Identifying Recent Adaptations in Large-Scale Genomic Data

Grossman, Sharon R.; Andersen, Kristian G.; Shlyakhter, Ilya; Tabrizi, Shervin; Winnicki, S; Yen, Angela; Park, Daniel J.; Griesemer, Dustin; Karlsson, Elinor K.; Wong, Sunny H.; Cabili, Moran N.; Adegbola, Richard A.; Bamezai, R.; Hill, Adrian V. S.; Vannberg, Fredrik; Rinn, John L.; Lander, Eric S.; Schaffner, Stephen F.; Sabeti, Pardis C.

doi:10.1016/j.cell.2013.01.035

Cited by 335 publications

(405 citation statements)

References 73 publications

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“…With the rapidly growing wealth of genomic data and capacity for whole proteome alignment, identification of all human PCEs has become accessible. This should lead to exciting studies aimed at understanding the likely functional consequences of important divergences due to countless rounds of evolutionary selection (37). Furthermore, this type of sequence analysis approach can be highly efficient at identifying useful discrepancies among homologous proteins from different organisms.…”

Section: Discussionmentioning

confidence: 99%

Functional significance of evolving protein sequence in dihydrofolate reductase from bacteria to humans

Liu

Hanoian

French

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

141

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With the rapidly growing wealth of genomic data, experimental inquiries on the functional significance of important divergence sites in protein evolution are becoming more accessible. Here we trace the evolution of dihydrofolate reductase (DHFR) and identify multiple key divergence sites among 233 species between humans and bacteria. We connect these sites, experimentally and computationally, to changes in the enzyme's binding properties and catalytic efficiency. One of the identified evolutionarily important sites is the N23PP modification (∼mid-Devonian, 415-385 Mya), which alters the conformational states of the active site loop in Escherichia coli dihydrofolate reductase and negatively impacts catalysis. This enzyme activity was restored with the inclusion of an evolutionarily significant lid domain (G51PEKN in E. coli enzyme; ∼2.4 Gya). Guided by this evolutionary genomic analysis, we generated a human-like E. coli dihydrofolate reductase variant through three simple mutations despite only 26% sequence identity between native human and E. coli DHFRs. Molecular dynamics simulations indicate that the overall conformational motions of the protein within a common scaffold are retained throughout evolution, although subtle changes to the equilibrium conformational sampling altered the free energy barrier of the enzymatic reaction in some cases. The data presented here provide a glimpse into the evolutionary trajectory of functional DHFR through its protein sequence space that lead to the diverged binding and catalytic properties of the E. coli and human enzymes.phylogenetic | EVB

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Section: Discussionmentioning

confidence: 99%

Functional significance of evolving protein sequence in dihydrofolate reductase from bacteria to humans

Liu

Hanoian

French

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

141

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“…While genome-wide association studies (GWAS) and whole genome scans for natural selection have identified numerous loci linked to human traits and diseases, correlation between nearby polymorphisms (linkage disequilibrium, or LD) within individual associations often leaves dozens to hundreds of potential causal variants to be interrogated (Grossman et al, 2013;Schaub et al, 2012). Mounting evidence suggests that at the majority of these loci, the causal variant(s) is a non-coding regulatory change rather than an amino acid substitution (Farh et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay

Tewhey¹,

Kotliar²,

Park³

et al. 2018

Cell

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114

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SummaryAlthough studies have identified hundreds of loci associated with human traits and diseases, pinpointing causal alleles remains difficult, particularly for non-coding variants. To address this challenge, we adapted the massively parallel reporter assay (MPRA) to identify variants that directly modulate gene expression. We applied it to 32,373 variants from 3,642 cis-expression quantitative trait loci and control regions. Detection by MPRA was strongly correlated with measures of regulatory function. We demonstrate MPRA's capabilities for pinpointing causal alleles, using it to identify 842 variants showing differential expression between alleles, including 53 well-annotated variants associated with diseases and traits. We investigated one in detail, a risk allele for ankylosing spondylitis, and provide direct evidence of a non-coding variant that alters expression of the prostaglandin EP 4 receptor. These results create a resource of concrete leads and illustrate the promise of this approach for comprehensively interrogating how non-coding polymorphism shapes human biology.

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“…Thus, the field of evolutionary genomics now has the potential to provide many new testable hypotheses of selection, which were not developed a priori. For example, a catalog of candidate variants for selection was recently published and one of these variants was experimentally characterized [102]. At this turning point in the field, we seek to underscore that many aspects of human evolution are best understood by investigating the life--history bottleneck of pregnancy and birth from the perspective of both the mother and the infant.…”

Section: Discussionmentioning

confidence: 99%