Genetic heterogeneity

Genetic heterogeneity occurs through the production of single or similar phenotypes through different genetic mechanisms. There are two types of genetic heterogeneity: allelic heterogeneity, which occurs when a similar phenotype is produced by different alleles within the same gene; and locus heterogeneity, which occurs when a similar phenotype is produced by mutations at different loci.[1]

Role in medical disorders

Marked genetic heterogeneity is correlated to multiple levels of causation in many common human diseases including cystic fibrosis, Alzheimer's disease, autism spectrum disorders, inherited predisposition to breast cancer,and non-syndromic hearing loss. These levels of causation are complex and occur through: (1) rare, individual mutations that when combined contribute to the development of common diseases; (2) the accumulation of many different rare, individual mutations within the same gene that contribute to the development of the same common disease within different individuals; (3) the accumulation of many different rare, individual mutations within the same gene that contribute to the development of different phenotypic variations of the same common disease within different individuals; and (4) the development of the same common disease in different individuals through different mutations.[2]
Increased understanding of the role of genetic heterogeneity and the mechanisms through which it produces common disease phenotypes will facilitate the development of effective prevention and treatment methods for these diseases.[3]

Cystic Fibrosis

Cystic fibrosis is an inherited autosomal recessive genetic disorder that occurs through a mutation in a single gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR). Research has identified over 2,000 cystic fibrosis associated mutations in the CFTR gene at varying degrees of frequency within the disease carrying population.[4] These mutations also produce varying degrees of disease phenotypes, and may also work in combinations to produce additive phenotypic effects.[5]

Alzheimer's Disease

Alzheimer's disease is a complicated neurodegenerative disorder with multiple phenotypic subtypes, including clinical and preclinical, that result from different genetic origins.[6] Current research on the amyloid cascade hypothesis has identified rare mutations in three genes that encode the amyloid precursor protein (APP), presenilin 1 (PS-1), and presenilin 2 (PS-2) that cause the autosomal dominant, early-onset form of familial Alzheimer's disease.[7] Research has also discovered the association of a fourth allele, apolipoprotein E4 (ApoE4), in the development of late-onset and sporadic forms of the disease, although the pathology of its role is still largely unknown.[8]

Autism spectrum disorders

Autism spectrum disorders are among the most highly heritable psychiatric disorders and display high levels of phenotypic variability.[9] Disorders on the Autism spectrum have high levels of genetic heterogeneity and result from multiple genetic pathways including single gene mutation disorders (such as Fragile X Syndrome), regional and submicroscopic variations in the number of gene copies (either heritable or de novo), rare and common genetic variants, and chromosomal aberrations.[10]

Inherited predisposition to breast cancer

Mutations in ten different genes have been found to contribute to a heritable increased risk of breast cancer and other cancer syndromes. These genes, when functional, contribute to a pathway that serves to preserve genomic integrity.[11] Mutations in BRCA1 and BRCA2 result in a high risk of both breast and ovarian cancers.[12] Mutations in p53 and PTEN increase risks of breast cancer associated with rare cancer syndromes. Mutations in CHECK2, ATM, NBS1, RAD50, BRIP1, and PALB2 can double the risk of breast cancer development.[13] Biallelic mutations, in which both copies of a particular gene are mutated, in BRCA2, BRIP1, and PALB2 also cause Fanconi anemia, a recessive syndrome that leads to progressive bone marrow failure.[14]

Non-syndromic hearing loss

Non-syndromic hearing loss can occur through multiple pathways including autosomal dominant, autosomal recessive, X-linked, and Y-linked inheritance patterns.[15] 69 genes and 145 loci have been discovered to be involved in the genetic heterogeneity of non-syndromic hearing loss, and the phenotype of the disorder is largely associated with its pattern of inheritance.[16]

Studying Genetic Heterogeneity

Initial research on genetic heterogeneity was conducted using genetic linkage analyses, which map genetic loci of related individuals to identify genomic differences.[17] Current research now relies largely on genome-wide association studies which examine the association of single-nucleotide polymorphisms (SNPs) to a particular disease in a population.[18]

