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What is Non-Genetic Inheritance?

Epigenetic mechanisms are highly complex, diverse and often poorly understood. A recent study, published in Cell, discusses the diverse features of non-genetic inheritance and offers recommendations for future research.

A key challenge in genetic research is incorporating inheritance mechanisms beyond the DNA sequence into evolutionary investigations. Non-genetic inheritance (NGI) involves a diverse range of mechanisms, which act together and independently in order to shape gene expression. Inherited gene regulation (IGR) describes the unified and diverse range of heritable factors which may change the gene expression of offspring.

There are 3 key features of Non-Genetic Inheritance Systems:

  1. They are functionally dependent on DNA sequence information. They are often believed to be totally separate but this is not true
  2. The precise mechanisms by which they act are highly diverse across taxa
  3. They act probabilistically, as interactive regulatory factors, rather than as deterministic epialleles with defined genomic locations and effects

A recent study discusses each of these features and offers recommendations for future empirical and theoretical research.

Non-Genetic Inheritance: Beyond DNA

Epigenetic mechanisms, such as DNA methylation, histone modifications and small non-coding RNAs, are commonly viewed as separate from DNA sequence transmission. They often arise stochastically or are induced by environmental factors, but many persist from one generation to the next. They have complex and potentially unpredictable dynamics. So is it time to review our understanding of inheritance and include these new mechanisms?

For evolutionary biologists, the role of inherited ‘non-genetic’ factors in evolution and their potential impacts on adaptation are pressing issues. Increasing evidence suggests that these mechanisms can influence phenotype in a range of organisms. These can include negative impacts. For example, parents with nutrient poor, high fat or sugar diets can transmit altered DNA methylation states to offspring, leading to metabolic or developmental disorders. Alternatively, stressful prenatal conditions can induce adaptive phenotypic changes in offspring encountering similar stresses. Such adjustments – unlike allele frequency change – can occur over just one generation. Thus, they are a potential mechanism for rapid adaptation to environmental change.

‘Non-Genetic’ and Genetic Aspects of Inheritance are Inseparable

Genome sequence variants and heritable factors are deeply interwoven, and much research could benefit from an interaction-based perspective. This is because IGR can never be fully independent of DNA sequence. For example, the action of a methylation mark is dependent on the functional properties of the DNA sequence at the targeted loci. In the presence of CpG dinucleotides, DNA methylation contributes to gene silencing. In comparison, in coding sequences, methylation marks are associated with transcription initiation.

On the other hand, some molecular mechanisms of IGR have levels of sequence independence. For example, epigenetic marks are able to spread along chromosomes to be copied to the new DNA strand during cell division. Thus, these molecular mechanisms exist on a continuum, from entirely sequence-determined to sequence-independent. Thus, in a conceptual or experimental setting, it is important to assume that both genetic and non-genetic factors contribute to any given phenomenon. Important insights could be gained by shifting existing research paradigms to also consider ‘Non-Genetic’ factors.

IGR Mechanisms are Phylogenetically and Functionally Diverse

Although the mechanisms underlying IGR are evolutionarily ancient, they are also highly diverse. Unlike DNA-based inheritance they are not universal across the genome and different taxa. Recognising and incorporating these differences into research designs can lead to important progress in understanding evolutionary implications.

The diversity of these mechanisms is clear on 3 levels. First, there is significant phylogenetic diversification in the molecular machinery for epigenetic markers. For example, whilst mammalian genomes possess 3 unique DNA methyltransferase genes, teleost fishes have between 5 and 12 of such genes.

Second, the function of certain genes and the temporal or spatial dynamics of epigenetic modifications often differ across different taxa. For example, modified histones are largely removed during mouse spermatogenesis, but retained to some extent in human sperm. Similarly, while all taxa feature maternal RNA, its clearance and maintenance dynamics differ widely.

Finally, biochemically identical markers can have vastly different implications in different taxa. In mammals, DNA methylation marks are found upstream of inactive genes. Conversely, these marks are concentrated within actively expressed genes in teleost fish.

Overall, whilst many features of DNA inheritance are highly conserved, NGI is highly diverse. This reduces the generalisability of findings from model organisms to other taxa with different evolutionary history. In these scenarios, the study suggests that the known properties of the species of interest should be analysed to guide further research steps. 

Similarly, the study suggests that a phylogenetic perspective should be used to choose specific research techniques. For example, affinity based techniques to measure DNA methylation such as meDIP do not function as effectively in species such as fish or invertebrates which contain loosely interspersed DNA methylation. 

IGR Mechanisms Are Probabilistic, Interactive and Context Dependent

The well-known examples of IGR, which are also commonly used as research models are often robustly heritable, deterministic and ‘allelic’. Take for example, mammalian imprinting, which occurs in the germline and leads to parental-origin-specific expression of a small subset of genes. However, in general, IGR displays non-deterministic properties and acts in a context-dependent manner.

IGR mechanisms integrate across large genomic regions, rather than operating at the level of nucleotide resolution. This is important as analyses which do not examine the overall state of a genomic region poorly capture this biological process. IGR also involves several mechanisms which co-occur spatially and temporally and influence each other. This produces complex chromatin landscapes. Overall, IGR mechanisms act as a cluster of interdependent molecular markers. Together, they act to increase the likelihood of a particular outcome for gene expression.

Final Comments

Incorporating inheritance mechanisms which go beyond DNA sequences will be a key challenge for research in coming years. Thus, by characterising these key features, the authors hope to bridge the gap in understanding that currently exists between evolutionary and molecular biologists. Much progress has been made in understanding the ecological and evolutionary role of NGI, but there is much more to be discovered.

Image credit: By anusorn nakdee –