Genomic Disorders: The Genomic Basis of Disease

Genome Dyn. ; doi: / The genomic basis of disease, mechanisms and assays for genomic disorders. Stankiewicz P(1), Lupski.
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Taken together, these data suggest that both allelic and non-allelic recombination possibly may take place at the same hotspots throughout the genome, wherein programmed DSBs occur and initiate recombination in meiosis. Resolution of Holliday structures formed between non-allelic LCR copies could result in rearrangements or gene conversion events. The latter could potentially be responsible for increased polymorphic variation at crossover preference regions or may further homogenize LCRs Additionally, meiotic recombination is known to be elevated near telomeres, possibly suggesting a role for the frequent involvement of this region in rearrangements 71 , In mammalian cells, interstitial telomeric sequences also present in humans 73 have been shown to increase rearrangements by up to fold The positional preference for strand exchange seen in NAHR may suggest the presence of additional architectural features at the hotspots that make the region more prone to recombination.

AT-rich palindromes are located near several of the hotspots, suggesting that a predisposition to DSBs may possibly influence the location of strand exchange 18 , 34 , 38 , Elevated gene conversion events in and adjacent to the palindromes were also documented 76 , Palindromes and other sequence features, such as triplet repeats, are able to form hairpin structures, potentially exposing DNA to an increased frequency of spontaneous DSBs and subsequent rearrangements, as seen in mammalian cells and patients with either Fragile X or Jacobsen syndromes Fig.

These sequences have not previously been implicated in human recombination events, although it is possible that their presence also increases the likelihood for DSBs, which then must be resolved by patch repair and heteroduplex resolution, potentially within the hotspot 13 , These same architectural features may be associated with rearrangements resulting from NHEJ, which are thought to be initiated by DSBs.

Few NHEJ recombinant junctions have been studied at the nucleotide sequence level, thus further investigations of the sequences near scattered breakpoints are warranted. Rather than a cis -acting nucleotide sequence stimulating recombination, another possibility for the positional preference of crossovers associated with rearrangements is a constraint on access to the DNA because of the chromatin structure of the region. An open chromatin structure may expose DNA to DSBs or other damage, that is then repaired in an aberrant fashion, yielding rearrangements.

The group of genomic disorders has evolved to encompass not only deletions, duplications, inversions and translocations, but also somatic rearrangements associated with malignancies.


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The aforementioned investigations have shown that the majority of genomic rearrangements are not random events, but in fact represent potential mechanical errors inherent in the maintenance of a genome complicated by complex architecture. Perhaps the same genome flexibility that has enabled us to evolve relatively rapidly also makes us as a species more susceptible to rearrangements associated with disease. We appreciate the critical reviews of Drs W. Mechanisms of genomic rearrangements. The substrates and products of recombination are shown. The LCRs are depicted as blue rectangles, due to high homology, but are different shades of blue, signifying the few cis -morphisms, or paralogous sequence variants, that distinguish them.

LCRs A and B, directly oriented shown by arrows misalign, and subsequent homologous recombination results in a deletion with a single recombinant LCR, shown as a two-tone blue rectangle. Restriction enzyme consensus sequences cut sites are depicted as vertical lines on either side of the recombinant LCR, with deletion of the consensus sequence between the two substrate LCRs. Digestion using this enzyme results in the isolation of a recombination-specific junction fragment, shown below.

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NHEJ right , utilizes two non-homologous sequences [red rectangle A and green oval B ] as substrates for recombination. The two sequences are joined via NHEJ, with deletion of the intervening fragment.

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Additional bases NN…NN are added at the deletion junction. 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. Sign In or Create an Account. Close mobile search navigation Article navigation. Implications of human genome architecture for rearrangement-based disorders: View large Download slide.

Email alerts New issue alert. Receive exclusive offers and updates from Oxford Academic. More on this topic Copy number gain at Xp Diverse mutational mechanisms cause pathogenic subtelomeric rearrangements. Replicative mechanisms of CNV formation preferentially occur as intrachromosomal events: Molecular genetics of Bloom's syndrome. Related articles in Web of Science Google Scholar.

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Percy's Pathology of Laboratory Rodents and Rabbits, Third Edition PDF Pathology of Laboratory Rodents and Rabbits has develop into a typical textual content for either veterinary pathologists and veterinarians in laboratory animal medication. Stankiewicz by Anthony 4. Published by admin View all posts by admin. Download e-book for iPad: A summary of the characterized proximal 17p evolutionary, constitutional i. Schematic representation of the genome architecture susceptible to rearrangements in the proximal chromosome 17p.