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References
  1. Scriver, Charles (January 27, 2006). "Allelic and Locus Heterogeneity". Encyclopedia of Life Sciences. John Wiley & Sons. doi:10.1038/npg.els.0005481. ISBN 978-0470016176.
  2. McClellan, Jon; King, Mary-Claire (April 16, 2010). "Genetic Heterogeneity in Human Disease". Cell. 141 (2): 210–7. doi:10.1016/j.cell.2010.03.032. PMID 20403315.
  3. Manolio, Teri; Collins, Francis; Cox, Nancy; Goldstein, David (October 8, 2009). "Finding the missing heritability of complex diseases". Nature. 461 (7265): 747–753. doi:10.1038/nature08494. PMC 2831613. PMID 19812666.
  4. Bobadilla, Joseph; Macek, Milan; Fine, Jason; Farrell, Phillip (May 3, 2002). "Cystic fibrosis: A worldwide analysis of CFTR mutations—correlation with incidence data and application to screening". Human Mutation. 19 (6): 575–606. doi:10.1002/humu.10041. PMID 12007216.
  5. Drumm, Mitchell; Ziady, Assem; Davis, Pamela (May 21, 2014). "Genetic Variation and Clinical Heterogeneity in Cystic Fibrosis". Annu Rev Pathol. 7: 267–282. doi:10.1146/annurev-pathol-011811-120900. PMC 4029837. PMID 22017581.
  6. Varol, Erdem; Sotiras, Aristeidis; Davatzikos, Christos (February 23, 2016). "HYDRA: Revealing heterogeneity of imaging and genetic patterns through a multiple max-margin discriminative analysis framework". NeuroImage. 145 (2017): 346–364. doi:10.1016/j.neuroimage.2016.02.041. PMC 5408358. PMID 26923371.
  7. Lambert, Jean-Charles; Amouyel, Phillipe (August 2007). "Genetic heterogeneity of Alzheimer's disease: Complexity and advances". Psychoneuroendocrinology. 32 (1): S62-70. doi:10.1016/j.psyneuen.2007.05.015. PMID 17659844.
  8. Ringman, JM; Goate, A; Masters, CL; Caims, NJ (November 2014). "Genetic heterogeneity in Alzheimer disease and implications for treatment strategies". Curr Neurol Neurosci Rep. 14 (11): 499. doi:10.1007/s11910-014-0499-8. PMC 4162987. PMID 25217249.
  9. Croft Swanwick, Catherine; Larsen, Eric; Banerjee-Basu, Sharmila (August 1, 2011). Genetic Heterogeneity of Autism Spectrum Disorders. InTech. p. 65. ISBN 978-953-307-495-5.
  10. Geschwind, Daniel (October 31, 2008). "Autism: Many Genes, Common Pathways?". Cell. 135 (3): 391–5. doi:10.1016/j.cell.2008.10.016. PMC 2756410. PMID 18984147.
  11. Walsh, Tom; King, Mary-Claire (February 2007). "Ten Genes for Inherited Breast Cancer". Cell. 11 (2): 103–5. doi:10.1016/j.ccr.2007.01.010. PMID 17292821.
  12. Walsh, Tom; King, Mary-Claire (February 2007). "Ten Genes for Inherited Breast Cancer". Cell. 11 (2): 103–5. doi:10.1016/j.ccr.2007.01.010. PMID 17292821.
  13. Walsh, Tom; King, Mary-Claire (February 2007). "Ten Genes for Inherited Breast Cancer". Cell. 11 (2): 103–5. doi:10.1016/j.ccr.2007.01.010. PMID 17292821.
  14. Walsh, Tom; King, Mary-Claire (February 2007). "Ten Genes for Inherited Breast Cancer". Cell. 11 (2): 103–5. doi:10.1016/j.ccr.2007.01.010. PMID 17292821.
  15. Zhong, Liu Xue; Kun, Shan; Jing, Qing; Jing, Cheng; Denise, Yan (June 2013). "Non-Syndromic Hearing Loss and High-Throughput Strategies to Decipher Its Genetic Heterogeneity". Journal of Otology. 8 (1): 6. doi:10.1016/S1672-2930(13)50002-X.
  16. Zhong, Liu Xue; Kun, Shan; Jing, Qing; Jing, Cheng; Denise, Yan (June 2013). "Non-Syndromic Hearing Loss and High-Throughput Strategies to Decipher Its Genetic Heterogeneity". Journal of Otology. 8 (1): 6. doi:10.1016/S1672-2930(13)50002-X.
  17. Teare, Dawn; Barrett, Jennifer (September 15, 2005). "Genetic linkage studies". The Lancet. 366 (9490): 1036–44. doi:10.1016/S0140-6736(05)67382-5. PMID 16168786.
  18. Geschwind, Daniel (October 31, 2008). "Autism: Many Genes, Common Pathways?". Cell. 135 (3): 391–5. doi:10.1016/j.cell.2008.10.016. PMC 2756410. PMID 18984147.
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