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  • 1
    Online Resource
    Online Resource
    Genomic investigations of unexplained acute hepatitis in children
    Springer Science and Business Media LLC ; 2023
    In:  Nature Vol. 617, No. 7961 ( 2023-05-18), p. 564-573
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 617, No. 7961 ( 2023-05-18), p. 564-573
    Abstract: Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK 1 . Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-023-06003-w
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 2
    Online Resource
    Online Resource
    A saturated map of common genetic variants associated with human height
    Springer Science and Business Media LLC ; 2022
    In:  Nature Vol. 610, No. 7933 ( 2022-10-27), p. 704-712
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 610, No. 7933 ( 2022-10-27), p. 704-712
    Abstract: Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-022-05275-y
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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    detail.hit.zdb_id: 1413423-8
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  • 3
    Online Resource
    Online Resource
    AIDS-protective HLA-B*27/B*57 and chimpanzee MHC class I molecules target analogous conserved areas of HIV-1/SIV cpz
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 34 ( 2010-08-24), p. 15175-15180
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 34 ( 2010-08-24), p. 15175-15180
    Abstract: In the absence of treatment, most HIV-1-infected humans develop AIDS. However, a minority are long-term nonprogressors, and resistance is associated with the presence of particular HLA-B*27/B*57 molecules. In contrast, most HIV-1-infected chimpanzees do not contract AIDS. In comparison with humans, chimpanzees experienced an ancient selective sweep affecting the MHC class I repertoire. We have determined the peptide-binding properties of frequent chimpanzee MHC class I molecules, and show that, like HLA-B*27/B*57, they target similar conserved areas of HIV-1/SIV cpz . In addition, many animals appear to possess multiple molecules targeting various conserved areas of the HIV-1/SIV cpz Gag protein, a quantitative aspect of the immune response that may further minimize the chance of viral escape. The functional characteristics of the contemporary chimpanzee MHC repertoire suggest that the selective sweep was caused by a lentiviral pandemic.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1009136107
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 4
    Online Resource
    Online Resource
    Evidence for an ancient selective sweep in the MHC class I gene repertoire of chimpanzees
    Proceedings of the National Academy of Sciences ; 2002
    In:  Proceedings of the National Academy of Sciences Vol. 99, No. 18 ( 2002-09-03), p. 11748-11753
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 99, No. 18 ( 2002-09-03), p. 11748-11753
    Abstract: MHC class I molecules play an essential role in the immune defense against intracellular infections. The hallmark of the MHC is its extensive degree of polymorphism at the population level. However, the present comparison of MHC class I gene intron variation revealed that chimpanzees have experienced a severe repertoire reduction at the orthologues of the HLA-A , -B , and -C loci. The loss of variability predates the (sub)speciation of chimpanzees and did not effect other known gene systems. Therefore the selective sweep in the MHC class I gene may have resulted from a widespread viral infection. Based on the present results and the fact that chimpanzees have a natural resistance to the development of AIDS, we hypothesize that the selective sweep was caused by the chimpanzee-derived simian immunodeficiency virus (SIVcpz), the closest relative of HIV-1, or a closely related retrovirus. Hence, the contemporary chimpanzee populations represent the offspring of AIDS-resistant animals, the survivors of a HIV-like pandemic that took place in the distant past.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.182420799
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2002
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  • 5
    Online Resource
    Online Resource
    Unparalleled complexity of the MHC class I region in rhesus macaques
    Proceedings of the National Academy of Sciences ; 2005
    In:  Proceedings of the National Academy of Sciences Vol. 102, No. 5 ( 2005-02), p. 1626-1631
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 5 ( 2005-02), p. 1626-1631
    Abstract: The highly polymorphic gene products of the classical MHC class I genes in humans ( HLA - A , HLA - B, and HLA - C ) play a critical role in the immune defense against intracellular infections. Because non-human primates are important models for AIDS vaccine research, rhesus monkeys from a thoroughly pedigreed and serotyped colony were subjected to full-length cDNA analysis of MHC class I gene transcripts. Rhesus macaques express multiple dominant Mamu - A and Mamu-B transcripts (majors) per chromosome, which are characterized by high expression levels. The presence of additional cDNAs with low levels of expression (minors) suggests evidence for transcriptional control of MHC class I genes. Moreover, phylogenetic analyses illustrate that most of the Mamu - A and Mamu - B loci/lineages identified display no or only limited levels of allelic polymorphism. Thus, MHC class I diversity in rhesus macaques is typified by the existence of an unmatched high number of Mamu - A and Mamu - B region configurations that exhibit polymorphism with regard to the number and combination of transcribed loci present per chromosome.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0409084102
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2005
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 6
    Online Resource
    Online Resource
    A highly divergent microsatellite facilitating fast and accurate DRB haplotyping in humans and rhesus macaques
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 21 ( 2007-05-22), p. 8907-8912
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 21 ( 2007-05-22), p. 8907-8912
