A significant fraction of height-determining genes has been identified by GWAS analysis. An additional example is that of human population stature. However, the genetic components identified to date only explain 20 % of this heritable fraction. As an example, Crohn’s disease is a recessive disorder which shows about 80 % heritability. Hence, the issue remained open, whereby identified genetic factors associated with complex diseases conferred far less disease risk than expected from empirical estimates of heritability. Epistatic components need to be integrated by estimates of the contribution of non-genetic factors, globally designated as the “missing heritability”. As a consequence, “pure” genetic models are prone to underestimate the interactions among loci, globally designated as epistasis. On the other hand, identified genetic factors associated with complex diseases have been found to confer far less disease risk than expected from empirical estimates of heritability and typically explain only a minority of the heritable traits. However, simple models of additive effects of ever-smaller components have remained as yet unproven. These findings led to postulate models whereby numerous genetic factors provide small, independent contributions to complex phenotypes, such effects being essentially additive. Several common disorders, such as type 2 diabetes, Crohn’s disease, and rheumatoid arthritis, were also shown to possess significant genetic components, as provided by multiple polymorphic loci. Genome-wide association studies (GWAS) have recently demonstrated that multiple genomic loci are linked to complex traits, such as body development and height ( and references therein). Specific genetic/DNA sequence variants are typically inherited transgenerationally as Mendelian alleles and are supposed to carry with them all the genetic information that acts as inheritable determinant. Patterns of heritable traits within the human population determine body phenotypes, through a deeply intertwined interaction between genetic components and the environment. Such mechanisms have been shown to include incomplete erasure of DNA methylation, parental effects, transmission of distinct RNA types (mRNA, non-coding RNA, miRNA, siRNA, piRNA), and persistence of subsets of histone marks. The knowledge acquired from epigenetic genome reprogramming during development, stem cell differentiation/de-differentiation, and model organisms is today shedding light on the mechanisms of (a) mitotic inheritance of epigenetic traits from cell to cell, (b) meiotic epigenetic inheritance from generation to generation, and (c) true transgenerational inheritance. Consistent components of complex traits, such as those linked to human stature/height, fertility, and food metabolism or to hereditary defects, have been shown to respond to environmental or nutritional condition and to be epigenetically inherited. Epigenetic programs may account for a significant fraction of the “missing heritability.” Epigenetic modifications, such as DNA methylation and chromatin assembly states, reflect the high plasticity of the genome and contribute to stably alter gene expression without modifying genomic DNA sequences. This discrepancy is known as “missing heritability”, and its underlying factors and molecular mechanisms are not established. Genome-wide association studies of complex physiological traits and diseases consistently found that associated genetic factors, such as allelic polymorphisms or DNA mutations, only explained a minority of the expected heritable fraction.
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