Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes

Overview

Journal PLoS Genet

Specialty Genetics

Date 2006 Jan 31

PMID 16444292

Citations 267

Authors

James R Lupski

Pawel Stankiewicz

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Genetics in Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency and Clinical Implications.

Concolino P, Falhammar H J Endocr Soc. 2025; 9(3):bvaf018.

PMID: 39911519 PMC: 11795198. DOI: 10.1210/jendso/bvaf018.

Template switching during DNA replication is a prevalent source of adaptive gene amplification.

Chuong J, Ben Nun N, Suresh I, Matthews J, De T, Avecilla G Elife. 2025; 13.

PMID: 39899365 PMC: 11790251. DOI: 10.7554/eLife.98934.

Template switching during DNA replication is a prevalent source of adaptive gene amplification.

Chuong J, Ben Nun N, Suresh I, Matthews J, De T, Avecilla G bioRxiv. 2024; .

PMID: 39464144 PMC: 11507740. DOI: 10.1101/2024.05.03.589936.

Annelid Comparative Genomics and the Evolution of Massive Lineage-Specific Genome Rearrangement in Bilaterians.

Lewin T, Liao I, Luo Y Mol Biol Evol. 2024; 41(9).

PMID: 39141777 PMC: 11371463. DOI: 10.1093/molbev/msae172.

Potocki-Lupski Syndrome in Ethiopian Child: A Case Report.

Deginet E, Abdissa D, Hailu T Pediatric Health Med Ther. 2024; 15:129-131.

PMID: 38558960 PMC: 10981369. DOI: 10.2147/PHMT.S451161.

References

Bien-Willner G, Stankiewicz P, Lupski J, Northup J, Velagaleti G . Interphase FISH screening for the LCR-mediated common rearrangement of isochromosome 17q in primary myelofibrosis. Am J Hematol. 2005; 79(4):309-13. DOI: 10.1002/ajh.20366. View

Kurotaki N, Shen J, Touyama M, Kondoh T, Visser R, Ozaki T . Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet Med. 2005; 7(7):479-83. DOI: 10.1097/01.gim.0000177419.43309.37. View

Yatsenko S, Treadwell-Deering D, Krull K, Lewis R, Glaze D, Stankiewicz P . Trisomy 17p10-p12 due to mosaic supernumerary marker chromosome: delineation of molecular breakpoints and clinical phenotype, and comparison to other proximal 17p segmental duplications. Am J Med Genet A. 2005; 138A(2):175-80. DOI: 10.1002/ajmg.a.30948. View

Girirajan S, Elsas 2nd L, Devriendt K, Elsea S . RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions. J Med Genet. 2005; 42(11):820-8. PMC: 1735950. DOI: 10.1136/jmg.2005.031211. View

Lee J, Madrid R, Sperle K, Ritterson C, Hobson G, Garbern J . Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann Neurol. 2005; 59(2):398-403. DOI: 10.1002/ana.20732. View

Potocki L, Chen K, Park S, Osterholm D, Withers M, Kimonis V . Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet. 1999; 24(1):84-7. DOI: 10.1038/71743. View

Bailey J, Yavor A, Massa H, Trask B, Eichler E . Segmental duplications: organization and impact within the current human genome project assembly. Genome Res. 2001; 11(6):1005-17. PMC: 311093. DOI: 10.1101/gr.gr-1871r. View

Eichler E . Recent duplication, domain accretion and the dynamic mutation of the human genome. Trends Genet. 2001; 17(11):661-9. DOI: 10.1016/s0168-9525(01)02492-1. View

Osborne L, Li M, Pober B, Chitayat D, Bodurtha J, Mandel A . A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat Genet. 2001; 29(3):321-5. PMC: 2889916. DOI: 10.1038/ng753. View

10.

Stankiewicz P, Lupski J . Genome architecture, rearrangements and genomic disorders. Trends Genet. 2002; 18(2):74-82. DOI: 10.1016/s0168-9525(02)02592-1. View

11.

Stankiewicz P, Parka S, Holder S, Waters C, Palmer R, Berend S . Trisomy 17p10-p12 resulting from a supernumerary marker chromosome derived from chromosome 17: molecular analysis and delineation of the phenotype. Clin Genet. 2002; 60(5):336-44. DOI: 10.1034/j.1399-0004.2001.600503.x. View

12.

Park S, Stankiewicz P, Bi W, Shaw C, Lehoczky J, Dewar K . Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs. Genome Res. 2002; 12(5):729-38. PMC: 186597. DOI: 10.1101/gr.82802. View

13.

Nobile C, Toffolatti L, Rizzi F, Simionati B, Nigro V, Cardazzo B . Analysis of 22 deletion breakpoints in dystrophin intron 49. Hum Genet. 2002; 110(5):418-21. DOI: 10.1007/s00439-002-0721-7. View

14.

Giglio S, Calvari V, Gregato G, Gimelli G, Camanini S, Giorda R . Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation. Am J Hum Genet. 2002; 71(2):276-85. PMC: 379160. DOI: 10.1086/341610. View

15.

Inoue K, Osaka H, Thurston V, Clarke J, Yoneyama A, Rosenbarker L . Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females. Am J Hum Genet. 2002; 71(4):838-53. PMC: 378540. DOI: 10.1086/342728. View

16.

Shaw C, Bi W, Lupski J . Genetic proof of unequal meiotic crossovers in reciprocal deletion and duplication of 17p11.2. Am J Hum Genet. 2002; 71(5):1072-81. PMC: 420000. DOI: 10.1086/344346. View

17.

Lupski J . 2002 Curt Stern Award Address. Genomic disorders recombination-based disease resulting from genomic architecture. Am J Hum Genet. 2003; 72(2):246-52. PMC: 379220. DOI: 10.1086/346217. View

18.

Slager R, Newton T, Vlangos C, Finucane B, Elsea S . Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet. 2003; 33(4):466-8. DOI: 10.1038/ng1126. View

19.

Gimelli G, Pujana M, Patricelli M, Russo S, Giardino D, Larizza L . Genomic inversions of human chromosome 15q11-q13 in mothers of Angelman syndrome patients with class II (BP2/3) deletions. Hum Mol Genet. 2003; 12(8):849-58. DOI: 10.1093/hmg/ddg101. View

20.

Stankiewicz P, Shaw C, Dapper J, Wakui K, Shaffer L, Withers M . Genome architecture catalyzes nonrecurrent chromosomal rearrangements. Am J Hum Genet. 2003; 72(5):1101-16. PMC: 1180264. DOI: 10.1086/374385. View