Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A

Lupski, James R.; Wise, Carol A.; Kuwano, Atsutoshi; Liu, Pentao; Parke, Julie T.; Glaze, Daniel G.; Ledbetter, David H.; Greenberg, Frank; Patel, Pragna I.

doi:10.1038/ng0492-29

Cited by 255 publications

(144 citation statements)

References 16 publications

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“…Similar to resistance, the cost reduction induced by the ID does not affect ace‐1 and most probably results from the partial restoration of gene‐dosage balance in coamplified loci (as the ~200 kb amplicon encompasses 10 other genes; Assogba et al., 2016). The increased gene dosage of the coamplified loci could indeed (i) alter biochemical equilibria between duplicated and nonduplicated interacting genes (Birchler & Veitia, 2007; Papp, Pal, & Hurst, 2003), (ii) overshoot optimal protein levels, thereby altering their function (Conrad & Antonarakis, 2007; Lupski et al., 1992), or (iii) increase the energy required for their production (Kalisky, Dekel, & Alon, 2007), all costs that may combine. Postduplication genomic rearrangements reducing the cost of gene‐dosage disturbance (such as the deletion studied here) are thus expected to be selected.…”

Section: Discussionmentioning

confidence: 99%

Adaptive deletion in resistance gene duplications in the malaria vector Anopheles gambiae

Assogba

Alout

Koffi

et al. 2018

Evolutionary Applications

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While gene copy‐number variations play major roles in long‐term evolution, their early dynamics remains largely unknown. However, examples of their role in short‐term adaptation are accumulating: identical repetitions of a locus (homogeneous duplications) can provide a quantitative advantage, while the association of differing alleles (heterogeneous duplications) allows carrying two functions simultaneously. Such duplications often result from rearrangements of sometimes relatively large chromosome fragments, and even when adaptive, they can be associated with deleterious side effects that should, however, be reduced by subsequent evolution. Here, we took advantage of the unique model provided by the malaria mosquito Anopheles gambiae s.l. to investigate the early evolution of several duplications, heterogeneous and homogeneous, segregating in natural populations from West Africa. These duplications encompass ~200 kb and 11 genes, including the adaptive insecticide resistance ace‐1 locus. Through the survey of several populations from three countries over 3–4 years, we showed that an internal deletion of all coamplified genes except ace‐1 is currently spreading in West Africa and introgressing from An. gambiae s.s. to An. coluzzii. Both observations provide evidences of its selection, most likely due to reducing the gene‐dosage disturbances caused by the excessive copies of the nonadaptive genes. Our study thus provides a unique example of the early adaptive trajectory of duplications and underlines the role of the environmental conditions (insecticide treatment practices and species ecology). It also emphasizes the striking diversity of adaptive responses in these mosquitoes and reveals a worrisome process of resistance/cost trade‐off evolution that could impact the control of malaria vectors in Africa.

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Section: Discussionmentioning

confidence: 99%

Adaptive deletion in resistance gene duplications in the malaria vector Anopheles gambiae

Assogba

Alout

Koffi

et al. 2018

Evolutionary Applications

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“…CNV can affect phenotypes and cause rare Mendelian disease traits such as Charcot-Marie-Tooth disease [136] and hereditary neuropathy [137]. It has also been shown to be associated with multiple complex diseases.…”

Section: Inheritance Of Copy Number Variationsmentioning

confidence: 99%

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

Baxter

Jordan²

2012

Rev Diabet Stud

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■ AbstractBy the year 2000, a draft of the human genome sequence was completed. Millions of single-nucleotide polymorphisms (SNPs) had been deposited into public databases, and high throughput technologies were under development for SNP genotyping. At that time, it was predicted that large case control association studies would provide far better resolution and power than genome-wide linkage studies. Type 1 diabetes was one of the first phenotypes to be examined by genome-wide association studies (GWAS), and to date over 50 genomic regions have been associated with the disease.In general, the great majority of these loci individually contribute a relatively small degree of risk, and most loci lie outside of coding sequences. The identification of molecular mechanisms from these genomic data therefore remains a significant challenge. Here, we summarize genetic candidate, linkage, and association studies of type 1 diabetes and discuss a potential strategy to identify mechanisms of disease from genomic data.

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“…1 -4 It was shown in 1992 that the region duplicated in Charcot -Marie -Tooth (CMT) was flanked by highly similar (498%) sequences. 5 Unequal crossing over between these duplicons leads both to this duplication and the reciprocal deletion, which was later shown to cause hereditary neuropathy with liability to pressure palsies (HNPP). 6 Duplicons, also known as low copy repeats (LCRs), have since been implicated in many other disorders.…”

Section: Introductionmentioning

confidence: 99%

Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications

et al. 2005

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Duplicons, that is, DNA sequences with minimum length 10 kb and a high sequence similarity, are known to cause unequal homologous recombination, leading to deletions and the reciprocal duplications. In this study, we designed a Multiplex Amplifiable Probe Hybridisation (MAPH) assay containing 63 exon-specific single-copy sequences from within a selection of the 169 regions flanked by duplicons that were identified, at a first pass, in 2001. Subsequently, we determined the frequency of chromosomal rearrangements among patients with developmental delay (DD) and/or congenital malformations (CM). In addition, we tried to identify new regions involved in DD/CM using the same assay. In 105 patients, six imbalances (5.8%) were detected and verified. Three of these were located in microdeletion-related regions, two alterations were polymorphic duplications and the effect of the last alteration is currently unknown. The same study population was tested for rearrangements in regions with no known duplicons nearby, using a set of probes derived from 58 function-selected genes. The latter screening revealed two alterations. As expected, the alteration frequency per unit of DNA is much higher in regions flanked by duplicons (fraction of the genome tested: 5.2%) compared to regions without known duplicons nearby (fraction of the genome tested: 24.5 -90.2%). We were able to detect three novel rearrangements, including the previously undescribed reciprocal duplication of the Williams Beuren critical region, a subduplicon alteration within this region and a duplication on chromosome band 16p13.11. Our results support the hypothesis that regions flanked by duplicons are enriched for copy number variations.

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Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A

Cited by 255 publications

References 16 publications

Adaptive deletion in resistance gene duplications in the malaria vector Anopheles gambiae

Adaptive deletion in resistance gene duplications in the malaria vector Anopheles gambiae

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications

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