Human evolution: the non-coding revolution

Franchini, Lucía F.; Pollard, Katherine S.

doi:10.1186/s12915-017-0428-9

Cited by 84 publications

(60 citation statements)

References 100 publications

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“…These lineage-specific accelerated regions (linARs) have more substitutions than expected in various combinations of all five lineages. The humanaccelerated linARs overlap previously identified HARs as much as expected based on prior comparisons of HARs derived with different data and methods (Supplemental Text) (Franchini and Pollard 2017). We describe relative numbers for different apes below.…”

Section: Resultssupporting

confidence: 61%

Developmental loci harbor clusters of accelerated regions that evolved independently in ape lineages

Kostka

Holloway

Pollard

2017

Preprint

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Some of the fastest evolving regions of the human genome are conserved non-coding elements with many human-specific DNA substitutions. These Human Accelerated Regions (HARs) are enriched nearby regulatory genes, and several HARs function as developmental enhancers. To investigate if this evolutionary signature is unique to humans, we quantified evidence of accelerated substitutions in conserved genomic elements across multiple lineages and applied this approach simultaneously to the genomes of five apes: human, chimpanzee, gorilla, orangutan, and gibbon. We find roughly similar numbers and genomic distributions of lineage-specific accelerated regions (linARs) in all five apes. In particular, apes share an enrichment of linARs in regulatory DNA nearby genes involved in development, especially transcription factors and other regulators. Many developmental loci harbor clusters of nonoverlapping linARs from multiple apes, suggesting that accelerated evolution in each species affected distinct regulatory elements that control a shared set of developmental pathways. Our statistical tests distinguish between GC-biased and unbiased accelerated substitution rates, allowing us to quantify the roles of different evolutionary forces in creating linARs. We find evidence of GC-biased gene conversion in each ape, but unbiased acceleration consistent with positive selection or loss of constraint is more common in all five lineages. It therefore appears that similar evolutionary processes created independent accelerated regions in the genomes of different apes, and that these lineage-specific changes to conserved non-coding sequences may have differentially altered expression of a core set of developmental genes across ape evolution.

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Section: Resultssupporting

confidence: 61%

Developmental loci harbor clusters of accelerated regions that evolved independently in ape lineages

Kostka

Holloway

Pollard

2017

Preprint

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“…Interestingly, HSGDs have often resulted in the formation of truncated paralogs and several of these truncated HSGDs have recently been implicated in regulating brain development [2][3][4]8,22,23]. This suggests that evolutionary changes affecting levels and patterns of expression not only occurred through modifications in regulators of gene expression at the genomic level [24], but also at the level of protein interactions through the emergence of insoluble proteins.…”

Section: Discussionmentioning

confidence: 99%

The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development

Schmidt

Kupferman

Stackmann

et al. 2019

Preprint

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Human-specific gene duplications (HSGD) have recently emerged as key modifiers of brain development and evolution. However, the molecular mechanisms underlying the function of HSGDs remain often poorly understood. In humans, a truncated duplication of SRGAP2A led to the emergence of two human-specific paralogs: SRGAP2B and SRGAP2C. The ancestral copy SRGAP2A limits synaptic density and promotes maturation of both excitatory (E) and inhibitory (I) synapses received by cortical pyramidal neurons (PNs). SRGAP2C binds to and inhibits all known functions of SRGAP2A leading to an increase in E and I synapse density and protracted synapse maturation, traits characterizing human cortical neurons. Here, we demonstrate how the evolutionary changes that led to the emergence of SRGAP2 HSGD generated proteins that, in neurons, are intrinsically unstable and upon hetero-dimerization with SRGAP2A, reduces SRGAP2A levels in a proteasome-dependent manner. Moreover, we show that, compared to SRGAP2B, and despite only a few non-synonymous mutations specifically targeting arginine residues, SRGAP2C is unique, compared to SRGAP2B, in its ability to induce long-lasting changes in synaptic density throughout adulthood. The non-synonymous mutations specifically targeting arginine residues led to the unique ability of SRGAP2C to inhibit SRGAP2A function and thereby contribute to the emergence of human-specific features of synaptic development during evolution.

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“…Interestingly, the remaining non-functional fraction of the genome covered only ~20.5% of the genome. To draw query alignments, we used used msa_split (Hubisz et al 2011) to draw alignments from non-coding human accelerated elements, ncHAEs (Pollard, Salama, King, et al 2006; Bird et al 2007; Bush and Lahn 2008; Prabhakar et al 2008; Franchini and Pollard 2017), a random subset of non-functional regions (as defined below), and DNA Hypersensitive Sites (DHSs) from 125 human cell types and tissues (Thurman et al 2012).…”

Section: Methodsmentioning

confidence: 99%

Identifying branch-specific positive selection throughout the regulatory genome using an appropriate neutral proxy

Berrío

Haygood

2019

Preprint

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AbstractAdaptive changes in cis-regulatory elements are an essential component of evolution by natural selection. Identifying adaptive and functional noncoding DNA elements throughout the genome is therefore crucial for understanding the relationship between phenotype and genotype. Here, we introduce a method we called adaptyPhy, which adds significant improvements to our earlier method that tests for branch-specific directional selection in noncoding sequences. The motivation for these improvements is to provide a more sensitive and better targeted characterization of directional selection and neutral evolution across the genome. We use ENCODE annotations to identify appropriate proxy neutral sequences and demonstrate that the conservativeness of the test can be modulated during the filtration of reference alignments. We apply the method to noncoding Human Accelerated Elements as well as open chromatin elements previously identified in 125 human tissues and cell lines to demonstrate its utility. We also simulate sequence alignments under different classes of evolution in order to validate the ability of adaptiPhy to distinguish positive selection from relaxation of constraint and neutral evolution. Finally, we evaluate the impact of query region length, proxy neutral sequence length, and branch count on test sensitivity.

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Human evolution: the non-coding revolution

Cited by 84 publications

References 100 publications

Developmental loci harbor clusters of accelerated regions that evolved independently in ape lineages

Developmental loci harbor clusters of accelerated regions that evolved independently in ape lineages

The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development

Identifying branch-specific positive selection throughout the regulatory genome using an appropriate neutral proxy

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