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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 -
Cell Mar 2019In the wake of the Human Genome Project (HGP), strong expectations were set for the timeline and impact of genomics on medicine-an anticipated transformation in the... (Review)
Review
In the wake of the Human Genome Project (HGP), strong expectations were set for the timeline and impact of genomics on medicine-an anticipated transformation in the diagnosis, treatment, and prevention of disease. In this Perspective, we take stock of the nascent field of genomic medicine. In what areas, if any, is genomics delivering on this promise, or is the path to success clear? Where are we falling short, and why? What have been the unanticipated developments? Overall, we argue that the optimism surrounding the transformational potential of genomics on medicine remains justified, albeit with a considerably different form and timescale than originally projected. We also argue that the field needs to pivot back to basics, as understanding the entirety of the genotype-to-phenotype equation is a likely prerequisite for delivering on the full potential of the human genome to advance the human condition.
Topics: Genetic Testing; Genome, Human; Genomics; Human Genome Project; Humans; Precision Medicine
PubMed: 30901547
DOI: 10.1016/j.cell.2019.02.003 -
Nature Reviews. Drug Discovery Mar 2017Most of the human genome encodes RNAs that do not code for proteins. These non-coding RNAs (ncRNAs) may affect normal gene expression and disease progression, making... (Review)
Review
Most of the human genome encodes RNAs that do not code for proteins. These non-coding RNAs (ncRNAs) may affect normal gene expression and disease progression, making them a new class of targets for drug discovery. Because their mechanisms of action are often novel, developing drugs to target ncRNAs will involve equally novel challenges. However, many potential problems may already have been solved during the development of technologies to target mRNA. Here, we discuss the growing field of ncRNA - including microRNA, intronic RNA, repetitive RNA and long non-coding RNA - and assess the potential and challenges in their therapeutic exploitation.
Topics: Animals; Biomarkers, Tumor; Drug Delivery Systems; Drug Discovery; Genome, Human; Humans; RNA, Long Noncoding; RNA, Untranslated
PubMed: 27444227
DOI: 10.1038/nrd.2016.117 -
Nature Medicine Feb 2022Two decades ago, the sequence of the first human genome was published. Since then, advances in genome technologies have resulted in whole-genome sequencing and... (Review)
Review
Two decades ago, the sequence of the first human genome was published. Since then, advances in genome technologies have resulted in whole-genome sequencing and microarray-based genotyping of millions of human genomes. However, genetic and genomic studies are predominantly based on populations of European ancestry. As a result, the potential benefits of genomic research-including better understanding of disease etiology, early detection and diagnosis, rational drug design and improved clinical care-may elude the many underrepresented populations. Here, we describe factors that have contributed to the imbalance in representation of different populations and, leveraging our experiences in setting up genomic studies in diverse global populations, we propose a roadmap to enhancing inclusion and ensuring equal health benefits of genomics advances. Our Perspective highlights the importance of sincere, concerted global efforts toward genomic equity to ensure the benefits of genomic medicine are accessible to all.
Topics: Genome, Human; Genomics; Humans; Whole Genome Sequencing
PubMed: 35145307
DOI: 10.1038/s41591-021-01672-4 -
Nature Apr 2022The human reference genome is the most widely used resource in human genetics and is due for a major update. Its current structure is a linear composite of merged... (Review)
Review
The human reference genome is the most widely used resource in human genetics and is due for a major update. Its current structure is a linear composite of merged haplotypes from more than 20 people, with a single individual comprising most of the sequence. It contains biases and errors within a framework that does not represent global human genomic variation. A high-quality reference with global representation of common variants, including single-nucleotide variants, structural variants and functional elements, is needed. The Human Pangenome Reference Consortium aims to create a more sophisticated and complete human reference genome with a graph-based, telomere-to-telomere representation of global genomic diversity. Here we leverage innovations in technology, study design and global partnerships with the goal of constructing the highest-possible quality human pangenome reference. Our goal is to improve data representation and streamline analyses to enable routine assembly of complete diploid genomes. With attention to ethical frameworks, the human pangenome reference will contain a more accurate and diverse representation of global genomic variation, improve gene-disease association studies across populations, expand the scope of genomics research to the most repetitive and polymorphic regions of the genome, and serve as the ultimate genetic resource for future biomedical research and precision medicine.
