Locus heterogeneity explained

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] 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. Likewise, it should not be confused with phenotypic heterogeneity, in which different phenotypes arise among organisms with identical genotypes and environmental conditions.^[2] Locus heterogeneity and allelic heterogeneity are the two components of genetic heterogeneity.^[3]

Locus heterogeneity may have major implications for a number of human diseases. For instance, it has been associated with retinitis pigmentosa,^[4] hypertrophic cardiomyopathy,^[5] osteogenesis imperfecta,^[6] familial hypercholesterolemia,^[7] and hearing loss.^[8] Heterogenous loci involved in formation of the same phenotype often contribute to similar biological pathways. 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.

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. Existing techniques have been modified and new techniques have been developed to overcome these challenges.^{[10] [11]}

Retinitis pigmentosa

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]

See also

• Allelic heterogeneity
• List of cutaneous conditions caused by mutations in keratins

Notes and References

1. Keith BP, Robertson DL, Hentges KE . Locus heterogeneity disease genes encode proteins with high interconnectivity in the human protein interaction network . Frontiers in Genetics . 5 . 434 . 2014-12-09 . 25538735 . 4260505 . 10.3389/fgene.2014.00434 . free .
2. Ackermann M . A functional perspective on phenotypic heterogeneity in microorganisms . Nature Reviews. Microbiology . 13 . 8 . 497–508 . August 2015 . 26145732 . 10.1038/nrmicro3491 . 29846214 .
3. Web site: NCI Dictionary of Genetics Terms. 2012-07-20. National Cancer Institute. en. 2019-11-27.
4. Daiger SP, Sullivan LS, Bowne SJ . Genes and mutations causing retinitis pigmentosa . Clinical Genetics . 84 . 2 . 132–41 . August 2013 . 23701314 . 3856531 . 10.1111/cge.12203 .
5. Solomon SD, Jarcho JA, McKenna W, Geisterfer-Lowrance A, Germain R, Salerni R, Seidman JG, Seidman CE . 6 . Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease . The Journal of Clinical Investigation . 86 . 3 . 993–9 . September 1990 . 1975599 . 296820 . 10.1172/JCI114802 .
6. Van Dijk FS, Sillence DO . Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment . American Journal of Medical Genetics. Part A . 164A . 6 . 1470–81 . June 2014 . 24715559 . 4314691 . 10.1002/ajmg.a.36545 .
7. Goldstein JL, Dana SE, Brunschede GY, Brown MS . Genetic heterogeneity in familial hypercholesterolemia: evidence for two different mutations affecting functions of low-density lipoprotein receptor . Proceedings of the National Academy of Sciences of the United States of America . 72 . 3 . 1092–6 . March 1975 . 236556 . 432472 . 10.1073/pnas.72.3.1092 . 1975PNAS...72.1092G . free .
8. Keats . Bronya J. B. . Berlin . Charles I. . 1999-01-01 . Genomics and Hearing Impairment . Genome Research . en . 9 . 1 . 7–16 . 10.1101/gr.9.1.7 . 1088-9051 . 9927480. free .
9. Rehman AU, Santos-Cortez RL, Drummond MC, Shahzad M, Lee K, Morell RJ, Ansar M, Jan A, Wang X, Aziz A, Riazuddin S, Smith JD, Wang GT, Ahmed ZM, Gul K, Shearer AE, Smith RJ, Shendure J, Bamshad MJ, Nickerson DA, Hinnant J, Khan SN, Fisher RA, Ahmad W, Friderici KH, Riazuddin S, Friedman TB, Wilch ES, Leal SM . 6 . Challenges and solutions for gene identification in the presence of familial locus heterogeneity . European Journal of Human Genetics . 23 . 9 . 1207–15 . September 2015 . 25491636 . 4538203 . 10.1038/ejhg.2014.266 .
10. Wang D, Huang J . Detecting linkage disequilibrium in the presence of locus heterogeneity . Annals of Human Genetics . 70 . Pt 3 . 397–409 . May 2006 . 16674561 . 10.1111/j.1529-8817.2005.00229.x . 25856694 .
11. Pal DK, Greenberg DA . Evaluating genetic heterogeneity in complex disorders . english . Human Heredity . 53 . 4 . 216–26 . 2002 . 12435885 . 10.1159/000066195 . 46285173 .
12. Hartong DT, Berson EL, Dryja TP . Retinitis pigmentosa . English . Lancet . 368 . 9549 . 1795–809 . November 2006 . 17113430 . 10.1016/S0140-6736(06)69740-7 . 24950783 .
13. Web site: RetNet: Summaries. sph.uth.edu. 2019-11-27.
14. Ferrari S, Di Iorio E, Barbaro V, Ponzin D, Sorrentino FS, Parmeggiani F . Retinitis pigmentosa: genes and disease mechanisms . Current Genomics . 12 . 4 . 238–49 . June 2011 . 22131869 . 3131731 . 10.2174/138920211795860107 .