Oligogenic inheritance

Oligogenic inheritance (Greek ὀλίγος – ὀligos = few, a little) describes a trait that is influenced by a few genes. Oligogenic inheritance represents an intermediate between monogenic inheritance in which a trait is determined by a single causative gene, and polygenic inheritance, in which a trait is influenced by many genes and often environmental factors.[1]

Historically, many traits were thought to be governed by a single causative gene (in what is deemed monogenic inheritance), however work in genetics revealed that these traits are comparatively rare, and in most cases so-called monogenic traits are predominantly influenced by one gene, but can be mediated by other genes of small effect.[2]

History

Around the 1930s/40s, evidence that multiple genes could affect the risk of disease that showed discrete inheritance patterns, due to differences in the age of onset of disease for siblings. The age of onset for sibling pairs was very similar, but between pairs of siblings could be quite different, and would in some cases cluster into several age brackets. This suggested a major gene that controlled the risk for a disease, and other genes that impacted age of onset.[3]

The recognition of diseases which were influenced by more than one gene highlighted a need to develop methodologies for detecting these oligogenic inheritance patterns, as they did not fit the more straightforward Mendelian model of inheritance. The developments of such methods accelerated the discovery of other examples of oligogenic traits, and sparked a change in the way genetic disease was perceived.[1]

Modifier genes

One example of oligogenic inheritance is a case where one gene is sufficient to cause a trait, however its penetrance or expressivity is influenced by another gene, called a modifier. An example of such a case is the gene TGFB1 which modified a person's risk of developing Alzheimer's disease if they are carrying the disease variant of the gene APP. The mechanism is thought to work through the modifier variant increasing the clearance of amyloid fibers in the aging brain, reducing plaque burden.[4]

Identification of oligogenic traits

A trait can be recognised as oligogenic through the following lines of evidence:[1]

  • Phenotype–genotype correlations: if phenotype can't be predicted to a single strongly correlated locus, but inclusion of genotype from another locus improves the correlation, this is evidence for the trait being oligogenic
  • Phenotypic differences in an animal model of the disease that are dependent on the genetic background: the effects of a potential modifier locus can be tested in an animal with another known causative mutation
  • Disparities between mutations and a Mendelian model of inheritance: if carriers of a mutation do not show the pattern of phenotypes expected under Mendelian inheritance, other models may better explain observed patterns of inheritance
  • The establishment of linkage to more than one locus or the failure to detect linkage using Mendelian models: when tracing mutations associated with a trait through a family tree, more than one mutation may show the same pattern of inheritance as the trait (in a case where multiple variants are required for a trait), or linkage may not be detected (in a case where one of several variants is sufficient for a trait)

Human properties with possible oligogenic inheritance
Dominant Recessive References
Widow's peak Straight frontal hair line [5][6]
Facial dimples * No facial dimples [7][8]
Able to taste PTC Unable to taste PTC [9]
Unattached (free) earlobe Attached earlobe [7][10][11]
Clockwise hair direction (left to right) Counter-clockwise hair direction (right to left) [12]
Cleft chin Smooth chin [13]
Ability to roll tongue (Able to hold tongue in a U shape) No ability to roll tongue [14]
Extra finger or toe Normal five fingers and toes [14]
Straight thumb Hitchhiker's thumb [14]
Freckles No freckles [7][15]
Wet-type earwax Dry-type earwax [10][16]
Shortness in fingers Normal finger length [14]
Webbed fingers Normal separated fingers [14]
Roman nose No prominent bridge [17]
Marfan's syndrome Normal body proportions [18]
Huntington's disease No nerve damage [19]
Normal mucus lining Cystic fibrosis [20]
Forged chin Receding chin [17]
White forelock Dark forelock [21]
Ligamentous angustus Ligamentous laxity [22]
Ability to eat sugar Galactosemia [23]
Total leukonychia and Bart pumphrey syndrome Partial leukonychia [24]
Absence of fish-like body odour Trimethylaminuria [25]
Lactose persistence * Lactose intolerance * [26]
Prominent chin (V-shaped) Less prominent chin (U-shaped) [27]
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See also
  • Gene
  • Monogenic inheritance
  • Polygenic inheritance