    Abstract: The DRB region of the MHC in primate species is known to display abundant region configuration polymorphism with regard to the number and content of genes present per haplotype. Furthermore, depending on the species studied, the different DRB genes themselves may display varying degrees of allelic polymorphism. Because of this combination of diversity (differential gene number) and polymorphism (allelic variation), molecular typing methods for the primate DRB region are cumbersome. All intact DRB genes present in humans and rhesus macaques appear to possess, however, a complex and highly divergent microsatellite. Microsatellite analysis of a sizeable panel of outbred rhesus macaques, covering most of the known Mamu-DRB haplotypes, resulted in the definition of unique genotyping patterns that appear to be specific for a given haplotype. Subsequent examination of a representative panel of human cells illustrated that this approach also facilitates high-resolution HLA-DRB typing in an easy, quick, and reproducible fashion. The genetic composition of this complex microsatellite is shown to be in concordance with the phylogenetic relationships of various HLA-DRB and Mamu-DRB exon 2 gene/lineage sequences. Moreover, its length variability segregates with allelic variation of the respective gene. This simple protocol may find application in a variety of research avenues such as transplantation biology, disease association studies, molecular ecology, paternity testing, and forensic medicine.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0702964104
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
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  • 7
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    Online Resource
    Reactivation by exon shuffling of a conserved HLA-DR3 -like pseudogene segment in a New World primate species
    Proceedings of the National Academy of Sciences ; 2006
    In:  Proceedings of the National Academy of Sciences Vol. 103, No. 15 ( 2006-04-11), p. 5864-5868
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 15 ( 2006-04-11), p. 5864-5868
    Abstract: The common marmoset ( Callithrix jacchus ), a New World monkey species with a limited MHC class II repertoire, is highly susceptible to certain bacterial infections. Genomic analysis of exon 2 sequences documented the existence of only one DRB region configuration harboring three loci. Two of these loci display moderate levels of allelic polymorphism, whereas the -DRB*W12 gene appears to be monomorphic. This study shows that only the Caja-DRB*W16 and -DRB*W12 loci produce functional transcripts. The Caja-DRB1*03 locus is occupied by a pseudogene, given that most of the transcripts, if detected at all, show imperfections and are present at low levels. Moreover, two hybrid transcripts were identified that feature the evolutionarily conserved peptide-binding motif characteristic for the Caja-DRB1*03 gene. Thus, the severely reduced MHC class II repertoire in common marmosets has been expanded by reactivation of a pseudogene segment as a result of exon shuffling.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0600643103
    RVK:
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2006
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  • 8
    Online Resource
    Online Resource
    The common marmoset: A new world primate species with limited Mhc class II variability
    Proceedings of the National Academy of Sciences ; 1998
    In:  Proceedings of the National Academy of Sciences Vol. 95, No. 20 ( 1998-09-29), p. 11745-11750
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 95, No. 20 ( 1998-09-29), p. 11745-11750
    Abstract: The common marmoset ( Callithrix jacchus ) is a New World primate species that is highly susceptible to fatal infections caused by various strains of bacteria. We present here a first step in the molecular characterization of the common marmoset’s Mhc class II genes by nucleotide sequence analysis of the polymorphic exon 2 segments. For this study, genetic material was obtained from animals bred in captivity as well as in the wild. The results demonstrate that the common marmoset has, like other primates, apparently functional Mhc - DR and - DQ regions, but the Mhc - DP region has been inactivated. At the - DR and - DQ loci, only a limited number of lineages were detected. On the basis of the number of alleles found, the - DQA and - B loci appear to be oligomorphic, whereas only a moderate degree of polymorphism was observed for two of three Mhc - DRB loci. The contact residues in the peptide-binding site of the Caja-DRB1*03 lineage members are highly conserved, whereas the -DRB*W16 lineage members show more divergence in that respect. The latter locus encodes five oligomorphic lineages whose members are not observed in any other primate species studied, suggesting rapid evolution, as illustrated by frequent exchange of polymorphic motifs. All common marmosets tested were found to share one monomorphic type of Caja - DRB*W12 allele probably encoded by a separate locus. Common marmosets apparently lack haplotype polymorphism because the number of Caja - DRB loci present per haplotype appears to be constant. Despite this, however, an unexpectedly high number of allelic combinations are observed at the haplotypic level, suggesting that Caja - DRB alleles are exchanged frequently between chromosomes by recombination, promoting an optimal distribution of limited Mhc polymorphisms among individuals of a given population. This peculiar genetic make up, in combination with the limited variability of the major histocompatability complex class II repertoire, may contribute to the common marmoset’s susceptibility to particular bacterial infections.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.95.20.11745
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1998
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  • 9
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    Strong male bias drives germline mutation in chimpanzees
    American Association for the Advancement of Science (AAAS) ; 2014
    In:  Science Vol. 344, No. 6189 ( 2014-06-13), p. 1272-1275
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 344, No. 6189 ( 2014-06-13), p. 1272-1275
    Abstract: Germline mutation determines rates of molecular evolution, genetic diversity, and fitness load. In humans, the average point mutation rate is 1.2 × 10 −8 per base pair per generation, with every additional year of father’s age contributing two mutations across the genome and males contributing three to four times as many mutations as females. To assess whether such patterns are shared with our closest living relatives, we sequenced the genomes of a nine-member pedigree of Western chimpanzees, Pan troglodytes verus . Our results indicate a mutation rate of 1.2 × 10 −8 per base pair per generation, but a male contribution seven to eight times that of females and a paternal age effect of three mutations per year of father’s age. Thus, mutation rates and patterns differ between closely related species.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.344.6189.1272
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2014
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    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
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