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Annual Review of Medicine 2012Following the "finished," euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making... (Review)
Review
Following the "finished," euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges.
Topics: Genetic Diseases, Inborn; Genetic Privacy; Genome, Human; HapMap Project; Human Genome Project; Humans
PubMed: 22248320
DOI: 10.1146/annurev-med-051010-162644 -
Lancet (London, England) Mar 2023
Topics: Humans; Gene Editing; Genome, Human
PubMed: 36933932
DOI: 10.1016/S0140-6736(23)00560-3 -
Seminars in Cell & Developmental Biology Nov 2022Not that long ago, the human genome was discovered to be mainly non-coding, that is comprised of DNA sequences that do not code for proteins. The initial paradigm that... (Review)
Review
Not that long ago, the human genome was discovered to be mainly non-coding, that is comprised of DNA sequences that do not code for proteins. The initial paradigm that non-coding is also non-functional was soon overturned and today the work to uncover the functions of non-coding DNA and RNA in human early embryogenesis has commenced. Early human development is characterized by large-scale changes in genomic activity and the transcriptome that are partly driven by the coordinated activation and repression of repetitive DNA elements scattered across the genome. Here we provide examples of recent novel discoveries of non-coding DNA and RNA interactions and mechanisms that ensure accurate non-coding activity during human maternal-to-zygotic transition and lineage segregation. These include studies on small and long non-coding RNAs, transposable element regulation, and RNA tailing in human oocytes and early embryos. High-throughput approaches to dissect the non-coding regulatory networks governing early human development are a foundation for functional studies of specific genomic elements and molecules that has only begun and will provide a wider understanding of early human embryogenesis and causes of infertility.
Topics: DNA Transposable Elements; Embryo, Mammalian; Genome, Human; Genomics; Humans; RNA, Long Noncoding
PubMed: 35177347
DOI: 10.1016/j.semcdb.2022.02.010 -
Progress in Molecular Biology and... 2021Genome editing, particularly the use of CRISPR-Cas9-based methodologies, is revolutionizing biology through its impacts on research and the translation of these into... (Review)
Review
Genome editing, particularly the use of CRISPR-Cas9-based methodologies, is revolutionizing biology through its impacts on research and the translation of these into applications in biomedicine. Somatic genome editing aimed at treating individuals with disease raises some significant ethical issues, but proposed heritable interventions, through the use of genome editing in gametes or embryos, raise a number of distinct social, ethical and political issues. This review will consider some proposed uses of heritable human genome editing (HHGE) and several of the objections to these that have been raised. Making sense of such proposed uses requires viewing HHGE as an assisted reproductive technology (ART) that, like preimplantation genetic testing (PGT) and mitochondrial replacement techniques (MRT), aims to prevent disease transmission during sexual reproduction, rather than acting as a therapy for an existing individual. Applications beyond the paradigm of disease prevention raise even more difficult scientific and ethical questions. Here, I will discuss various themes that are prominent in discussions of the science and ethics of HHGE, including impacts on human dignity and society, the language of HHGE used for public dialogue and the governance of HHGE.
Topics: CRISPR-Cas Systems; Gene Editing; Genome, Human; Germ Cells; Humans; Reproductive Techniques, Assisted
PubMed: 34175039
DOI: 10.1016/bs.pmbts.2020.12.008 -
Disease Models & Mechanisms Dec 2021We provide an Editorial perspective on approaches to improve ethnic representation in the human genome reference sequence, enabling its widespread use in genomic...
We provide an Editorial perspective on approaches to improve ethnic representation in the human genome reference sequence, enabling its widespread use in genomic studies and precision medicine to benefit all peoples.
Topics: Genome, Human; Humans
PubMed: 34935906
DOI: 10.1242/dmm.049426 -
Trends in Genetics : TIG Jun 2022The path to completion of the functional annotation of the haploid human genome reference build, exploration of the clan genomics hypothesis, understanding human gene... (Review)
Review
The path to completion of the functional annotation of the haploid human genome reference build, exploration of the clan genomics hypothesis, understanding human gene and genome functional biology, and gene genome and organismal evolution, is in reach.
Topics: Diploidy; Gene Dosage; Genome, Human; Genomic Medicine; Genomics; Humans
PubMed: 35450748
DOI: 10.1016/j.tig.2022.03.001 -
Nature Genetics Nov 2014
Topics: Editorial Policies; Genetic Variation; Genome, Human; Humans; Peer Review, Research; Periodicals as Topic
PubMed: 25352097
DOI: 10.1038/ng.3140 -
Cold Spring Harbor Molecular Case... Feb 2022After a long and largely disappointing detour, Genome Research has reidentified Rare Diseases as a major opportunity for improving health care and a clue to...