References
  1. Badano, Jose L.; Katsanis, Nicholas (October 2002). "Beyond Mendel: an evolving view of human genetic disease transmission". Nature Reviews Genetics. 3 (10): 779–789. doi:10.1038/nrg910. PMID 12360236.
  2. Robinson, Jon F.; Katsanis, Nicholas (2010). "Oligogenic Disease". Vogel and Motulsky's Human Genetics. Springer, Berlin, Heidelberg: 243–262. doi:10.1007/978-3-540-37654-5_8. ISBN 978-3-540-37653-8.
  3. Haldane, J. B. S. (January 1941). "The relative importance of principal and modifying genes in determining some human diseases". Journal of Genetics. 41 (2–3): 149–157. doi:10.1007/BF02983018.
  4. Wyss-Coray, Tony; Lin, Carol; Yan, Fengrong; Yu, Gui-Qiu; Rohde, Michelle; McConlogue, Lisa; Masliah, Eliezer; Mucke, Lennart (1 May 2001). "TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice". Nature Medicine. 7 (5): 612–618. doi:10.1038/87945. PMID 11329064.
  5. Campbell, Neil; Reece, Jane (2005). Biology. San Francisco: Benjamin Cummings. p. 265. ISBN 0-07-366175-9.
  6. McKusick, Victor A. (10 February 2009). "Widow's Peak". Online Mendelian Inheritance in Man. Johns Hopkins University. 194000.
  7. "Genetics/Reproduction". ScienceNet – Life Science. Singapore Science Centre. Archived from the original on 2003-09-25.
  8. McKusick, Victor A. (25 June 1994). "Dimples, Facial". Online Mendelian Inheritance in Man. Johns Hopkins University. 126100.
  9. Wooding, Stephen (28 June 2004). "Natural selection at work in genetic variation to taste". Medical News Today. Archived from the original on 2007-12-13.
  10. Cruz-Gonzalez, L.; Lisker, R. (1982). "Inheritance of ear wax types, ear lobe attachment and tongue rolling ability". Acta Anthropogenet. 6 (4): 247–54. PMID 7187238.
  11. McKusick, Victor A.; Lopez, A (30 July 2010). "Earlobe Attachment, Attached vs. Unattached". Online Mendelian Inheritance in Man. Johns Hopkins University. 128900.
  12. McDonald, John H. (8 December 2011). "Hair Whorl". Myths of Human Genetics. University of Delaware.
  13. McKusick, Victor A. (23 March 2013). "Cleft Chin". Online Mendelian Inheritance in Man. Johns Hopkins University. 119000.
  14. Hadžiselimović R. (2005). Bioantropologija – Biodiverzitet recentnog čovjeka/Bioanthropology – Biodiversity of recent man. Sarajevo: INGEB. ISBN 9958-9344-2-6.
  15. Xue-Jun Zhang; et al. (2004). "A Gene for Freckles Maps to Chromosome 4q32–q34". Journal of Investigative Dermatology. 122 (2): 286–290. doi:10.1046/j.0022-202x.2004.22244.x. PMID 15009706.
  16. McKusick, Victor A.; O'Neill, Marla J. F. (22 November 2010). "Apocrine Gland Secretion, Variation in". Online Mendelian Inheritance in Man. Johns Hopkins University. 117800.
  17. "Mendelian Traits in Humans" (PDF). Human Genetics. San Diego Supercomputer Center (SDSC).
  18. Chen, Harold. Buehler, Bruce (ed.). "Genetics of Marfan Syndrome". Medscape. WebMD LLC.
  19. Stafford, Kate; Mannor, Michael. "Mutations and Genetic Disease". Genetic Diseases. ThinkQuest. Archived from the original on 2007-01-03.
  20. "Autosomal Recessive: Cystic Fibrosis, Sickle Cell Anemia, Tay Sachs Disease". Medical Genetics. Children's Hospital of Pittsburgh. 3 February 2008. Archived from the original on 2009-08-24.
  21. "Inherited Human Traits". EdQuest. Archived from the original on 2012-02-01.
  22. Scott, C. I. (1971). "Unusual facies, joint hypermobility, genital anomaly and short stature: A new dysmorphic syndrome". Birth Defects Original Article Series. 7 (6): 240–246. PMID 5173168.
  23. Fankhauser, D. B. (2 Feb 2006). "Human Heritable Traits". University of Cincinnati Clermont College. Archived from the original on 2012-02-23.
  24. Tüzün, Yalçın; Karaku, Özge (2009). "Leukonychia" (PDF). Journal of the Turkish Academy of Dermatology. JTAD. Archived from the original (PDF) on 2016-03-03. Retrieved 2017-02-19.
  25. "Learning About Trimethylaminuria". genome.gov. National Human Genome Research Institute.
  26. Bowen, R. (25 April 2009). "Lactose Intolerance (Lactase Non-Persistence)". Colorado State University.
  27. Jablecki, Donna Mae. "Variations on a Human Face" (PDF). Science Experiments on File. Facts on File.
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