Topics: Genome, Human; Genomics; Haplotypes; High-Throughput Nucleotide Sequencing; Humans; Sequence Analysis, DNA
PubMed: 35444317
DOI: 10.1038/s41586-022-04601-8 -
Nature Biotechnology Apr 2018We report the sequencing and assembly of a reference genome for the human GM12878 Utah/Ceph cell line using the MinION (Oxford Nanopore Technologies) nanopore sequencer....
We report the sequencing and assembly of a reference genome for the human GM12878 Utah/Ceph cell line using the MinION (Oxford Nanopore Technologies) nanopore sequencer. 91.2 Gb of sequence data, representing ∼30× theoretical coverage, were produced. Reference-based alignment enabled detection of large structural variants and epigenetic modifications. De novo assembly of nanopore reads alone yielded a contiguous assembly (NG50 ∼3 Mb). We developed a protocol to generate ultra-long reads (N50 > 100 kb, read lengths up to 882 kb). Incorporating an additional 5× coverage of these ultra-long reads more than doubled the assembly contiguity (NG50 ∼6.4 Mb). The final assembled genome was 2,867 million bases in size, covering 85.8% of the reference. Assembly accuracy, after incorporating complementary short-read sequencing data, exceeded 99.8%. Ultra-long reads enabled assembly and phasing of the 4-Mb major histocompatibility complex (MHC) locus in its entirety, measurement of telomere repeat length, and closure of gaps in the reference human genome assembly GRCh38.
Topics: Genome, Human; Genomics; High-Throughput Nucleotide Sequencing; Humans; Nanopores; Sequence Analysis, DNA
PubMed: 29431738
DOI: 10.1038/nbt.4060 -
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 -
Medecine Sciences : M/S 2022
Topics: Genome, Human; Human Genome Project; Humans; Sequence Analysis, DNA
PubMed: 35766840
DOI: 10.1051/medsci/2022086 -
International Journal of Molecular... Jun 2022About 19,000-20,000 protein-coding genes in the human genome have been identified [...].
About 19,000-20,000 protein-coding genes in the human genome have been identified [...].
Topics: Genetics, Medical; Genome, Human; Humans
PubMed: 35743065
DOI: 10.3390/ijms23126625 -
Trends in Genetics : TIG Nov 2018As transcription of the human genome is quite pervasive, it is possible that many novel functions of the noncoding genome have yet to be identified. Often the noncoding... (Review)
Review
As transcription of the human genome is quite pervasive, it is possible that many novel functions of the noncoding genome have yet to be identified. Often the noncoding genome's functions are carried out by their RNA transcripts, which may rely on their structures and/or extensive interactions with other molecules. Recent technology developments are transforming the fields of RNA biology from studying one RNA at a time to transcriptome-wide mapping of structures and interactions. Here, we highlight the recent advances in transcriptome-wide RNA interaction analysis. These technologies revealed surprising versatility of RNA to participate in diverse molecular systems. For example, tens of thousands of RNA-RNA interactions have been revealed in cultured cells as well as in mouse brain, including interactions between transposon-produced transcripts and mRNAs. In addition, most transcription start sites in the human genome are associated with noncoding RNA transcribed from other genomic loci. These recent discoveries expanded our understanding of RNAs' roles in chromatin organization, gene regulation, and intracellular signaling.
Topics: Gene Expression Profiling; Gene Expression Regulation; Genome, Human; Humans; RNA, Untranslated; Transcription, Genetic; Transcriptome
PubMed: 30177410
DOI: 10.1016/j.tig.2018.08.001