Genetic heterogeneity

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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]

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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. Research has identified over 2,000 cystic fibrosis associated mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator 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]

Related Research Articles

<span class="mw-page-title-main">Genetic disorder</span> Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

<span class="mw-page-title-main">Penetrance</span> Proportion of individuals that express the trait associated with a gene variant

Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation that exhibit clinical symptoms among all individuals with such mutation. For example: If a mutation in the gene responsible for a particular autosomal dominant disorder has 75% penetrance, then 75% of those with the mutation will go on to develop the disease, showing its phenotype, whereas 25% will not. 

<span class="mw-page-title-main">Germline mutation</span> Inherited genetic variation

A germline mutation, or germinal mutation, is any detectable variation within germ cells. Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote. After this fertilization event occurs, germ cells divide rapidly to produce all of the cells in the body, causing this mutation to be present in every somatic and germline cell in the offspring; this is also known as a constitutional mutation. Germline mutation is distinct from somatic mutation.

Forward genetics is a molecular genetics approach of determining the genetic basis responsible for a phenotype. Forward genetics provides an unbiased approach because it relies heavily on identifying the genes or genetic factors that cause a particular phenotype or trait of interest.

<span class="mw-page-title-main">Pleiotropy</span> Influence of a single gene on multiple phenotypic traits

Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. Mutation in a pleiotropic gene may have an effect on several traits simultaneously, due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function.

<span class="mw-page-title-main">Birt–Hogg–Dubé syndrome</span> Rare autosomal dominant cancer syndrome

Birt–Hogg–Dubé syndrome (BHD), also Hornstein–Birt–Hogg–Dubé syndrome, Hornstein–Knickenberg syndrome, and fibrofolliculomas with trichodiscomas and acrochordons is a human, adult onset, autosomal dominant genetic disorder caused by the FLCN gene. It can cause susceptibility to kidney cancer, renal and pulmonary cysts, and noncancerous tumors of the hair follicles, called fibrofolliculomas. The symptoms seen in each family are unique, and can include any combination of the three symptoms. Fibrofolliculomas are the most common manifestation, found on the face and upper trunk in over 80% of people with BHD over the age of 40. Pulmonary cysts are equally common (84%) and 24% of people with BHD eventually experience a collapsed lung. Kidney tumors, both cancerous and benign, occur in 14–34% of people with BHD; the associated kidney cancers are often rare hybrid tumors.

In genetics, expressivity is the degree to which a phenotype is expressed by individuals having a particular genotype. Alternatively, it may refer to the expression of a particular gene by individuals having a certain phenotype. Expressivity is related to the intensity of a given phenotype; it differs from penetrance, which refers to the proportion of individuals with a particular genotype that share the same phenotype.

<span class="mw-page-title-main">Haploinsufficiency</span> Concept in genetics

Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type phenotype. Haploinsufficiency may arise from a de novo or inherited loss-of-function mutation in the variant allele, such that it yields little or no gene product. Although the other, standard allele still produces the standard amount of product, the total product is insufficient to produce the standard phenotype. This heterozygous genotype may result in a non- or sub-standard, deleterious, and (or) disease phenotype. Haploinsufficiency is the standard explanation for dominant deleterious alleles.

<span class="mw-page-title-main">Heritability of autism</span>

The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation; if the heritability of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis. Although the genetics of autism are complex, autism spectrum disorder (ASD) is explained more by multigene effects than by rare mutations with large effects.

<span class="mw-page-title-main">Papillorenal syndrome</span> Medical condition

Papillorenal syndrome is an autosomal dominant genetic disorder marked by underdevelopment (hypoplasia) of the kidney and colobomas of the optic nerve.

Collagen IV is a type of collagen found primarily in the basal lamina. The collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, collagen IV lacks the regular glycine in every third residue necessary for the tight, collagen helix. This makes the overall arrangement more sloppy with kinks. These two features cause the collagen to form in a sheet, the form of the basal lamina. Collagen IV is the more common usage, as opposed to the older terminology of "type-IV collagen". Collagen IV exists in all metazoan phyla, to whom they served as an evolutionary stepping stone to multicellularity.

