gene + environment + triggers + chance = phenotype 基因+环境+触发+概率=表型

Know then thyself, presume not God to scan;
The proper study of mankind is man.
— Alexander Pope, Essay on Man

PAST

Several genome‐wide association studies (GWAS) [1-13] have been reported and provide evidence for over 40 genes involved in psoriasis causation (Table 1. Psoriasis susceptibility genes and their function).

Table 1. Psoriasis susceptibility genes and their function
gene table

In humans, a mutant Table 1. gene increases the risk for psoriasis — but not all people carrying the Table 1. gene mutation develop psoriasis. As we know currently, even if the gene(s) (Table 1) is/are inherited, psoriasis is not absolutely presented as its capacity to become expressed into an actual attribute varies from one individual to another.

NOW

Examination of twins has shown concordance for psoriasis in 20% of monozygotic twins compared to 9% for dizygotic twins, corresponding to an estimated heritability of 68% [14-16] . (Monozygotic twins, who are truly genetically identical, are derived from the splitting of a single fertilized egg; dizygotic twins, who are merely genetic siblings, are derived from the simultaneous fertilization of two eggs by two sperm).

For instance, one person with the Table 1. gene(s) mutation might develop an severe generalized pustular psoriasis. Another with the same mutation might develop an plaque psoriasis; and yet another might not develop psoriasis at all.

We still do not know what causes the difference of outcomes between these three person — is it some combination of age, exposures, other genes, and bad luck? You cannot use just the Table 1 genotype mutation to predict the final outcome with certainty.

phenotype (disorder) = genotype (gene) + environment + triggers + chance (luck)

The above formula [17] may captured the essence of the interactions between heredity, chance, environment, variation, and evolution in determining the form and fate of an organism.

FUTURE

How do genes interact with environment, triggers, chances to cause order versus disorder? For that matter, what is order versus disorder? How do the variations in genes cause variations in human form and function? How do multiple genes influence a single outcome? How can there be so much uniformity among humans, yet such diversity? How can the variants in genes sustain a common physiology, yet also produce unique pathologies? What we known is just a drop in the ocean.

genome1

人贵在自知，莫揣测天意；
要了解人类，尚须以人为本。
— 亚历山大教皇《人论》

过去

在人类基因组关联研究(GWAS)中[1-13]，有40多种基因突变会增加罹患乳银屑病（牛皮癣）的风险(表1. 银屑病基因及其功能)。表1的突变基因增加了银屑病的风险 — 但并非所有携带表1基因的人都会罹患银屑病。我们目前知道，即使基因（表1）已被遗传，银屑病也并非绝对对应出现，因为其表达为实际属性的能力因人而异。

现在

对双胞胎的研究显示，单卵双胞胎中有20％患有银屑病，而双卵双生子中只有9％，遗传力估算值为68％[14-16]。 （单卵双胞胎在遗传基因上是完全相同的，是从单个受精卵分裂而来；双卵双胞胎，仅是遗传基因相似，是由两个精子同时受精两个卵而得）。

例如，具有表1基因的一个人，基因突变可能会导致严重的泛发性脓疱型牛皮癣；另一个突变相同的人可能会发展成斑块状牛皮癣；还有一个可能根本不会发展成牛皮癣。我们至今仍然不知道是什么原因导致这三位的结果出现差异，是与年龄、环境、激发因素、其他基因以及随机巧合等综合因素有关吗？表1基因突变并不能对于最终结果做出准确预测。

表型(失调）= 基因+环境+触发+随机概率

尽管上述公式[17]不仅抓住了遗传、概率、环境、变异与进化之间交互作用的本质，而且还反映了决定生物体形态与命运的演变过程。

将来

基因与环境、触发器、随机概率交互作用影响常态与病态的机制是什么呢？什么是有序与无序？基因变异是如何导致人类形态与功能产生变异的呢？多个基因是如何共同影响某个单一结果的呢？不同的基因变异在维持相同生理功能的同时，又是如何产生独特病理变化的呢？我们所知的是沧海一栗，我们所未知的是汪洋大海。

 

Reference:

  1. Greb, J., Goldminz, A., Elder, J. et al. Psoriasis. Nat Rev Dis Primers, 16082 (2016). https://doi.org/10.1038/nrdp.2016.82
  2. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007; 445:866–73.
  3. Tomfohrde J, Silverman A, Barnes R, et al. Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q. Science 1994; 264:1141–5.
  4. Capon F, Munro M, Barker J, Trembath R. Searching for the major histocompatibility complex psoriasis susceptibility gene. J Invest Dermatol 2002;118:745–51.
  5. Feng BJ, Sun LD, Soltani‐Arabshahi R, et al. Multiple loci within the major histocompatibility complex confer risk of psoriasis. PLOS Genet 2009;5:e1000606.
  6. Knight J, Spain SL, Capon F, et al. Conditional analysis identifies three novel major histocompatibility complex loci associated with psoriasis. Hum Mol Genet 2012;21:5185–92.
  7. Asumalahti K, Ameen M, Suomela S, et al. Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis. J Invest Dermatol 2003;120:627–32.
  8. Allen MH, Ameen H, Veal C, et al. The major psoriasis susceptibility locus PSORS1 is not a risk factor for late‐onset psoriasis. J Invest Dermatol 2005;124:103–6.
  9. Jordan CT, Cao L, Roberson ED, et al. PSORS2 is due to mutations in CARD14. Am J Hum Genet. 2012;90:784–95.
  10. Jordan CT, Cao L, Roberson ED, et al. Rare and common variants in CARD14, encoding an epidermal regulator of NF‐kappaB, in psoriasis. Am J Hum Genet 2012;90:796–808.
  11. Nair RP, Duffin KC, Helms C, et al. Genome‐wide scan reveals association of psoriasis with IL‐23 and NF‐kappaB pathways. Nat Genet 2009;41:199–204.
  12. Zhang XJ, Huang W, Yang S, et al. Psoriasis genome‐wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat Genet 2009;41:205–10.
  13. Delin Ran, Minglong Cai, Xuejun Zhang, Genetics of psoriasis: a basis for precision medicine, Precision Clinical Medicine, Volume 2, Issue 2, June 2019, Pages 120–130
  14. Capon F, Burden AD, Trembath RC, Barker JN. Psoriasis and other complex trait dermatoses: from loci to functional pathways. J Invest Dermatol 2012;132:915–22.
  15. Bergboer JG, Zeeuwen PL, Schalkwijk J. Genetics of psoriasis: evidence for epistatic interaction between skin barrier abnormalities and immune deviation. J Invest Dermatol 2012;132:2320–1.
  16. Tejasvi T, Stuart PE, Chandran V, et al. TNFAIP3 gene polymorphisms are associated with response to TNF blockade in psoriasis. J Invest Dermatol 2012;132:593–600.
  17. Siddhartha Mukherjee. The Gene: An Intimate History. Scribner 2016. P225