After a long and largely disappointing detour, Genome Research has reidentified Rare Diseases as a major opportunity for improving health care and a clue to understanding gene and genome function. In this Special Issue of on Rare Diseases, several invited Perspectives, numerous Case Reports, and this Editorial itself address recent breakthroughs as well as unsolved problems in this wide field. These range from exciting prospects for gap-free diagnostic whole-genome sequencing to persisting problems related to identifying and distinguishing pathogenic and benign variants; and from the good news that soon, the United Kingdom will no longer be the only country to have introduced whole-genome sequencing into health care to the sobering conclusion that in many countries the clinical infrastructure for bringing Genome Medicine to the patient is still lacking. With less than 5000 genes firmly implicated in disease, the identification of at least twice as many disease genes is a major challenge, and the elucidation of their function is an even larger task. But given the renewed interest in rare diseases, their importance for health care, and the vast and growing spectrum of concepts and methods for studying them, the future of Human Genome Research is bright.
Topics: Genome, Human; Genome-Wide Association Study; Humans; Rare Diseases; United Kingdom; Whole Genome Sequencing
PubMed: 35332074
DOI: 10.1101/mcs.a006210 -
Human Genomics Dec 2023The following outlines ethical reasons for widening the Human Genome Organisation's (HUGO) mandate to include ecological genomics. MAIN: The environment influences an... (Review)
Review
BACKGROUND
The following outlines ethical reasons for widening the Human Genome Organisation's (HUGO) mandate to include ecological genomics. MAIN: The environment influences an organism's genome through ambient factors in the biosphere (e.g. climate and UV radiation), as well as the agents it comes into contact with, i.e. the epigenetic and mutagenic effects of inanimate chemicals and pollution, and pathogenic organisms. Emerging scientific consensus is that social determinants of health, environmental conditions and genetic factors work together to influence the risk of many complex illnesses. That paradigm can also explain the environmental and ecological determinants of health as factors that underlie the (un)healthy ecosystems on which communities rely. We suggest that The Ecological Genome Project is an aspirational opportunity to explore connections between the human genome and nature. We propose consolidating a view of Ecogenomics to provide a blueprint to respond to the environmental challenges that societies face. This can only be achieved by interdisciplinary engagement between genomics and the broad field of ecology and related practice of conservation. In this respect, the One Health approach is a model for environmental orientated work. The idea of Ecogenomics-a term that has been used to relate to a scientific field of ecological genomics-becomes the conceptual study of genomes within the social and natural environment.
CONCLUSION
The HUGO Committee on Ethics, Law and Society (CELS) recommends that an interdisciplinary One Health approach should be adopted in genomic sciences to promote ethical environmentalism. This perspective has been reviewed and endorsed by the HUGO CELS and the HUGO Executive Board.
Topics: Humans; Ecosystem; Genome, Human; Genomics; Human Genome Project
PubMed: 38111041
DOI: 10.1186/s40246-023-00560-x -
Nature Communications Aug 2023Long-read sequencing has dramatically increased our understanding of human genome variation. Here, we demonstrate that long-read technology can give new insights into...
Long-read sequencing has dramatically increased our understanding of human genome variation. Here, we demonstrate that long-read technology can give new insights into the genomic architecture of individual cells. Clonally expanded CD8+ T-cells from a human donor were subjected to droplet-based multiple displacement amplification (dMDA) to generate long molecules with reduced bias. PacBio sequencing generated up to 40% genome coverage per single-cell, enabling detection of single nucleotide variants (SNVs), structural variants (SVs), and tandem repeats, also in regions inaccessible by short reads. 28 somatic SNVs were detected, including one case of mitochondrial heteroplasmy. 5473 high-confidence SVs/cell were discovered, a sixteen-fold increase compared to Illumina-based results from clonally related cells. Single-cell de novo assembly generated a genome size of up to 598 Mb and 1762 (12.8%) complete gene models. In summary, our work shows the promise of long-read sequencing toward characterization of the full spectrum of genetic variation in single cells.
Topics: Humans; Genome Size; Genome, Human; Genomics; CD8-Positive T-Lymphocytes; Cell Cycle
PubMed: 37620373
DOI: 10.1038/s41467-023-40898-3