Oligogenic inheritance explained

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.

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:

• 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	^[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
Straight thumb	Hitchhiker's thumb
Freckles	No freckles	^[15]
Wet-type earwax	Dry-type earwax	^[16]
Shortness in fingers	Normal finger length
Webbed fingers	Normal separated fingers
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
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]

See also

• Gene
• Monogenic inheritance
• Polygenic inheritance

Notes and References

1. Badano. Jose L.. Katsanis. Nicholas. Beyond Mendel: an evolving view of human genetic disease transmission. Nature Reviews Genetics. October 2002. 3. 10. 779–789. 10.1038/nrg910. 12360236. 4714288 .
2. Book: Robinson. Jon F.. Katsanis. Nicholas. Vogel and Motulsky's Human Genetics . Oligogenic Disease . 2010. 243–262. 10.1007/978-3-540-37654-5_8. Springer, Berlin, Heidelberg. en. 978-3-540-37653-8.
3. Haldane. J. B. S.. The relative importance of principal and modifying genes in determining some human diseases. Journal of Genetics. January 1941. 41. 2–3. 149–157. 10.1007/BF02983018. 186235733 .
4. Wyss-Coray. Tony. Lin. Carol. Yan. Fengrong. Yu. Gui-Qiu. Rohde. Michelle. McConlogue. Lisa. Masliah. Eliezer. Mucke. Lennart. TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice. Nature Medicine. 1 May 2001. 7. 5. 612–618. 10.1038/87945. 11329064. 26048084 .
5. Book: Neil Campbell %28scientist%29

   . Campbell . Neil . Neil Campbell %28scientist%29 . Jane . Reece . Biology . . 2005 . San Francisco . 265 . 0-07-366175-9 .

6. Web site: Widow's Peak . Online Mendelian Inheritance in Man . 194000 . Victor A. . McKusick . Johns Hopkins University . 10 February 2009 .
7. Web site: Genetics/Reproduction . Singapore Science Centre . ScienceNet – Life Science . dead . 2003-09-25 . https://web.archive.org/web/20030925150701/http://www.science.edu.sg/ssc/detailed.jsp?artid=4862&type=6&root=4&parent=4&cat=40 .
8. Web site: Dimples, Facial . Online Mendelian Inheritance in Man . 126100 . Victor A. . McKusick . Johns Hopkins University . 25 June 1994 .
9. Web site: Natural selection at work in genetic variation to taste . Stephen . Wooding . Medical News Today . 28 June 2004 . live . 2007-12-13 . https://web.archive.org/web/20071213232429/http://www.medicalnewstoday.com/articles/10009.php .
10. Cruz-Gonzalez . L. . Lisker . R. . Inheritance of ear wax types, ear lobe attachment and tongue rolling ability . Acta Anthropogenet. . 1982 . 6 . 4 . 247–54 . 7187238 .
11. Web site: Earlobe Attachment, Attached vs. Unattached . Online Mendelian Inheritance in Man . 128900 . Victor A. . McKusick . A . Lopez . Johns Hopkins University . 30 July 2010 .
12. Web site: Hair Whorl . Myths of Human Genetics . McDonald . John H. . University of Delaware . 8 December 2011 .
13. Web site: Cleft Chin . Online Mendelian Inheritance in Man . 119000 . Victor A. . McKusick . Johns Hopkins University . 23 March 2013 .
14. Book: Hadžiselimović R.. 2005 . Bioantropologija – Biodiverzitet recentnog čovjeka/Bioanthropology – Biodiversity of recent man.. INGEB. Sarajevo. 9958-9344-2-6.
15. Xue-Jun Zhang . A Gene for Freckles Maps to Chromosome 4q32–q34 . Journal of Investigative Dermatology . 2004 . 122 . 2 . 286–290 . 10.1046/j.0022-202x.2004.22244.x. 15009706 . etal. free .
16. Web site: Apocrine Gland Secretion, Variation in . Online Mendelian Inheritance in Man . 117800 . Victor A. . McKusick . Marla J. F. . O'Neill . Johns Hopkins University . 22 November 2010 .
17. Web site: Mendelian Traits in Humans . Human Genetics . San Diego Supercomputer Center (SDSC) .
18. Genetics of Marfan Syndrome . Medscape . Harold . Chen . Bruce . Buehler . WebMD LLC . 11 January 2021.
19. Web site: Mutations and Genetic Disease . Kate . Stafford . Michael . Mannor . Genetic Diseases . ThinkQuest . dead . 2007-01-03 . https://web.archive.org/web/20070103234613/http://library.thinkquest.org/17109/diseases.htm .
20. Web site: Autosomal Recessive: Cystic Fibrosis, Sickle Cell Anemia, Tay Sachs Disease . Medical Genetics . Children's Hospital of Pittsburgh . 3 February 2008 . dead . 2009-08-24 . https://web.archive.org/web/20090824211049/http://www.chp.edu/CHP/P02142 .
21. Web site: Inherited Human Traits . EdQuest . live . 2012-02-01 . https://web.archive.org/web/20120201141515/http://www.edquest.ca/component/content/article/25/ .
22. Scott . C. I.. Unusual facies, joint hypermobility, genital anomaly and short stature: A new dysmorphic syndrome. Birth Defects Original Article Series. 7. 6. 240–246. 1971. 5173168.
23. Web site: Human Heritable Traits . Fankhauser . D. B. . University of Cincinnati Clermont College . 2 Feb 2006 . dead . https://web.archive.org/web/20120223222416/http://biology.clc.uc.edu/fankhauser/labs/BioLab_112/Human_Genetics.html . 2012-02-23 .
24. Leukonychia . Yalçın . Tüzün . Özge . Karaku . Journal of the Turkish Academy of Dermatology . JTAD . 2009 . 2017-02-19 . https://web.archive.org/web/20160303225703/http://www.jtad.org/2009/1/jtad93101r.pdf . 2016-03-03 . dead .
25. Web site: Learning About Trimethylaminuria . genome.gov . National Human Genome Research Institute .
26. Web site: Lactose Intolerance (Lactase Non-Persistence) . R. . Bowen . Colorado State University . 25 April 2009 .
27. Web site: Variations on a Human Face . Donna Mae . Jablecki . Science Experiments on File . Facts on File .