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We have a dedicated site for Germany. Over the last years this notion changed significantly as scientists discovered that a large part of this DNA contains various genomic elements that have important roles in cell physiology. In addition, all these elements were implicated to contribute in the pathogenesis or progression of various human diseases. For every genomic element, the physiologic role in the organism, its role in evolution and any possible involvement in human diseases will be discussed.

Bits of Mystery DNA, Far From ‘Junk,’ Play Crucial Role

Additionally, interaction between these elements in normal or pathologic condition will be discussed. Since a large amount of new knowledge is generated daily in regards to these genomic elements, this book will attempt to combine all the information in a single publication that can serve as a reference for future studies.

The second part of the book will deal with transposons, retrotransposons and DNA transposons. Finally the third part of the book will discuss DNA elements that include DNA repeats, conserved non-coding sequences, distal genomic elements, introns, pseudogenes, CpG islands and telomeres.

A Functional Classification of Genomic Elements Informed by the Principles of Evolution

For miRNAs and CNVs a separate chapter will be dedicated to their role in human diseases since an extensive amount of information exists about these two elements. JavaScript is currently disabled, this site works much better if you enable JavaScript in your browser. Biomedical Sciences Human Genetics.

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These replication timing QTLs rtQTL can be affected in a cis manner by local genetic variants and also be involved in the long-range regulation of gene expression Non-synonymous variants and their effects on protein functions can be predicted by computational methods based on quantifying constraint on the affected residue from conserved protein sequences. However, such an approach cannot be applied to non-coding variants. Therefore, alternative types of computational methods utilizing various genomic and epigenomic annotations have been developed, such as the tool named Genome-Wide Annotation of VAriants GWAVA that can support prioritization of non-coding variants The regulatory mutations from the Human Gene Mutation database HGMD 32 were used as the disease variant set for training data, and common SNPs of the Genomes Project 33 were selected as the control variant set for GWAVA to identify annotations useful for discriminating functional non-coding variants from benign variants The ability of CADD to measure deleteriousness of human genetic variants has been achieved by training a support vector machine to contrast the annotations of fixed derived alleles in the human genomes i.

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Notably, CADD can also be applied to short insertions and deletions indels in the non-coding regions. The above computational methods could provide functional predictions for non-coding variants; however, further functional especially in vivo assays are important experimental steps to investigate the molecular mechanism of non-coding variants in human disease. A classic approach to study functional consequences of human disease-associated SNV has been to engineer variation into mouse models.


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An analogous approach applicable to large CNVs associated with genomic disorders, such as the Smith—Magenis deletion syndrome and Potocki—Lupski duplication syndrome 35 , has been of proven utility for elucidating functional evidence for the role of dosage-sensitive genes and mirror traits 35— However, evolutionary conservation is still the prerequisite for functional assays of non-coding variants using genome editing technologies in model organisms. When the non-coding variants of interest are not conserved in mouse, it has also been feasible to directly obtain the human genetic variant of interest using the stem cell technologies, such as patient-derived iPSCs, for further in vitro functional assays 41 , CNVs, whose functional effects were elucidated by studies of genomic disorders, play an important role in human Mendelian traits and complex diseases 43— These large pathogenic CNVs frequently affect multiple genes or truncate a specific functional gene, which can consequently lead to clinical conditions via the molecular mechanisms of gene dosage effect haploinsufficiency and triplosensitivity , gene interruption, gene fusion and other effects on gene function including non-coding variant effects Evidence documented during the past few years supports that CNVs in the non-coding regions can also be pathogenic by a position effect mechanism Functional CNVs both deletions and duplications have been frequently identified in upstream non-coding regions of disease-associated genes Fig.

In some instances, the CNVs in the non-coding regions downstream to a candidate gene can also be pathogenic by perturbing gene regulation; for example, the kb duplications downstream to the PLP1 gene is associated with spastic paraplegia type 2 with axonal peripheral neuropathy A Functional CNVs in the gene-flanking regions are associated with human diseases not to scale. Deletion del is shown in green bar, duplication dup in red and inversion in blue.

Intriguingly, deletions and duplications in either upstream or downstream regions of a specific gene can result in different clinical phenotypes as shown at the SOX9 locus Fig.

1000 Genomes Project: Defining Genetic Variation in People

In contrast, upstream duplications of SOX9 with variable sizes have been observed to cause female-to-male sex reversal This suggests the existence of very long-range cis -regulatory elements in the flanking regions of SOX9 Interestingly, genomic duplications of such cis -regulatory elements of SOX9 can also lead to brachydactyly-anonychia in Cooks syndrome The variable phenotypes manifested by overlapping CNVs upstream to the SOX9 gene may reflect the different cis -regulatory elements located in the non-overlapping regions Alternatively, the inconsistent phenotypes may also suggest potential position effects and misexpression of these genes outside of the CNV regions.