The low copy repeats are shown in rectangles color-coded or similar symbols for given repeats , along with the distribution of the rearrangement breakpoints. Upper Diverse alterations constitutional, evolutionary, somatic thus far documented for this region. They are color coded for matching the involved segment on 17p. Lower Schematic representation of the isodicentric chromosome 17q, formally designated idic 17 p The presence of the specific dosage-sensitive gene within the 17p Point mutations leading to gain-of-function are predicted to cause PTLS but such patients have not yet been identified.

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NAHR is a frequent mechanism underlying disease-associated genomic rearrangements. Experimental observations have implicated the existence of recombination hotspots for the occurrence of the crossovers within the LCRs 33 , 49 , Two LCRs involved in a particular NAHR can be interchromosomal, intrachromosomal, or intrachromatidal, and they can be either directly or inversely oriented to each other. The rearrangement will generate different products accordingly, i. Experimentally, deletions occur twice as often as duplications during meiosis in male germ cells The high frequency of interspersed LCRs in the human genome predicts many regions of genomic instability that could potentially undergo NAHR-mediated rearrangements and be associated with genomic disorders.

Such an approach was used to screen patient cohorts with defined phenotypes, such as mental retardation and congenital anomalies, enabling the detection of five microdeletions at 17q Therefore, knowledge of the NAHR mechanism has played a pivotal role in uncovering new human syndromes with profound consequences for clinical genetics. Following detection of DSBs, NHEJ rejoins the broken DNA ends without the requirement for homology; this process requires the preparation of damaged ends using base removal and insertions of new bases, without ensuring sequence restoration around the break Microhomologies between the switched template and the original fork are used to prime replication.

DNA deletion or duplication can be generated depending on whether the template switching occurred to a new replication fork located upstream or downstream. Inversions can also be produced depending on the direction of the fork progression and if the leading or the lagging strands are used on the switched template.

In this model, the replication fork stalls, by virtue of the presence of a nick on the template strand resulting in a collapsed fork as the replication fork proceeds through the nick. The presence of complex rearrangements in several genomic disorders has been increasingly detected due to the greater resolution of the advanced genome technologies.

Remarkably, Zhang et al. The presence of LCRs in a specific genomic region increases the probability of occurrences of new rearrangements, such as duplications, deletions, gene conversions, and inversions therein or in the flanking segments This observation is supported by a recent comparative study in primates where it was shown that LCRs do not arise randomly, but are likely to arise within or adjacent to another LCR already present 24 , 72 , Therefore, the unique regions flanking LCRs will eventually undergo rearrangements that can either create new LCRs or add new complexities to the previous one; additionally, ectopic homologous recombination and gene conversion can produce homogenization, maintaining the sequence conservation within the LCRs This finding was supported by the results of Lee et al.

Later a statistically significant association between LCRs and the distal breakpoints of duplications involving the MECP2 gene in male patients with neurodevelopmental delay was shown In vertebrates, the visual pigments are the products of five families of Opsin genes that probably have arisen by multiple gene duplication events at least million years ago Mya reviewed in ref. The ability to absorb three different wavelengths short, medium, and long in the retina is not found among many mammals and constitutes a distinctive feature of the primates.

Such evolutionary acquisition enabled primates to see three primary colors blue, green, and red , changing their vision from dichromatic to trichromatic.

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Interestingly, in humans, differences regarding the sensitivity to distinguish red—green colors are very common. In our cohort of patients with MECP2 duplication, the stronges breakpoint bias was observed in patients with complex rearrangements triplications embedded within duplications 56 in which both duplication and triplication breakpoints map within a low copy repeat pair termed LCRs K Fig.

In addition, inversion events occurred at least 10 independent times along the eutherian evolution Schematic representation of the MECP2 telomeric region. Top Blue boxes represent the pathogenic rearrangements documented in the literature thus far: Blue arrows show alignment of the join points of the patients carrying complex rearrangements triplications embedded in duplications.

Bottom Human structural variation yellow rectangles includes CNVs and inversions; evolutionary genomic rearrangements orange rectangles include the duplication of the Opsin gene and further acquisition of the trichromatic color vision during the primate evolution in addition to a recurrent inversion that has been occurring multiple times in eutherians. In his seminal work, Ohno 83 proposed that gene duplications coupled with rapid sequence diversification may play a fundamental role in evolution. Increasing evidence from experimental studies in diverse organisms has confirmed his prediction.

