Genetic variants, including single-nucleotide variants (SNVs) and copy number variants (CNVs), in the non-coding regions of the human genome can play an important role in human traits and complex ...diseases. Most of the genome-wide association study (GWAS) signals map to non-coding regions and potentially point to non-coding variants, whereas their functional interpretation is challenging. In this review, we discuss the human non-coding variants and their contributions to human diseases in the following four parts. (i) Functional annotations of non-coding SNPs mapped by GWAS: we discuss recent progress revealing some of the molecular mechanisms for GWAS signals affecting gene function. (ii) Technical progress in interpretation of non-coding variants: we briefly describe some of the technologies for functional annotations of non-coding variants, including the methods for genome-wide mapping of chromatin interaction, computational tools for functional predictions and the new genome editing technologies useful for dissecting potential functional consequences of non-coding variants. (iii) Non-coding CNVs in human diseases: we review our emerging understanding the role of non-coding CNVs in human disease. (iv) Compound inheritance of large genomic deletions and non-coding variants: compound inheritance at a locus consisting of coding variants plus non-coding ones is described.
Human diseases are caused by alleles that encompass the full range of variant types, from single-nucleotide changes to copy-number variants, and these variations span a broad frequency spectrum, from ...the very rare to the common. The picture emerging from analysis of whole-genome sequences, the 1000 Genomes Project pilot studies, and targeted genomic sequencing derived from very large sample sizes reveals an abundance of rare and private variants. One implication of this realization is that recent mutation may have a greater influence on disease susceptibility or protection than is conferred by variations that arose in distant ancestors.
Genome Mosaicism—One Human, Multiple Genomes Lupski, James R.
Science (American Association for the Advancement of Science),
07/2013, Letnik:
341, Številka:
6144
Journal Article
Recenzirano
With recent advances in genome-wide assays, it is becoming increasingly apparent that a human individual is made up of a population of cells, each with its own "personal" genome. Thus, mosaicism is ...perhaps much more common within multicellular organisms than our limited genomic assays have detected thus far, and may represent the rule rather than the exception. To what extent does it play a role in normal development and disease?
Of over 7000 patients referred to a diagnostic laboratory, 28% had diagnoses based on DNA sequencing, 5% of whom had two or more diagnoses. Their phenotypes could be better understood by considering ...whether the implicated genes affect independent biologic processes or organ systems.
Medical genetics focuses on the relationship between observed phenotypes and their underlying genotypes, modes of transmission, and risks of recurrence. Expected patterns of mendelian inheritance are often used to confirm the identification of disease genes, and deviations from mendelian expectations have led to the discovery of more complicated genetic underpinnings of disease (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).
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Multiple (or dual) molecular diagnoses involve more than one clinical diagnosis and more than one genetic locus (Figure 1), each segregating independently.
Diagnostic whole-exome sequencing affords opportunities for providing insights into relationships . . .
Chromosome structural changes with nonrecurrent endpoints associated with genomic disorders offer windows into the mechanism of origin of copy number variation (CNV). A recent report of nonrecurrent ...duplications associated with Pelizaeus-Merzbacher disease identified three distinctive characteristics. First, the majority of events can be seen to be complex, showing discontinuous duplications mixed with deletions, inverted duplications, and triplications. Second, junctions at endpoints show microhomology of 2-5 base pairs (bp). Third, endpoints occur near pre-existing low copy repeats (LCRs). Using these observations and evidence from DNA repair in other organisms, we derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs. We propose that breakage of replication forks in stressed cells that are deficient in homologous recombination induces an aberrant repair process with features of break-induced replication (BIR). Under these circumstances, single-strand 3' tails from broken replication forks will anneal with microhomology on any single-stranded DNA nearby, priming low-processivity polymerization with multiple template switches generating complex rearrangements, and eventual re-establishment of processive replication.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Both the human genetic and genomics sciences will play an increasing role in genomic medicine practice.Disease represents perturbations from biological homeostasis.Biological balance, complementarity, and gene dosage are fundamental principles of biology, human organismal developmental biology, and rare disease traits.Molecular diagnostic and therapeutic intervention demand better understanding of a locus gene dosage effects.
With the recent burst of technological developments in genomics, and the clinical implementation of genome-wide assays, our understanding of the molecular basis of genomic disorders, specifically the ...contribution of structural variation to disease burden, is evolving quickly. Ongoing studies have revealed a ubiquitous role for genome architecture in the formation of structural variants at a given locus, both in DNA recombination-based processes and in replication-based processes. These reports showcase the influence of repeat sequences on genomic stability and structural variant complexity and also highlight the tremendous plasticity and dynamic nature of our genome in evolution, health and disease susceptibility.
During the last quarter of the twentieth century, our knowledge about human genetic variation was limited mainly to the heterochromatin polymorphisms, large enough to be visible in the light ...microscope, and the single nucleotide polymorphisms (SNPs) identified by traditional PCR-based DNA sequencing. In the past five years, the rapid development and expanded use of microarray technologies, including oligonucleotide array comparative genomic hybridization and SNP genotyping arrays, as well as next-generation sequencing with "paired-end" methods, has enabled a whole-genome analysis with essentially unlimited resolution. The discovery of submicroscopic copy-number variations (CNVs) present in our genomes has changed dramatically our perspective on DNA structural variation and disease. It is now thought that CNVs encompass more total nucleotides and arise more frequently than SNPs. CNVs, to a larger extent than SNPs, have been shown to be responsible for human evolution, genetic diversity between individuals, and a rapidly increasing number of traits or susceptibility to traits; such conditions have been referred to as genomic disorders. In addition to well-known sporadic chromosomal microdeletion syndromes and Mendelian diseases, many common complex traits including autism and schizophrenia can result from CNVs. Both recombination- and replication-based mechanisms for CNV formation have been described.
Clinical characterization of a patient phenotype has been the quintessential approach for elucidating a differential diagnosis and a hypothesis to explore a potential clinical diagnosis. This has ...resulted in a language of medicine and a semantic ontology, with both specialty‐ and subspecialty‐specific lexicons, that can be challenging to translate and interpret. There is no ‘Rosetta Stone’ of clinical medicine such as the genetic code that can assist translation and interpretation of the language of genetics. Nevertheless, the information content embodied within a clinical diagnosis can guide management, therapeutic intervention, and potentially prognostic outlook of disease enabling anticipatory guidance for patients and families. Clinical genomics is now established firmly in medical practice. The granularity and informative content of a personal genome is immense. Yet, we are limited in our utility of much of that personal genome information by the lack of functional characterization of the overwhelming majority of computationally annotated genes in the haploid human reference genome sequence. Whereas DNA and the genetic code have provided a ‘Rosetta Stone’ to translate genetic variant information, clinical medicine, and clinical genomics provide the context to understand human biology and disease. A path forward will integrate deep phenotyping, such as available in a clinical synopsis in the Online Mendelian Inheritance in Man (OMIM) entries, with personal genome analyses.
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