Clan Genomics and the Complex Architecture of Human Disease

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Oct 4

PMID 21962505

Citations 216

Authors

James R Lupski

John W Belmont

Eric Boerwinkle

Richard A Gibbs

Affiliations

Soon will be listed here.

Abstract

Human diseases are caused by alleles that encompass the full range of variant types, from single-nucleotide changes to copy-number variants, and these variations span a broad frequency spectrum, from the very rare to the common. The picture emerging from analysis of whole-genome sequences, the 1000 Genomes Project pilot studies, and targeted genomic sequencing derived from very large sample sizes reveals an abundance of rare and private variants. One implication of this realization is that recent mutation may have a greater influence on disease susceptibility or protection than is conferred by variations that arose in distant ancestors.

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References

Boerwinkle E, Utermann G . Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism. Am J Hum Genet. 1988; 42(1):104-12. PMC: 1715322. View

Cohn J, Friedman K, Noone P, Knowles M, Silverman L, Jowell P . Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med. 1998; 339(10):653-8. DOI: 10.1056/NEJM199809033391002. View

HALDANE J . The rate of spontaneous mutation of a human gene. 1935. J Genet. 2005; 83(3):235-44. DOI: 10.1007/BF02717892. View

Wang J, Wang W, Li R, Li Y, Tian G, Goodman L . The diploid genome sequence of an Asian individual. Nature. 2008; 456(7218):60-5. PMC: 2716080. DOI: 10.1038/nature07484. View

Dipple K, McCabe E . Phenotypes of patients with "simple" Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet. 2000; 66(6):1729-35. PMC: 1378056. DOI: 10.1086/302938. View

Poller W, Meisen C, Olek K . DNA polymorphisms of the alpha 1-antitrypsin gene region in patients with chronic obstructive pulmonary disease. Eur J Clin Invest. 1990; 20(1):1-7. DOI: 10.1111/j.1365-2362.1990.tb01769.x. View

Athma P, Rappaport R, Swift M . Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet. 1996; 92(2):130-4. DOI: 10.1016/s0165-4608(96)00328-7. View

Le Marechal C, Masson E, Chen J, Morel F, Ruszniewski P, Levy P . Hereditary pancreatitis caused by triplication of the trypsinogen locus. Nat Genet. 2006; 38(12):1372-4. DOI: 10.1038/ng1904. View

. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008; 455(7210):237-41. PMC: 3912847. DOI: 10.1038/nature07239. View

10.

Sankaran V, Menne T, Xu J, Akie T, Lettre G, Van Handel B . Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008; 322(5909):1839-42. DOI: 10.1126/science.1165409. View

11.

Vernimmen D, Marques-Kranc F, Sharpe J, Sloane-Stanley J, Wood W, Wallace H . Chromosome looping at the human alpha-globin locus is mediated via the major upstream regulatory element (HS -40). Blood. 2009; 114(19):4253-60. DOI: 10.1182/blood-2009-03-213439. View

12.

Divac A, Nikolic A, Mitic-Milikic M, Nagorni-Obradovic L, Petrovic-Stanojevic N, Dopudja-Pantic V . High frequency of the R75Q CFTR variation in patients with chronic obstructive pulmonary disease. J Cyst Fibros. 2004; 3(3):189-91. DOI: 10.1016/j.jcf.2004.05.049. View

13.

Wang X, Moylan B, Leopold D, Kim J, Rubenstein R, Togias A . Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population. JAMA. 2000; 284(14):1814-9. DOI: 10.1001/jama.284.14.1814. View

14.

Fellermann K, Stange D, Schaeffeler E, Schmalzl H, Wehkamp J, Bevins C . A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. Am J Hum Genet. 2006; 79(3):439-48. PMC: 1559531. DOI: 10.1086/505915. View

15.

Vissers L, de Ligt J, Gilissen C, Janssen I, Steehouwer M, De Vries P . A de novo paradigm for mental retardation. Nat Genet. 2010; 42(12):1109-12. DOI: 10.1038/ng.712. View

16.

Wheeler D, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A . The complete genome of an individual by massively parallel DNA sequencing. Nature. 2008; 452(7189):872-6. DOI: 10.1038/nature06884. View

17.

Lupski J, Slaugenhaupt S, Pentao L, Guzzetta V, Trask B, Saucedo-Cardenas O . DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell. 1991; 66(2):219-32. DOI: 10.1016/0092-8674(91)90613-4. View

18.

Singleton A, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J . alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003; 302(5646):841. DOI: 10.1126/science.1090278. View

19.

Conrad D, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y . Origins and functional impact of copy number variation in the human genome. Nature. 2009; 464(7289):704-12. PMC: 3330748. DOI: 10.1038/nature08516. View

20.

Hersh C, Dahl M, Ly N, Berkey C, Nordestgaard B, Silverman E . Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a meta-analysis. Thorax. 2004; 59(10):843-9. PMC: 1746834. DOI: 10.1136/thx.2004.022541. View