The Fundamental Law of Genetics

In the first lecture of my genetics course, I introduce the following as The Fundamental Law of Genetics: 

Phenotype = Genotype + Environment    (1)

The phenotype (observed traits) of an organism depends on genetic factors and environmental factors. One example of a phenotype is blood pressure. Your blood pressure (and whether or not you have high blood pressure) depends on genetic factors (alleles) you inherit from your parents as well as environmental factors (the world we live in influences traits) such as diet and exercise. 

The concept of genotype is central to genetics and is defined as the identity of alleles for genes in an individual i.e. which “version” (allele) for each gene. The gene is the basic unit of heredity, and at a molecular level, encompasses a region of DNA that is transcribed into RNA and then (typically) translated into protein. The DNA sequence of a gene can be altered by mutation to give rise to different versions or alleles which may possess different functional properties (after being transcribed/translated into protein) that influence the phenotype. Your genotype is basically the specification of what allele you have at each gene, e.g. mutant or wild-type allele and if mutant, which mutation(s). 

Humans are diploid and thus carry two sets of genes, each set contributed by one of two parents. Genes are positioned on chromosomes, each a single molecule of DNA, and we receive one set of 23 chromosomes from Mom and one set of 23 chromosomes from Dad. The human genome contains ~20,000 gene pairs, and the complete genotype of an individual is the identity of alleles at all of these genes.

That is a lot of information to process but if you understand the above (i.e. bold terms) then you are well on your way to understanding genetics including human genetics.

At the end of the course, in the human genetics section, I introduce the quantitative version of The Fundamental Law of Human Genetics:

V_P = V_G + V_E    (2)

The variable V represents variance, and the subscript P is phenotype, G is genotype, and E is environment. In other words, phenotypic variance equals genotypic variance plus environmental variance. Genotypic variance is the variation in phenotype caused by differences in genotype among individuals. V_G = 0 in the case of identical twins who possess identical genotypes. Environmental variance is the variation in phenotype caused by differences in environment among individuals. V_E = 0, when two individuals share the exact same environment such as two plants growing next to each other.

Most traits are continuous, taking on a range of values rather than a few discrete possibilities. For example, we can measure the (systolic) blood pressure in a population, and then plot the distribution of values. Most likely, the result will be a Gaussian (normal) distribution whose parameters are the mean (center) and variance (width) of the bell-shaped curve. For a healthy population, the mean systolic blood pressure may be around 120 mmHg with a standard deviation (square root of variance) of roughly 15 mmHg. Thus in this example, the phenotypic variance is 15 X 15 = 225 (mmHg)². According to eq. (2), we should be able to decompose the blood pressure phenotypic variance into genotypic variance and environmental variance (see Figure below).

Figure 25.4(c) from Genetics: From Genes to Genomes. This figure represents a distribution of plant stem lengths, but for the example, the x-axis is systolic blood pressure, and the y-axis is number of people.

In a thought experiment, for the trait of blood pressure in a large population, I can clone myself and send one clone to live with each member of the population fully sharing the environment (e.g. diet) of that person. I can then measure the blood pressure of the clones (all with identical genotypes) after a period of time, and the phenotypic variance among the clones would be V_E (due to environmental differences). Alternatively, each member of the population could all come and live with me and share my environment. After a period of time we could measure the blood pressure of the population and that would be V_G (due to genotypic differences). According to eq. (2), the phenotypic variance of the original population should equal V_G + V_E.

Of course the thought experiment is not practical, but of even greater importance is that eq. (2) is an approximation of the more complete equation:

V_P = V_G + V_GE + V_E        (3)

where V_GE represents the phenotypic variance from Gene-Environment interaction (GxE). Intuitively, V_GE describes how certain genotypes may have a bigger (or smaller) than expected impact on a trait in certain environmental settings. For example, an allele that promotes increased excretion of excess sodium by the kidneys would have a bigger impact reducing blood pressure for a high-salt diet compared to a low-salt diet. Mathematically, V_GE represents the residual from the simple linear model of additive genetic factors plus additive environmental factors in eq. (2). In other words in the thought experiment, most likely V_P would not equal V_G + V_E because V_GE does not equal 0.

Finally, according to the Lynch and Walsh textbook (Genetics and Analysis of Quantitative Traits), V_GE can be decomposed into a genotype-environment interaction term (as described above) and a genotype-environment covariance term which measures how certain genotypes are physically associated with certain environments, i.e. not randomly distributed across environments. For example, immigrants from India tend to be associated with wealthier environments in America.

My next genetics post will be on the concept of heritability.