Human core duplicon gene families: game changers or game players?
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ABSTRACT:
SUBMITTER: Bekpen C
PROVIDER: S-EPMC6920530 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Duplicated sequences are important sources of genetic instability and in the evolution of new gene function within species. Hominids have a preponderance of intrachromosomal duplications organized in an interspersed fashion, as opposed to tandem duplications, which are common in other mammalian genomes such as mouse, dog, and cow. Multiple lines of evidence, including sequence divergence, comparative primate genomes, and fluorescence in situ hybridization (FISH) analyses, point to an excess of segmental duplications in the common ancestor of humans and African great apes. We find that much of the interspersed human duplication architecture within chromosomes is focused around common sequence elements referred to as "core duplicons." These cores correspond to the expansion of gene families, some of which show signatures of positive selection and lack orthologs present in other mammalian species. This genomic architecture predisposes apes and humans not only to extensive genetic diversity, but also to large-scale structural diversity mediated by nonallelic homologous recombination. In humans, many de novo large-scale genomic changes mediated by these duplications are associated with neuropsychiatric and neurodevelopmental disease. We propose that the disadvantage of a high rate of new mutations is offset by the selective advantage of newly minted genes within the cores.
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Project description:Despite the tremendous success of the classical "isolate, inactivate, and inject" approach to vaccine development, new breakthroughs in vaccine research are increasingly reliant on novel approaches that incorporate cutting edge technology and advances in innate and adaptive immunology, microbiology, virology, pathogen biology, genetics, bioinformatics, and many other disciplines in order to: (1) deepen our understanding of the key biological processes that lead to protective immunity, (2) observe vaccine responses on a global, systems level, and (3) directly apply the new knowledge gained to the development of next-generation vaccines with improved safety profiles, enhanced efficacy, and even targeted utility in select populations. Here we highlight five key components foundational to vaccinomics efforts: applied immunogenomics, next generation sequencing and other cutting-edge "omics" technologies, advanced bioinformatics and analysis techniques, and finally, systems biology applied to immune profiling and vaccine responses. We believe these "game changers" will play a critical role in moving us toward the rational and directed development of new vaccines in the 21st century.
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Project description:BackgroundHuman subtelomeric segmental duplications ('subtelomeric repeats') comprise about 25% of the most distal 500 kb and 80% of the most distal 100 kb in human DNA. A systematic analysis of the duplication substructure of human subtelomeric regions was done in order to develop a detailed understanding of subtelomeric sequence organization and a nucleotide sequence-level characterization of subtelomeric duplicon families.ResultsThe extent of nucleotide sequence divergence within subtelomeric duplicon families varies considerably, as does the organization of duplicon blocks at subtelomere alleles. Subtelomeric internal (TTAGGG)n-like tracts occur at duplicon boundaries, suggesting their involvement in the generation of the complex sequence organization. Most duplicons have copies at both subtelomere and non-subtelomere locations, but a class of duplicon blocks is identified that are subtelomere-specific. In addition, a group of six subterminal duplicon families are identified that, together with six single-copy telomere-adjacent segments, include all of the (TTAGGG)n-adjacent sequence identified so far in the human genome.ConclusionIdentification of a class of duplicon blocks that is subtelomere-specific will facilitate high-resolution analysis of subtelomere repeat copy number variation as well as studies involving somatic subtelomere rearrangements. The significant levels of nucleotide sequence divergence within many duplicon families as well as the differential organization of duplicon blocks on subtelomere alleles may provide opportunities for allele-specific subtelomere marker development; this is especially true for subterminal regions, where divergence and organizational differences are the greatest. These subterminal sequence families comprise the immediate cis-elements for (TTAGGG)n tracts, and are prime candidates for subtelomeric sequences regulating telomere-specific (TTAGGG)n tract length in humans.
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