A normal life depends on the functioning of genes. Such a phenomenon is generally called as genetic dependence. In a specific sense, the genetic dependence is defined as the extent to which the normal life depends on the functioning of a gene. It can be described in three aspects, i.e., genetic dependence nature, genetic dependence stage, and genetic dependence quantity. Genes differ much in dependence feature, which is one of the key determinants of genetic variants.
Genetic dependence nature (GDN)
Each gene plays a distinct role. Absence of a gene has distinct impact on the normal life. Based on the fate of abolishing genes (gene knock-out), GDN of genes can be classified into vital, obligatory, fractional, and dispensable/replaceable.
Vital, abolishment of the gene leads to embryonic or early death.
Obligatory, abolishment of the gene causes disease.
Fractional, abolishment of the gene is associated detectable mild biological alterations but not apparent disorders.
Dispensable/replaceable, abolishment of the gene has no detectable effect.
Apparently, GDN is one of the determinants of pathogenic potential of genes.
Genetic dependence stage (GDS)
Genes express and function during a special period of development or throughout the life span. In this database, GDS is classified into whole life, embryonic, postnatal, and mature.
Whole life, the gene expresses and functions from embryonic stage throughout the life span.
Embryonic, the gene expresses and functions only or mainly during embryonic stage and then gives its role to other genes or terminates functioning.
Postnatal, the gene expresses and functions post-natally and then on.
Mature, the gene begins to express and function with maturing.
GDS is associated with some features of phenotype, such as onset age and evolution.
Genetic dependence quantity (GDQ) or genetic dependence level (GDL)
The human genome is diploid. Normally, only a portion of functioning of the two copies of a gene is required to maintain its biophysiological function. The low limit of required quantity of genetic function is defined as GDQ or GDL. Genetic function is reflected by function of the encoded protein. Therefore, the low limit of residual activity of a protein required to maintain its biophysiological function could be considered as functional GDQ.
Factitiously, the full scale of functional potential of a gene, which is contributed by two copies of the gene in diploid, can be quantified as 100%. GDQ is less than 100%; and the rest, a considerable portion of the genetic functional potential, serves as reserve (Figure a), which is required to protect an individual from defective alternations in genes; and each gene differs in GDQ. A variant is pathogenic when its impairment is large enough to run out of the reserve and damage the GDQ (Figure b). Thus, variants with similar damaging effect, such as variants of haploinsufficiency, present different pathogenicities in genes of different GDQ; and GDQ is an essential consideration in evaluating the pathogenicity/causality of the variants. The following figure exhibits the relationship between pathogenicity of a variant and GDQ.
Generally, GDQ of a gene could be determined based on evidences from gene knock-out (KO), inheritance pattern of the gene-associated disease, and correlation between functional impairment and the disease.
From the perspective of genetic KO, GDQ can be grossly divided into >50% and <50%. GDQ is estimated to be >50% when heterozygous KO of the gene causes abnormal phenotype. GDQ is estimated to be <50% when heterozygous KO model is asymptomatic, whereas homozygous KO of the gene results in abnormal phenotypes or embryonic/early death.
In genes associated with defined genetic diseases, GDQs are grossly indicated by the inheritance pattern. In dominant genetic disorders, impairment of one of the two copies of the gene results in disease, indicating that the GDQ is > 50%; whereas in recessive disorders, biallelic mutations are required to cause disease, indicating the GDQ is ≤ 50%. Similarly, gross GDQ is indicated by XLD/XLR inheritance.
In practice, the quantitative data on functional impairment of a gene could be obtained from studies on mosaicism, splicing analysis, and residual activity. Analysis of the correlation between phenotype severity and functional deficiency helps us to define GDQ of the gene quantitatively.