Gene regulation and the origins of human biological uniqueness

doi:10.1016/j.tig.2009.12.009

Trends in Genetics

Volume 26, Issue 3, March 2010, Pages 110-118

https://doi.org/10.1016/j.tig.2009.12.009 Get rights and content

What makes us human? It is likely that changes in gene expression and regulation, in addition to those in protein-coding genes, drove the evolution of uniquely human biological traits. In this review, we discuss how efforts to annotate regulatory functions in the human genome are being combined with maps of human-specific sequence acceleration to identify cis-regulatory elements with human-specific activity. Although the evolutionary interpretation of these events is a subject of considerable debate, the technical and analytical means are now at hand to identify the set of evolutionary genetic events that shaped our species.

Section snippets

Cis-regulatory change in human evolution

We consider ourselves to be unique among species. Our capacity for invention, language and abstract thought-indeed, the ability to reflect on the issue at all- sets us apart from all other living things, including our closest primate relatives. For most of human history the question of human uniqueness fell within the realm of religion or metaphysics, rather than natural science. With the sequencing of the human genome and the genomes of many non-human primate species, locating the origins of

Identifying cis-regulatory functions in the human genome

Developmental gene regulation is inherently complex. Thousands of genes must be expressed in highly specific spatial and temporal patterns if the embryo is to develop properly. Locating the components of the developmental regulatory code in the human genome is a central preoccupation of genomics, and is the first barrier to identifying human-specific regulatory changes relevant to human evolution. Thousands of promoters have been identified on the basis of their inherent proximity to genes, as

Annotating human-specific gene regulatory functions

The in vivo studies described above, combined with large-scale ex vivo studies such as ENCODE, have begun to reveal the cis-regulatory landscape of the human genome [14]. These studies provide the knowledge base for parallel genome-wide efforts to annotate uniquely human cis-regulatory functions. The outlines of this new field are just beginning to emerge, but two complementary approaches are likely to provide the greatest insight into human-specific biology. In the first approach, genome-wide

The question of adaptation

It has yet to be determined to what extent human-specific, non-coding sequence acceleration indicates adaptive changes in regulatory functions during human evolution. In other words, are the human-specific substitutions in HACNSs the relics of ancient positive selection for DNA sequence changes that increased fitness by altering the activities of cis-regulatory elements, or are they neutral events? The high frequency of human-specific A to G and T to C substitutions in some HARs and HACNSs,

Concluding remarks

We now have the means to identify and characterize the complete repertoire of gene regulatory changes contributing to human evolution. There are several crucial challenges that need to be met. We need to refine and expand maps of human-specific sequence change to include other modes of sequence change, such as indels. We also need to integrate maps of human-specific, cis-regulatory function with atlases of human-specific, trans-factor binding events, epigenetic modifications, and changes in

Acknowledgements

We thank members of the Noonan laboratory for insightful discussions. This work was supported by funds from the Edward J. Mallinckrodt Foundation, the Kavli Institute for Neuroscience, and the Yale University School of Medicine. The authors declare no conflict of interest.