The medical genetics of Jews have been studied to identify and prevent some rare genetic diseases that, while still rare, are more common than average among people of Jewish descent. There are several autosomal recessive genetic disorders that are more common than average in ethnically Jewish populations, particularly Ashkenazi Jews, because of relatively recent population bottlenecks and because of consanguineous marriage. These two phenomena reduce genetic diversity and raise the chance that two parents will carry a mutation in the same gene and pass on both mutations to a child.

Cognitive genomics is the sub-field of genomics pertaining to cognitive function in which the genes and non-coding sequences of an organism's genome related to the health and activity of the brain are studied. By applying comparative genomics, the genomes of multiple species are compared in order to identify genetic and phenotypical differences between species. Observed phenotypical characteristics related to the neurological function include behavior, personality, neuroanatomy, and neuropathology. The theory behind cognitive genomics is based on elements of genetics, evolutionary biology, molecular biology, cognitive psychology, behavioral psychology, and neurophysiology.

Locus heterogeneity occurs when mutations at multiple genomic loci are capable of producing the same phenotype, and each individual mutation is sufficient to cause the specific phenotype independently. 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. Locus heterogeneity and allelic heterogeneity are the two components of genetic heterogeneity.

<span class="mw-page-title-main">Hereditary cancer syndrome</span> Inherited genetic condition that predisposes a person to cancer

A hereditary cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancer and may also cause early onset of these cancers. Hereditary cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.

Genetic studies on Arabs refers to the analyses of the genetics of ethnic Arab people in the Middle East and North Africa. Arabs are genetically diverse as a result of their intermarriage and mixing with indigenous people of the pre-Islamic Middle East and North Africa following the Arab and Islamic expansion. Genetic ancestry components related to the Arabian Peninsula display an increasing frequency pattern from west to east over North Africa. A similar frequency pattern exist across northeastern Africa with decreasing genetic affinities to groups of the Arabian Peninsula along the Nile river valley across Sudan and the more they go south. This genetic cline of admixture is dated to the time of Arab expansion and immigration to North Africa (Maghreb) and northeast Africa.

A human disease modifier gene is a modifier gene that alters expression of a human gene at another locus that in turn causes a genetic disease. Whereas medical genetics has tended to distinguish between monogenic traits, governed by simple, Mendelian inheritance, and quantitative traits, with cumulative, multifactorial causes, increasing evidence suggests that human diseases exist on a continuous spectrum between the two.

WNT4 deficiency is a rare genetic disorder that affects females and it results in the underdevelopment and sometimes absence of the uterus and vagina. WNT4 deficiency is caused by mutations of the WNT4 gene. Abnormally high androgen levels are found in the blood and can initiate and promote the development of male sex characteristics. This is seen as male pattern of hair growth on the chest and face. Those with this genetic defect develop breasts but do not have their period. Mayer–Rokitansky–Küster–Hauser syndrome is a related but distinct syndrome. Some women who have an initial diagnosis of MRKH have later been found to have WNT4 deficiency. Most women with MRKH syndrome do not have genetic mutations of the WNT4 gene. The failure to begin the menstrual cycle may be the initial clinical sign of WNT4 deficiency. WNT4 deficiency can cause significant psychological challenges and counseling is recommended.

Johanna Rommens is a Canadian geneticist who was on the research team which identified and cloned the CFTR gene, which when mutated, is responsible for causing cystic fibrosis (CF). She later discovered the gene responsible for Shwachman-Diamond syndrome, a rare genetic disorder that causes pancreatic and hematologic problems. She is a Senior Scientist Emeritus at SickKids Research Institute and a professor in the Department of Molecular Genetics at the University of Toronto.

Familial sleep traits are heritable variations in sleep patterns, resulting in abnormal sleep-wake times and/or abnormal sleep length.

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. Bibcode:2009Natur.461..747M. 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. S2CID   8114580.
  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. S2CID   34882295.
  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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