Beyond the "Dominant" and "Recessive" Patterns of Inheritance

Abstract

This study aimed to investigate whether genes with different modes of inheritance differ in the presence of promoter-enriched CGI loci. For each autosomal chromosome, the author searched for variations in the total number of diseases' phenotypes with autosomal dominant (AD) and recessive (AR) inheritance for a list of promoter-poor CGI (CGI-) and promoter-enriched CGI (CGI+) genes using the OMIM database. Then, the CGI- and CGI+ genes displaying random allelic or bi-allelic expression were examined. The author evaluated whether there was a distinct distribution of AD and AR diseases in the groups of chromosomes based on their SNP hotspot density. The same analysis was conducted for the X chromosome. The SPSS statistical package was utilized. The distribution of AD and AR diseases between CGI- and CGI+ bi-allelic genes significantly differed in autosomal chromosomes 6 and 17, which show intermediate SNP hotspot density. Additionally, a statistically significant difference was observed in AD and AR diseases in the remaining autosomal chromosomes with low SNP hotspots between their randomly allelic expressed CGI- and CGI+ genes. Specifically, AD diseases were related to CGI- genes, while AR diseases were associated with CGI+ genes. In the X chromosome, X-linked dominant (XLD) diseases were mainly found in CGI+ genes, and X-linked recessive (XLR) diseases were found in CGI- genes, regardless of the X-inactivation process. It is essential to study inheritance and classify genetic variants in a more stochastic way than the terms "Dominant" and "Recessive," and their derivatives, such as "Codominant" and "Incomplete Dominant," are applied in Mendelian and non-Mendelian inheritance. This concept may further explain the "Reduced Penetrance" and "Variable Expressivity" in certain human diseases. All the above suggests a need to reassess how genetic and epigenetic data are studied and utilized for genetic counseling or precision medicine.

Keywords: CpG islands; Mendelian inheritance; allele specific expression; allelic imbalance; epialleles; genetic heterogeneity; genetic variant; methylation; non-Mendelian inheritance; single nucleotide polymorphism; variant classification.

Figure 1

Autosomal chromosomes have been grouped based on their SNP hotspot density to display the percentage of their: (i) CGI− (promoter-poor CpG islands; CGI) genes and CGI+ (promoter-enriched CGI) genes that follow either the autosomal dominant (AD) or recessive (AR) inheritance pattern and (ii) CGI− and CGI+ mono-allelic or bi-allelic expressed genes with AD or AR inheritance pattern.