p values were corrected for comparisons of multiple HLA alleles (pc) by multiplication of the raw p value by the estimated number of HLA alleles present within the loci examined. Findings HLA-B*5701 was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in four (2%) of the 167 abacavir tolerant patients (odds ratio 117 [95% CI 29—481], pc<0·0001), and the HLA-DR7 and HLA-DQ3 combination was found in 13 (72%) of hypersensitive and five (3%) of tolerant patients (73 [20—268], pc<0·0001). HLA-B*5701, HLA-DR7, and HLA-DQ3 were present in combination in 13 (72%) hypersensitive patients and none of the tolerant patients (822 [43—15 675], pc<0·0001). Other MHC markers also present on the 57·1 ancestral haplotype to which the three markers above belong confirmed the presence of haplotype-specific linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. Within the entire abacavir-exposed cohort (n=200), presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative predictive value of 97%. Interpretation Genetic susceptibility to abacavir hypersensitivity is car

Abacavir (ABC) is a potent nucleoside analogue inhibitor of HIV reverse transcriptase. Approximately 5% of individuals given abacavir develop a potentially life threatening hypersensitivity reaction. These reactions typically occur within six weeks of exposure and recur rapidly on rechallenge. It has been proposed that patients may be predisposed to such reactions by genetic polymorphisms in genes involved in systemic inflammatory responses. We investigated the effect of MHC alleles on the risk of hypersensitivity to abacavir in 200 participants in the Western Australian HIV Cohort Study exposed to the drug. Eighteen definite cases of abacavir hypersensitivity (ABC HSR) were identified and 167 individuals had more than six weeks exposure to abacavir without developing hypersensitivity (ABC non-HSR). Fifteen individuals who experienced some symptoms but did not meet the criteria for definite ABC HSR were excluded. There were striking differences in the frequency of some of the HLA alleles in the ABC HSR and non-HSR groups. In the ABC HSR group, HLA- B*5701 was found in 14/18 cases (78%) compared to 4/167 (2.3%) in the ABC non-HSR group (OR = 117, p < 0.0001) whilst the combination of DRB1*0701and DQ3 was found in 13/18 (72%) of the HSR cases and 5/167 (3.0%) of the non-HSR cases (OR = 72, p < 0.0001). These alleles HLA-B*5701, DRB1*0701 and DQ3 are markers of the 57.1 ancestral haplotype (AH). We therefore examined the presence of the combination of all three markers in the 2 groups: 13/18 (72%) of the HSR cases and none of the 167 ABC non-HSR patients had all 3 markers (OR = 822, p < 0.0001). Other markers characteristic of the 57.1 AH (D6S1014*137, C4A6, D6S273*135, TNF-238A, MICA*194, MIB*344) were examined to confirm the presence of and to map the extent of the 57.1 AH. All 14 ABC HSR cases with HLA-B*5701 had markers characteristic of 57.1 AH centromeric of HLA-B up to and including D6S273. Two additional control populations (381 HIV infected patients unexposed

Background The use of abacavir a potent HIV—1 nucleosideanalogue reverse—transcriptase inhibitor is complicated by a potentially life-threatening hypersensitivity syndrome in about 5% of cases. Genetic factors influencing the immune response to abacavir might confer susceptibility. We aimed to find associations between MHC alleles and abacavir hypersensitivity in HIV—1-positive individuals treated with abacavir. Methods MHC region typing was done in the first 200 Western Australian HIV Cohort Study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases, and was excluded in 167 individuals with more than 6 weeks' exposure to the drug (abacavir tolerant). 15 individuals experienced some symptoms but did not meet criteria for abacavir hypersensitivity. p values were corrected for comparisons of multiple HLA alleles (pc) by multiplication of the raw p value by the estimated number of HLA alleles present within the loci examined. Findings HLA-B*5701 was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in four (2%) of the 167 abacavir tolerant patients (odds ratio 117 [95% CI 29—481], pc<0·0001), and the HLA-DR7 and HLA-DQ3 combination was found in 13 (72%) of hypersensitive and five (3%) of tolerant patients (73 [20—268], pc<0·0001). HLA-B*5701, HLA-DR7, and HLA-DQ3 were present in combination in 13 (72%) hypersensitive patients and none of the tolerant patients (822 [43—15 675], pc<0·0001). Other MHC markers also present on the 57·1 ancestral haplotype to which the three markers above belong confirmed the presence of haplotype-specific linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. Within the entire abacavir-exposed cohort (n=200), presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative predictive value of 97%. Interpretation Genetic susceptibility to abacavir hypersensitivity is car

No abstract available

[2],viii,28p. ; 4⁰., The dedication signed: 'Sayer Rudd, M.D. and man-midwife'., Reproduction of original from the British Library., English Short Title Catalog, ESTCT58007., Electronic data. Farmington Hills, Mich. : Thomson Gale, 2003. Page image (PNG). Digitized image of the microfilm version produced in Woodbridge, CT by Research Publications, 1982-2002 (later known as Primary Source Microfilm, an imprint of the Gale Group)., (DLPS) 004834806.0001.000, (ESTC) T58007, http://quod.lib.umich.edu/t/text/accesspolicy.html, To the extent possible under law, the Text Creation Partnership has waived all copyright and related or neighboring rights to this keyboarded and encoded edition of the work described above, according to the terms of the CC0 1.0 Public Domain Dedication (http://creativecommons.org/publicdomain/zero/1.0/). This waiver does not extend to any page images or other supplementary files associated with this work, which may be protected by copyright or other license restrictions. Please go to http://www.lib.umich.edu/tcp/ecco/ for more information.

[2],viii,28p. ; 4⁰., The dedication signed: 'Sayer Rudd, M.D. and man-midwife'., Reproduction of original from the British Library., English Short Title Catalog, ESTCT58007., Electronic data. Farmington Hills, Mich. : Thomson Gale, 2003. Page image (PNG). Digitized image of the microfilm version produced in Woodbridge, CT by Research Publications, 1982-2002 (later known as Primary Source Microfilm, an imprint of the Gale Group)., (DLPS) 004834806.0001.000, (ESTC) T58007, http://quod.lib.umich.edu/t/text/accesspolicy.html, To the extent possible under law, the Text Creation Partnership has waived all copyright and related or neighboring rights to this keyboarded and encoded edition of the work described above, according to the terms of the CC0 1.0 Public Domain Dedication (http://creativecommons.org/publicdomain/zero/1.0/). This waiver does not extend to any page images or other supplementary files associated with this work, which may be protected by copyright or other license restrictions. Please go to http://www.lib.umich.edu/tcp/ecco/ for more information.

The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture1. The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate2–4. Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans—including 278 individuals from England—alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France5,6.

The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture1. The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate2–4. Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans—including 278 individuals from England—alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France5,6.

The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture1. The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate2-4. Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans-including 278 individuals from England-alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France5,6.

We describe a method for determining the parental HLA haplotypes of a single individual without recourse to conventional segregation genetics. Blood samples were cultured to identify and sort chromosome 6 by bivariate flow cytometry. Single chromosome 6 amplification products were confirmed with a single nucleotide polymorphism (SNP) array and verified by deep sequencing to enable assignment of both alleles at the HLA loci, defining the two haplotypes. This study exemplifies a rapid and efficient method of haplotyping that can be applied to any chromosome pair, or indeed all chromosome pairs, using a single sorting operation. The method represents a cost-effective approach to complete phasing of SNPs, which will facilitate a deeper understanding of the links between SNPs, gene regulation and protein function.