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Locus heterogeneity occurs when mutations at multiple genomic loci are capable of producing the same phenotype (ie. a single trait, pattern of traits, or disorder), and each individual mutation is sufficient to cause the specific phenotype independently.[1][2] Locus heterogeneity should not be confused with allelic heterogeneity, in which a single phenotype can be produced by multiple mutations, all of which are at the same locus on a chromosome.[2] Likewise, it should not be confused with phenotypic heterogeneity, in which different phenotypes arise among organisms with identical genotypes and environmental conditions.[3] Locus heterogeneity and allelic heterogeneity are the two components of genetic heterogeneity.[4]
Locus heterogeneity may have major implications for a number of human diseases. For instance, it has been associated with retinitis pigmentosa[5], hypertrophic cardiomyopathy[6], osteogenesis imperfecta[7], and familial hypercholesterolemia.[8] Heterogenous loci involved in formation of the same phenotype often contribute to similar biological pathways.[2] The role and degree of locus heterogeneity is an important consideration in understanding disease phenotypes and in the development of therapeutic treatment for these diseases.[2]
The detection of causal genes for diseases impacted by locus heterogeneity is difficult with genetic analysis methods such as linkage analysis and genome sequencing.[9] These methods rely on comparison of affected family members, but when different family members have different disease-causing genes, such genes may not be accurately identified.[9] Existing techniques have been modified and new techniques have been developed to overcome these challenges.[9][10][11]
Retinitis Pigmentosa[edit]
Retinitis pigmentosa is a condition that causes damage to the light-sensitive cells of the retina.[12] There have been over 60 genes identified whose mutations independently cause retinitis pigmentosa, and these can be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern.[13] Examples of such genes include the rhodopsin gene (RHO), the gene encoding for retinitis pigmentosa GTPase regulator (RGPR), and the gene encoding retinitis pigmentosa 2 protein (RP2).[14]
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- ^ "Locus Heterogeneity - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2019-10-09.
- ^ a b c d Keith, Benjamin P.; Robertson, David L.; Hentges, Kathryn E. (2014-12-09). "Locus heterogeneity disease genes encode proteins with high interconnectivity in the human protein interaction network". Frontiers in Genetics. 5. doi:10.3389/fgene.2014.00434. ISSN 1664-8021. PMC 4260505. PMID 25538735.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Ackermann, Martin (2015-07-06). "A functional perspective on phenotypic heterogeneity in microorganisms". Nature Reviews Microbiology. 13 (8): 497–508. doi:10.1038/nrmicro3491. ISSN 1740-1526.
- ^ "Definition of genetic heterogeneity - NCI Dictionary of Cancer Terms". National Cancer Institute. 2012-07-20. Retrieved 2019-11-07.
- ^ Daiger, S P; Sullivan, L S; Bowne, S J (2013-06-19). "Genes and mutations causing retinitis pigmentosa". Clinical Genetics. 84 (2): 132–141. doi:10.1111/cge.12203. ISSN 0009-9163.
- ^ Solomon, S. D.; Jarcho, J. A.; McKenna, W.; Geisterfer-Lowrance, A.; Germain, R.; Salerni, R.; Seidman, J. G.; Seidman, C. E. (1990-09-01). "Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease". The Journal of Clinical Investigation. 86 (3): 993–999. doi:10.1172/JCI114802. ISSN 0021-9738. PMID 1975599.
- ^ Dijk, F. S. Van; Sillence, D. O. (2014). "Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment". American Journal of Medical Genetics Part A. 164 (6): 1470–1481. doi:10.1002/ajmg.a.36545. ISSN 1552-4833. PMC 4314691. PMID 24715559.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Goldstein, J. L.; Dana, S. E.; Brunschede, G. Y.; Brown, M. S. (1975-03-01). "Genetic heterogeneity in familial hypercholesterolemia: evidence for two different mutations affecting functions of low-density lipoprotein receptor". Proceedings of the National Academy of Sciences. 72 (3): 1092–1096. doi:10.1073/pnas.72.3.1092. ISSN 0027-8424. PMID 236556.
- ^ a b c Rehman, Atteeq U; Santos-Cortez, Regie Lyn P; Drummond, Meghan C; Shahzad, Mohsin; Lee, Kwanghyuk; Morell, Robert J; Ansar, Muhammad; Jan, Abid; Wang, Xin; Aziz, Abdul; Riazuddin, Saima (September 2015). "Challenges and solutions for gene identification in the presence of familial locus heterogeneity". European Journal of Human Genetics. 23 (9): 1207–1215. doi:10.1038/ejhg.2014.266. ISSN 1018-4813. PMC 4538203. PMID 25491636.
- ^ Wang, D.; Huang, J. (2008-06-28). "Detecting linkage disequilibrium in the presence of locus heterogeneity". Annals of Human Genetics. 70 (3): 397–409. doi:10.1111/j.1529-8817.2005.00229.x. ISSN 0003-4800.
- ^ Pal, Deb K.; Greenberg, David A. (2002). "Evaluating Genetic Heterogeneity in Complex Disorders". Human Heredity. 53 (4): 216–226. doi:10.1159/000066195. ISSN 0001-5652.
- ^ Hartong, Dyonne T; Berson, Eliot L; Dryja, Thaddeus P (2006-11-18). "Retinitis pigmentosa". The Lancet. 368 (9549): 1795–1809. doi:10.1016/S0140-6736(06)69740-7.
- ^ "RetNet: Summaries". sph.uth.edu. Retrieved 2019-10-05.
- ^ Ferrari, Stefano; Di Iorio, Enzo; Barbaro, Vanessa; Ponzin, Diego; Sorrentino, Francesco S; Parmeggiani, Francesco (June 2011). "Retinitis Pigmentosa: Genes and Disease Mechanisms". Current Genomics. 12 (4): 238–249. doi:10.2174/138920211795860107. ISSN 1389-2029. PMC 3131731. PMID 22131869.