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Gene regulatory divergence between species can result from cis-acting local changes to regulatory element DNA sequences or global trans-acting changes to the regulatory environment. Understanding how these mechanisms drive regulatory evolution has been limited by challenges in identifying trans-acting changes. We present a comprehensive approach to directly identify cis- and trans-divergent regulatory elements between human and rhesus macaque lymphoblastoid cells using assay for transposase-accessible chromatin coupled to self-transcribing active regulatory region (ATAC-STARR) sequencing. In addition to thousands of cis changes, we discover an unexpected number (∼10,000) of trans changes and show that cis and trans elements exhibit distinct patterns of sequence divergence and function. We further identify differentially expressed transcription factors that underlie ∼37% of trans differences and trace how cis changes can produce cascades of trans changes. Overall, we find that most divergent elements (67%) experienced changes in both cis and trans, revealing a substantial role for trans divergence—alone and together with cis changes—in regulatory differences between species.
Mouse models of human evolution
2014, Current Opinion in Genetics and Development
Citation Excerpt :
One frequently used application of this technology is to transfect a reporter gene driven by an enhancer to assay enhancer activity. In principle all tissues and developmental stages can be examined, but in practice, activity is often assayed just during early stages of mouse development since whole embryos can be quickly screened for reporter gene activity [38]. While probably a considerable fraction of enhancers have changed their activity during human evolution [39•], compensatory changes could still lead to an overall conserved gene expression patterns [40].
The genotype–phenotype map of human evolution is difficult to access since humans cannot be crossed with other species. Most of the ∼20 million genetic changes that occurred since the human and the chimpanzee lineage split, are fixed and hence completely correlated with all phenotypic changes that occurred during human evolution. While patterns of selection and functional information on genomic regions are crucial to prioritize on particular genetic changes, experimental access is needed to test the resulting genotype–phenotype hypotheses and to better understand their mechanisms. The validity and the practicability of such functional assays might be the major limiting factors for understanding human evolution on a functional genetic level. While the mouse as a system for modeling human diseases is well established, it has only more recently been used to study aspects of human evolution, revealing first insights into the evolution of regulatory elements, synapse densities, brain size or speech. Together with a mouse model of a recent, still polymorphic human change, these studies allow careful optimism that at least some aspects of human evolution can be functionally studied in mice.
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Evolutionary changes in enhancers are widely associated with variation in human traits and diseases. However, studies comprehensively quantifying levels of selection on enhancers at multiple evolutionary periods during recent human evolution and how enhancer evolution varies across human tissues are lacking. To address these questions, we integrated a dataset of 41,561 transcribed enhancers active in 41 different human tissues (FANTOM Consortium) with whole genome sequences of 1,668 individuals from the African, Asian, and European populations (1000 Genomes Project). Our analyses based on four different metrics (Tajima’s D, F_ST, H12, nS_L) showed that ∼5.90% of enhancers showed evidence of recent positive selection and that genes associated with enhancers under very recent positive selection are enriched for diverse immune-related functions. The distributions of these metrics for brain and testis enhancers were often statistically significantly different and in the direction suggestive of less positive selection compared to those of other tissues; the same was true for brain and testis enhancers that are tissue-specific compared to those that are tissue-broad and for testis enhancers associated with tissue-enriched and non-tissue-enriched genes. These differences varied considerably across metrics and tissues and were generally in the form of changes in distributions’ shapes rather than shifts in their values. Collectively, these results suggest that many human enhancers experienced recent positive selection throughout multiple time periods in human evolutionary history, that this selection occurred in a tissue-dependent and immune-related functional context, and that much like the evolution of their protein-coding gene counterparts, the evolution of brain and testis enhancers has been markedly different from that of enhancers in other tissues.
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Trends in Genetics

ReviewGene regulation and the origins of human biological uniqueness

Section snippets

Cis-regulatory change in human evolution

Identifying cis-regulatory functions in the human genome

Annotating human-specific gene regulatory functions

The question of adaptation

Concluding remarks

Acknowledgements

Cell

Cell

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Trends Genet.

Am. J. Hum. Genet.

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Nature

Accelerated evolution of conserved noncoding sequences in humans

Science

An RNA gene expressed during cortical development evolved rapidly in humans

Nature

Forces shaping the fastest evolving regions in the human genome

PLoS Genet.

An initial map of insertion and deletion (INDEL) variation in the human genome

Genome Res.

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Quart. Rev. Biol.

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Science

The evolutionary significance of cis-regulatory mutations

Nat. Rev. Genet.

In vivo enhancer analysis of human conserved non-coding sequences

Nature

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Nat. Genet.

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Nature

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Nature

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Nat. Genet.

ChIP-seq accurately predicts tissue-specific activity of enhancers

Nature

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Nature

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Science

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Nature

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PLoS Biol

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Evolution

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Nature

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Nature

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Nature

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Genome Res.

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Nature

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Nature

Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes

Genome Res.

Review
Gene regulation and the origins of human biological uniqueness