Sequence Divergence and Retrotransposon Insertion Underlie Interspecific Epigenetic Differences in Primates -Review

While DNA sequence alterations form the cornerstone of classical evolutionary understanding, a hidden layer awaits exploration: epigenetics. These chemical modifications on DNA and its packaging proteins, without altering the actual sequence, can dramatically influence gene expression and shape phenotypic differences. The study "Sequence Divergence and Retrotransposon Insertion Underlie Interspecific Epigenetic Differences in Primates" delves into this fascinating realm, exploring how epigenetic variations contribute to the diversity within primates, particularly between humans and chimpanzees.

Imagine two individuals sharing 98% of their DNA sequrbces, yet exhibiting distinct personalities and preferences. This analogy aptly describes the puzzling differences between humans and chimpanzees, whose DNA sequence boasts a staggering 98.8% similarity. For decades scientists used comparative genomics to infer relationships. 

This leads to some preposterous conclusions - see daffodil. Or humans 94% similar to dogs.

With the advent of epigenetics these studies are turning to comparative epigenetics.

This study proposes that epigenetic differences bridge this gap, acting as invisible scripts dictating how similar genetic blueprints translate into diverse phenotypes.

By comparing the epigenomes of induced pluripotent stem cells (iPSCs) derived from humans and chimpanzees, researchers embarked on a quest to decipher these hidden epigenetic signatures. iPSCs, with their remarkable ability to revert to an embryonic-like state, provided a unique platform to examine the fundamental epigenetic programming of each species.

A Tale of Two Epigenomes:

Intriguingly, while the gene expression patterns (transcriptomes) of human and chimpanzee iPSCs were largely comparable, their epigenomes painted a contrasting picture. Specifically, researchers analyzed two histone modifications: H3K4me3, associated with gene activation, and H3K27me3, linked to gene silencing. Interestingly, some regions displayed species-specific H3K4me3 or H3K27me3 patterns, suggesting distinct epigenetic landscapes shaping gene expression in each species.

But could these epigenetic differences simply reflect chance variations? The study delved deeper, uncovering a fascinating link between sequence divergence and the epigenetic landscape. While most species-specific epigenetic regions did not coincide with substantial DNA sequence differences, the presence of human-specific LTR5 retrotransposon insertions painted a captivating picture. These mobile genetic elements, once considered NeoDarwinian "Junk DNA," appear to have played a surprising role in shaping the human epigenome.

From Junk to Jewels:

Intriguingly, these LTR5 insertions were found to be associated with regions displaying H3K4me3 marks. This suggests that the insertions created binding sites for pluripotency-related transcription factors, potentially activating nearby genes in a species-specific manner. This finding highlights the transformative potential of even seemingly insignificant sequence alterations, where once-dismissed "Junk DNA" can become pivotal players in shaping gene expression and evolution.

The story doesn't end there. The study also revealed species-specific differences in bivalent domains, regions harboring both H3K4me3 and H3K27me3 marks, poised for potential activation or silencing during development. Human iPSCs exhibited more species-specific H3K27me3 regions, leading to more abundant bivalent domains. This suggests that humans might have a greater potential for developmental flexibility compared to chimpanzees, hinting at unique mechanisms underlying human development and evolution.

Beyond the Surface:

While this study offers invaluable insights into interspecific epigenetic differences in primates, further exploration is crucial. Delving deeper into the functional consequences of these variations on gene expression and phenotype will illuminate their impact on the diverse tapestry of life. Additionally, investigating the evolutionary forces driving epigenetic diversification across different primate lineages could shed light on the intricate dance between environment, adaptation, and epigenetic change.

Ultimately, the findings of this study transcend the realm of primate evolution, holding potential implications for understanding human diseases. Abnormal epigenetic patterns are increasingly linked to various illnesses, including cancer and developmental disorders. By deciphering the mechanisms underlying epigenetic diversification, we gain valuable tools to potentially diagnose and treat these diseases, paving the way for a future where understanding the hidden layer of epigenetics translates into improved human health.

Unveiling the Hidden Canvas: Epigenetics Paints Primate Diversity, Calling for an Extended Synthesis

While Darwinian evolution focused on DNA sequence alterations, a hidden layer paints the picture of life: epigenetics. This study, "Sequence Divergence and Retrotransposon Insertion Underlie Interspecific Epigenetic Differences in Primates," delves into this realm, revealing how epigenetic variations contribute to primate diversity, particularly between humans and chimpanzees, and calling for an extended evolutionary synthesis.

Epigenetic differences, chemical modifications of DNA and its packaging proteins, emerge as key players. By comparing induced pluripotent stem cells (iPSCs) from both species, researchers unveiled these hidden signatures.

Decoding the Epigenetic Canvas:

• Sequence Divergence Guides the Brushstrokes: While most species-specific epigenetic regions lacked major DNA sequence differences, intriguing patterns emerged. Human-specific insertions of LTR5 retrotransposons, mobile genetic elements, were associated with H3K4me3 marks. These insertions appeared to create binding sites for pluripotency-related transcription factors, potentially activating nearby genes in a species-specific manner. This highlights the power of non-coding DNA changes to impact epigenetics and gene expression.