Similarly, RNA sequencing of lymphoblast lines from carriers of 16p A pathogenicity model of SV-rearranged structure of neighboring topologically associated domains TADs, the regulatory units within which enhancers and promoters can interact and their associated enhancer and boundary elements was proposed It was observed that 16q The smallest overlapping region of these 16q Utilizing genome-wide CNV detection technologies, genetic researchers have identified many large genomic CNVs as the causative genetic factors of human diseases Accordingly, more and more pathogenic loci have been incorporated into molecular diagnostic panels 64 , However, in some rare instances, these pathogenic CNVs can also be found in human populations at a very low frequency or transmitted from unaffected parents.

These variable phenotypes suggested the possible existence of some modifying genetic factors in addition to the large genomic CNVs. Frequent 1q This deletion in the TAR patients can be inherited from unaffected parents, suggesting an autosomal recessive inheritance Non-coding CNVs can also be the second allele at a locus consistent with a recessive model.


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In a recent study on Burn—McKeown syndrome, large 18q23 deletions were identified as the first recessive alleles in 4 out of 11 patients Interestingly, a low-frequency 34 bp deletion of the TXNL4A gene promoter regions was shared by all the above four cases with large 18q23 deletions. Dual luciferase assays showed that this promoter deletion can dramatically reduce TXNL4A expression In the above two loci, RBM8A and TXNL4A , the non-coding pathogenic variations are suggested to be recessive 67 , 68 , consistent with compound inheritance of two autosomal recessive alleles.

However, more complexity has been recently revealed in the TBX6 locus of human chromosome 16p Deletion CNVs of 16p This 16p How did the same genomic deletion cause different clinical conditions? In addition, the inter-individual phenotypic variability has also been observed between the deletion carriers in the same family Therefore, the popular mechanism of haploinsufficiency cannot completely explain the clinical disorders associated with 16p Instead, based on the genetic model of autosomal recessive inheritance, some groups tried to find the additional functional mutations in the coding genes within the 16p Intriguingly, a common haplotype of TBX6 has been identified in the deletion carriers with congenital scoliosis In vitro functional assays suggest that two non-coding SNPs, which define the above scoliosis risk haplotype, can moderately downregulate the gene expression level of TBX6 , representing a hypomorphic allele of TBX6 Thus, variability of expression in a deletion CNV can result from non-coding variants on the remaining allele.

Common functional SNVs may be more likely to contribute to variability of clinical expression of microdeletion syndromes than rare variant alleles in coding sequences Accordingly, the genome technologies of WES 81—83 and genome-wide microarrays 64 , 65 have been widely used for gene discovery and for molecular diagnostics of pathogenic SNVs and CNVs for human diseases, especially congenital disorders.

However, recent progress in genetic and genomic studies has identified functional genetic variants in non-coding regions of the human genome. Therefore, whole genome sequencing WGS could be informative and promising for the future clinical practice 84 , 85 not only because of its ability to characterize non-coding functional variants but also because it enables robust identification of SV, including CNV and copy number neutral SV such as inversions and translocations.

This research trend also demands the technical and methodological innovations to assist in functional interpretation and data mining from millions of non-coding variants that can be found in a single human genome Conflict of Interest statement. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

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Non-coding genetic variants in human disease | Human Molecular Genetics | Oxford Academic

Volume Article Contents. Technical Progress in Interpretation of Non-coding Variants. Non-coding genetic variants in human disease Feng Zhang. Oxford Academic. Google Scholar. James R. Cite Citation. Permissions Icon Permissions. Abstract 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.

Figure 1.

Genomic Elements in Health, Disease and Evolution

Open in new tab Download slide. Search ADS. Gender differences relating to metabolic syndrome and proinflammation in Finnish subjects with elevated blood pressure. Chromatin marks identify critical cell types for fine mapping complex trait variants. Restless legs syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon.


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  4. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay.

    Distinct patterns of genetic variations in potential functional elements in long noncoding RNAs. Changes in insulin sensitivity and insulin release in relation to glycemia and glucose tolerance in 6, Finnish men. A common functional regulatory variant at a type 2 diabetes locus upregulates ARAP1 expression in the pancreatic beta cell. Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

    Structural variation-associated expression changes are paralleled by chromatin architecture modifications. Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Identification of common genetic variants controlling transcript isoform variation in human whole blood.

    A general framework for estimating the relative pathogenicity of human genetic variants. Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models. Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup 17 p