Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.

Chen, Jianhai; Landback, Patrick; Arsala, Deanna; Guzzetta, Alexander; Xia, Shengqian; Atlas, Jared; Sosa, Dylan; Zhang, Yong; Cheng, Jingqiu; Shen, Bairong; Long, Manyuan

doi:10.1101/2023.11.14.567139

Cited by 3 publications

(1 citation statement)

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“…Empirical evidence has highlighted the essential and innovative roles of evolutionary new genes in biological systems (Chen, et al 2013; Heinen, et al 2009; Long and Langley 1993; Long, et al 2013; Tautz 2014; Xia, et al 2021; Xie, et al 2019a; Xie, et al 2019b; Zhuang, et al 2019). One proposed mechanism for the rapid functional diversification of new genes is their low pleiotropic constraints as a competitive advantage compared to older and conserved genes (Chen, et al 2023a; Hoekstra and Coyne 2007).…”

Section: Discussionmentioning

confidence: 99%

One million years of solitude: the rapid evolution of de novo protein structure and complex

Chen,

Li,

Xia

et al. 2023

Preprint

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Recent studies have established that de novo genes, evolving from non-coding sequences, enhance protein diversity through a stepwise process. However, the pattern and rate of their structural evolution over time remain unclear. Here, we addressed these issues within a short evolutionary timeframe (∼1 million years for 97% of rice de novo genes). We found that de novo genes evolve faster than gene duplicates in the intrinsic disordered regions (IDRs, such as random coils), secondary structural elements (such as α-helix and β-strand), hydrophobicity, and molecular recognition features (MoRFs). Specifically, we observed an 8-14% decay in random coils and IDR lengths per million years per protein, and a 2.3-6.5% increase in structured elements, hydrophobicity, and MoRFs. These patterns of structural evolution align with changes in amino acid composition over time. We also revealed significantly higher positive charges but smaller molecular weights for de novo proteins than duplicates. Tertiary structure predictions demonstrated that most de novo proteins, though not typically well-folded on their own, readily form low-energy and compact complexes with extensive residue contacts and conformational flexibility, suggesting “a faster-binding” scenario in de novo proteins to promote interaction. Our findings illuminate the rapid evolution of protein structure in the early life of de novo proteins in rice genome, originating from noncoding sequences, highlighting their quick transformation into active, complex-forming components within a remarkably short evolutionary timeframe.

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Section: Discussionmentioning

confidence: 99%

One million years of solitude: the rapid evolution of de novo protein structure and complex

Chen,

Li,

Xia

et al. 2023

Preprint

Self Cite

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Functional associations of evolutionarily recent human genes exhibit sensitivity to the 3D genome landscape and disease

Fleck,

Luria,

Garag

et al. 2024

Preprint

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Genome organization is intricately tied to regulating genes and associated cell fate decisions. In this study, we examine the positioning and functional significance of human genes, grouped by their evolutionary age, within the 3D organization of the genome. We reveal that genes of different evolutionary origin have distinct positioning relationships with both domains and loop anchors, and remarkably consistent relationships with boundaries across cell types. While the functional associations of each group of genes are primarily cell type-specific, such associations of conserved genes maintain greater stability across 3D genomic features and disease than recently evolved genes. Furthermore, the expression of these genes across various tissues follows an evolutionary progression, such that RNA levels increase from young genes to ancient genes. Thus, the distinct relationships of gene evolutionary age, function, and positioning within 3D genomic features contribute to tissue-specific gene regulation in development and disease.

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Genetic Basis, Quantitative Nature, and Functional Relevance of Evolutionarily Conserved DNA Methylation

Dong,

Schaffner,

et al. 2024

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DNA methylation (DNAm) is a key epigenetic mark that modulates regulatory elements and gene expression, playing a crucial role in mammalian development and physiological function. Despite extensive characterization of DNAm profiles across species, little is known about its evolutionary conservation. Here, we conducted a comparative epigenome-wide analysis of great apes to identify and characterize sequence- and methylation-conserved CpGs (MCCs). Using 202 DNAm arrays, alongside 6 matched genotype and 13 matched transcriptomic datasets, we identified 11,500 MCCs for which methylation was evolutionarily related to sequences of CpGs and methylation quantitative trait loci. MCCs were the most stable across healthy human tissues and exhibited weaker genetic associations than other CpGs. Moreover, MCCs showed minimal associations with demographic, environmental factors, and noncancer diseases, yet demonstrated stronger associations with certain cancers than other CpGs, particularly gastrointestinal cancers. Functional enrichment analysis revealed that genes associated with MCC methylation in cancer were enriched for cancer driver genes and canonical cancer pathways, highlighting a significant regulatory role for MCCs in tumorigenesis. Collectively, our findings reveal the extent of DNAm conservation in great ape evolution, its association with genetic conservation, and its relevance to human diseases. These integrative analyses offer evolutionary insights into epigenetic variation and its functional implications in human populations.

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Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.

Cited by 3 publications

References 169 publications

One million years of solitude: the rapid evolution of de novo protein structure and complex

One million years of solitude: the rapid evolution of de novo protein structure and complex

Functional associations of evolutionarily recent human genes exhibit sensitivity to the 3D genome landscape and disease

Genetic Basis, Quantitative Nature, and Functional Relevance of Evolutionarily Conserved DNA Methylation

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