• The Unique Canvas of Human Bivalent Domains: The study revealed intriguing differences in bivalent domains, harboring both H3K4me3 and H3K27me3 marks, poised for potential activation or silencing during development. Human iPSCs exhibited more species-specific H3K27me3 regions, leading to more abundant bivalent domains. This suggests humans might have greater developmental flexibility compared to chimpanzees, potentially contributing to our complex cognitive abilities.

• A Later Act in the Developmental Drama: Interestingly, only a small portion of the species-specific epigenetic regions overlapped with enhancer elements active in cranial neural crest cells, suggesting that differences in the epigenetic state of developmental enhancers might emerge later in development, potentially fine-tuning specific aspects of neural crest cell lineages.

Beyond the Brushstrokes: An Extended Evolutionary Synthesis:

This study paints a captivating picture of how seemingly minor epigenetic modifications can lead to significant phenotypic differences. By uncovering the intricate interplay between sequence divergence, retrotransposon insertions, and specific epigenetic marks, it offers valuable insights into the mechanisms underlying species diversification. However, this is just the first brushstroke on a vast canvas, calling for an extended evolutionary synthesis that:

• Deciphers the Functional Consequences: Beyond identifying differences, understanding their impact on gene expression and phenotypic traits is crucial. Functional studies exploring how these epigenetic marks influence gene regulation and cellular processes are necessary to fully grasp their evolutionary significance.

• Unravels the Evolutionary Script: What forces drive epigenetic diversification across different primate lineages? Investigating the selective pressures and environmental factors shaping these variations will shed light on the evolutionary dynamics shaping primate diversity.

• Translates the Epigenetic Code: Can these findings be translated into understanding human diseases potentially linked to abnormal epigenetic patterns? Exploring the potential links between epigenetic dysregulation and disorders like cancer and neurodegenerative diseases holds immense potential for future medical applications.

In conclusion, this study highlights the significance of epigenetics in understanding primate diversity, prompting an extended evolutionary synthesis that incorporates this hidden layer. As we continue to explore this epigenetic canvas, we unlock not only a deeper understanding of our evolutionary tapestry but also potentially unlock future avenues for biomedical research and personalized medicine.

Snippets

Sequence Divergence and Retrotransposon Insertion Underlie Interspecific Epigenetic Differences in Primates

Changes in the epigenome can affect the phenotype without the presence of changes in the genomic sequence.

Given the high identity of the human and chimpanzee genome sequences, a substantial portion of their phenotypic divergence likely arises from epigenomic differences between the two species.

The transcriptome and epigenomes for trimethylated histone H3 at lysine-4 (H3K4me3) and at lysine-27 (H3K27me3) showed high levels of similarity between the two species.

However, there were some differences in histone modifications.

gains in binding motifs for pluripotency-related transcription factors, especially POU5F1 and SOX2, were frequently found in species-specific H3K4me3 regions.

We also revealed that species-specific insertions of retrotransposons, including the LTR5_Hs subfamily in human and a newly identified LTR5_Pt subfamily in chimpanzee, created species-specific H3K4me3 regions associated with increased expression of nearby genes.

Human iPSCs have more species-specific H3K27me3 regions, resulting in more abundant bivalent domains.

Only a limited number of these species-specific H3K4me3 and H3K27me3 regions overlap with species-biased enhancers in cranial neural crest cells, suggesting that differences in the epigenetic state of developmental enhancers appear late in development.

Therefore, iPSCs serve as a suitable starting material for studying evolutionary changes in epigenome dynamics during development.

Humans and chimpanzees share approximately 98–99% identity in their genomic sequences

but they show many phenotypic differences

It has been shown that small changes in the amino acid sequence of proteins, as well as gains of new proteins in one species, created these interspecific differences; the former is exemplified by sequence changes in FOXP2

it is also considered that interspecific differences can arise from changes in gene expression patterns

which could arise from genetic changes in cis-regulatory elements, such as enhancers.

Gene expression is regulated by epigenetic modifications, such as methylation and acetylation of histone proteins and methylation of DNA, in regulatory regions and gene bodies.

It is conceivable that, with or without changes in the underlying DNA sequence, interspecific differences in epigenetic modifications play an important role in the divergence of the transcriptome and phenotype

Some of these differences in DNA methylation arise from genetic changes, such as those in TF-binding sites (TFBSs) and insertion of retrotransposons (Fukuda et al. 2017). A previous report

many of the changes in enhancer activity are associated with changes in the underlying genetic sequence

It has recently been shown that structural variations (insertions, deletions, and inversions) in genomes contribute to interspecies differences in active chromatin marks, such as histone H3 trimethylation at lysine-4 (H3K4me3)

However, not all epigenetic changes can be explained in terms of genetic changes, leaving a possibility for changes in the epigenetic program during development.

While the transcriptome and epigenome profiles were highly conserved between the two species, there were differences in the histone modifications, some of which were associated with the transcriptional divergence.