Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: Molecular mechanism and phenotypic manifestations

Inoue, Ken; Osaka, Hitoshi; Imaizumi, Kiyoshi; Nezu, Atsuo; Takanashi, Jun‐ichi; Arii, Junko; Murayama, Keiko; Ono, Jiro; Kikawa, Yoshiharu; Mito, Takashi; Shaffer, Lisa G.; Lupski, James R.

doi:10.1002/1531-8249(199905)45:5<624::aid-ana11>3.0.co;2-1

Cited by 125 publications

(126 citation statements)

References 34 publications

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…As duplication events are known to incur a fitness cost [50,53], the fitness function of duplicated genes most probably resembles an inverted parabola, such that it contains a clearly defined maximum [28,53]. Numerous observations that gene duplications that increase protein dosage can be pathogenic [61,72,73,74,75] further support the model of optimum copy number for each gene.…”

Section: Discussionmentioning

confidence: 99%

Selection in the evolution of gene duplications

et al. 2002

View full text Add to dashboard Cite

BackgroundGene duplications have a major role in the evolution of new biological functions. Theoretical studies often assume that a duplication per se is selectively neutral and that, following a duplication, one of the gene copies is freed from purifying (stabilizing) selection, which creates the potential for evolution of a new function.ResultsIn search of systematic evidence of accelerated evolution after duplication, we used data from 26 bacterial, six archaeal, and seven eukaryotic genomes to compare the mode and strength of selection acting on recently duplicated genes (paralogs) and on similarly diverged, unduplicated orthologous genes in different species. We find that the ratio of nonsynonymous to synonymous substitutions (Kn/Ks) in most paralogous pairs is <<1 and that paralogs typically evolve at similar rates, without significant asymmetry, indicating that both paralogs produced by a duplication are subject to purifying selection. This selection is, however, substantially weaker than the purifying selection affecting unduplicated orthologs that have diverged to the same extent as the analyzed paralogs. Most of the recently duplicated genes appear to be involved in various forms of environmental response; in particular, many of them encode membrane and secreted proteins.ConclusionsThe results of this analysis indicate that recently duplicated paralogs evolve faster than orthologs with the same level of divergence and similar functions, but apparently do not experience a phase of neutral evolution. We hypothesize that gene duplications that persist in an evolving lineage are beneficial from the time of their origin, due primarily to a protein dosage effect in response to variable environmental conditions; duplications are likely to give rise to new functions at a later phase of their evolution once a higher level of divergence is reached.

show abstract

Section: Discussionmentioning

confidence: 99%

Selection in the evolution of gene duplications

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Nevertheless, it remains to be determined to what extent NHEJ is a mechanism for genome rearrangement. NHEJ may potentially have a more prominent role in nonrecurrent rearrangements [55–57]. …”

Section: Nhej—an Alternative Pathwaymentioning

confidence: 99%

Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes

Lupski¹,

Stankiewicz²

2005

PLoS Genet

520

429

View full text Add to dashboard Cite

Rearrangements of our genome can be responsible for inherited as well as sporadic traits. The analyses of chromosome breakpoints in the proximal short arm of Chromosome 17 (17p) reveal nonallelic homologous recombination (NAHR) as a major mechanism for recurrent rearrangements whereas nonhomologous end-joining (NHEJ) can be responsible for many of the nonrecurrent rearrangements. Genome architectural features consisting of low-copy repeats (LCRs), or segmental duplications, can stimulate and mediate NAHR, and there are hotspots for the crossovers within the LCRs. Rearrangements introduce variation into our genome for selection to act upon and as such serve an evolutionary function analogous to base pair changes. Genomic rearrangements may cause Mendelian diseases, produce complex traits such as behaviors, or represent benign polymorphic changes. The mechanisms by which rearrangements convey phenotypes are diverse and include gene dosage, gene interruption, generation of a fusion gene, position effects, unmasking of recessive coding region mutations (single nucleotide polymorphisms, SNPs, in coding DNA) or other functional SNPs, and perhaps by effects on transvection.

show abstract

“…PLP1 gene duplications are typically arranged in a tandem head-to-tail orientation at Xq22 and are thought to form by coupled homologous and nonhomologous recombination (7,8,11 ). Each duplication event includes the entire PLP1 locus, appears unique, and varies in size from 100 kb to 4.6 Mb (7,8,11 ).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…Each duplication event includes the entire PLP1 locus, appears unique, and varies in size from 100 kb to 4.6 Mb (7,8,11 ). Proximal duplication breakpoints vary widely between families, whereas distal breakpoints tend to cluster around low-copy repeats (7,8,11 ). Atypical PLP1 duplications, termed submicroscopic transposons (3 ), in which the extra copy of PLP1 is many megabases away from the Xq22 locus, have been found at Xp22.1, Xp11.4, and Xq26 (3,12 ).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Multiplex Ligation-Dependent Probe Amplification for Rapid Detection of Proteolipid Protein 1 Gene Duplications and Deletions in Affected Males and Carrier Females with Pelizaeus–Merzbacher Disease

Warshawsky

Chernova²,

Hübner

et al. 2006

Clinical Chemistry

View full text Add to dashboard Cite

Background: Pelizaeus-Merzbacher disease is a rare X-linked neurodegenerative disorder caused by sequence variations in the proteolipid protein 1 gene (PLP1). PLP1 gene duplications account for ϳ50%-75% of cases and point variations for ϳ15%-20% of cases; deletions and insertions occur infrequently. We used multiplex ligation-dependent probe amplification (MLPA) to detect PLP1 gene alterations, especially gene duplications and deletions. Methods: We performed MLPA on 102 samples from individuals with diverse PLP1 gene abnormalities and from controls, including 50 samples previously characterized for the PLP1 gene by quantitative PCR but which were anonymized for prior results and sex. Results: All males with PLP1 gene duplications (n ‫؍‬ 13), 1 male with a triplication, 2 males with whole gene deletions, and all controls (n ‫؍‬ 72) were unambiguously assigned to their correct genotype. Of 4 female carriers tested by MLPA and quantitative PCR, 3 were duplication carriers by both methods, and 1 was a triplication

show abstract

Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: Molecular mechanism and phenotypic manifestations

Cited by 125 publications

References 34 publications

Selection in the evolution of gene duplications

Selection in the evolution of gene duplications

Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes

Multiplex Ligation-Dependent Probe Amplification for Rapid Detection of Proteolipid Protein 1 Gene Duplications and Deletions in Affected Males and Carrier Females with Pelizaeus–Merzbacher Disease

Contact Info

Product

Resources

About