In primates, LCRs are implicated in lineage-specific gene creation and potentially in speciation as well. A comparative study between human and chimpanzee genomes estimated that 2. In contrast, single-base pair differences account for 1. The salivary amylase gene AMY1 , which encodes a protein that catalyzes the first step in digestion of dietary starch and glycogen, constitutes an interesting example.

It has approximately three times more copies in humans compared to chimpanzees and copy-number differences correlate positively with the higher levels of salivary amylase protein The copy number of AMY1 shows evidence of positive selection in populations with high-starch consumption, suggesting that its copy-number increase in humans was selectively favored due to the concomitant increase of starch consumption in agricultural societies Also, the human-specific amplification of the aquaporin-7 gene AQP7 , coupled to positive selection, provides another example of adaptative traits that emerged after lineage-specific gene duplication; the aquaporin-7 protein is involved in water, glycerol, and urea membrane transport and may have contributed to enabling the human capacity for endurance running 89 , Remarkably, they showed that the neuronal-expressed DUF domain, which presents the highest number of copies in humans compared to primates, is apparently under positive selection It is estimated that perhaps as many as 34 human genes encode a DUF domain; these genes map to several genomic sites on chromosome 1 with the majority localized to the 1q In fact, rearrangements involving 1q Deletions have also been recently associated with schizophrenia 5 , The association of microdeletion with microcephaly and duplication with macrocephaly can be potentially explained by the copy-number alteration of the human-specific paralog of the gene HYDIN.

In mice, mutations causing premature termination of the Hydin gene product were reported to cause hydrocephalus Along with gene duplication, exon shuffling is also implicated in the generation of novel genes and proteins and, once more, the LCRs might play a pivotal role underlying that event. In , Walter Gilbert launched the concept of exon shuffling when he proposed that recombination between introns could rearrange exons, creating new transcription units, and consequently new proteins could be formed In the primate lineage, including humans, there is evidence of exon shuffling generating novel genes, e.

Some additional evidence for exon shuffling observed in human and mouse subjects is listed in Table 1. The original COX10 distal CMT1A-REP is highly expressed in multiple tissues ; its protein product farnesylates the heme group incorporated into cytochrome oxidase that is important for mitochondrial function.

Duplication of selected LCRs during molecular evolution of the primates updated from ref. The figure is not to scale. This figure was adapted, with permission, from ref. TBC1D3 itself is derived from a segmental duplication that underwent multiple gene duplications during primate evolution Interestingly, TBC1D3 underwent mutations with respect to its closest homolog, USP6NL and acquired the features of an adaptor molecule involved in the macropinocytic process However, the underlying mechanisms are not fully understood.

Two mechanisms have been proposed, illegitimate recombination and retrotransposed exon insertion ; nevertheless, many exon rearrangements are not readily explained by either mechanism.


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Recently, our group 58 reported complex rearrangements, including triplications, detected at the join points of duplications in patients with PTLS and in patients with PMP22 duplication and deletions. The sequencing of the join points of the deletion involving just one exon of the PMP22 gene revealed a complex pattern including a small insertion in an inverted orientation. Some of the changes are large enough to be visualized by light microscopy whereas others require special techniques, e.

Therefore, CNVs may frequently occur de novo and can be associated with sporadic birth defects. This contention is supported by a recent study on neonates with various birth defects in which a high frequency of de novo pathological CNVs was identified In patients with a clinical indication of suspected chromosomal abnormalities, the rate of de novo CNV detection was as high as Atavism is a concept proposed by Darwin in to term the reappearance of ancestral characteristics in individuals of a species in further generations.

Evidence for atavistic traits has been found in horses and whales Hypertrichosis is a rare condition characterized by excessive generalized or localized hairiness Recently, Sun et al. They identified nonrecurrent microdeletions in three CGHT families and also found one de novo microduplication in a sporadic patient, as causative of the trait. The candidate gene has not yet been identified but they postulated a long-range position effect potentially due to the presence of the SOX9 gene nearby. In conclusion, the development of the concept of genomic disorders, and the definition of the mechanisms for formation e.

Such studies revealed a great deal of new information about human genome structure and evolution and delineated the role of the genomic architecture, including repetitive e. Adaptative traits can be driven by structural variation as exemplified by the amylase AMY1 copy-number variation associated with the change of human eating habits. Moreover, increasing data regarding human CNVs and how they can convey neuropsychiatric phenotypes suggest that CNVs may play a major role in human cognition and other complex traits.


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