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Article ; Online: Function and Constraint in Enhancer Sequences with Multiple Evolutionary Origins.

Fong, Sarah L / Capra, John A

2022 Volume 14, Issue 11

Abstract: Thousands of human gene regulatory enhancers are composed of sequences with multiple evolutionary origins. These evolutionarily "complex" enhancers consist of older "core" sequences and younger "derived" sequences. However, the functional relationship ... ...

Abstract	Thousands of human gene regulatory enhancers are composed of sequences with multiple evolutionary origins. These evolutionarily "complex" enhancers consist of older "core" sequences and younger "derived" sequences. However, the functional relationship between the sequences of different evolutionary origins within complex enhancers is poorly understood. We evaluated the function, selective pressures, and sequence variation across core and derived components of human complex enhancers. We find that both components are older than expected from the genomic background, and complex enhancers are enriched for core and derived sequences of similar evolutionary ages. Both components show strong evidence of biochemical activity in massively parallel report assays. However, core and derived sequences have distinct transcription factor (TF)-binding preferences that are largely similar across evolutionary origins. As expected, given these signatures of function, both core and derived sequences have substantial evidence of purifying selection. Nonetheless, derived sequences exhibit weaker purifying selection than adjacent cores. Derived sequences also tolerate more common genetic variation and are enriched compared with cores for expression quantitative trait loci associated with gene expression variability in human populations. In conclusion, both core and derived sequences have strong evidence of gene regulatory function, but derived sequences have distinct constraint profiles, TF-binding preferences, and tolerance to variation compared with cores. We propose that the step-wise integration of younger derived with older core sequences has generated regulatory substrates with robust activity and the potential for functional variation. Our analyses demonstrate that synthesizing study of enhancer evolution and function can aid interpretation of regulatory sequence activity and functional variation across human populations.
MeSH term(s)	Humans ; Enhancer Elements, Genetic ; Genomics ; Evolution, Molecular
Language	English
Publishing date	2022-10-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2495328-3
ISSN	1759-6653 ; 1759-6653
ISSN (online)	1759-6653
ISSN	1759-6653
DOI	10.1093/gbe/evac159
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Article ; Online: Linking rare and common disease vocabularies by mapping between the human phenotype ontology and phecodes.

McArthur, Evonne / Bastarache, Lisa / Capra, John A

JAMIA open

2023 Volume 6, Issue 1, Page(s) ooad007

Abstract: Enabling discovery across the spectrum of rare and common diseases requires the integration of biological knowledge with clinical data; however, differences in terminologies present a major barrier. For example, the Human Phenotype Ontology (HPO) is the ... ...

Abstract	Enabling discovery across the spectrum of rare and common diseases requires the integration of biological knowledge with clinical data; however, differences in terminologies present a major barrier. For example, the Human Phenotype Ontology (HPO) is the primary vocabulary for describing features of rare diseases, while most clinical encounters use International Classification of Diseases (ICD) billing codes. ICD codes are further organized into clinically meaningful phenotypes via phecodes. Despite their prevalence, no robust phenome-wide disease mapping between HPO and phecodes/ICD exists. Here, we synthesize evidence using diverse sources and methods-including text matching, the National Library of Medicine's Unified Medical Language System (UMLS), Wikipedia, SORTA, and PheMap-to define a mapping between phecodes and HPO terms via 38 950 links. We evaluate the precision and recall for each domain of evidence, both individually and jointly. This flexibility permits users to tailor the HPO-phecode links for diverse applications along the spectrum of monogenic to polygenic diseases.
Language	English
Publishing date	2023-02-28
Publishing country	United States
Document type	Journal Article
ISSN	2574-2531
ISSN (online)	2574-2531
DOI	10.1093/jamiaopen/ooad007
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Article ; Online: Cis-regulatory Landscape Size, Constraint, and Tissue Specificity Associate with Gene Function and Expression.

Benton, Mary Lauren / Ruderfer, Douglas M / Capra, John A

Genome biology and evolution

2023 Volume 15, Issue 7

Abstract: Multiple distal cis-regulatory elements (CREs) often cooperate to regulate gene expression, and the presence of multiple CREs for a gene has been proposed to provide redundancy and robustness to variation. However, we do not understand how attributes of ... ...

Abstract	Multiple distal cis-regulatory elements (CREs) often cooperate to regulate gene expression, and the presence of multiple CREs for a gene has been proposed to provide redundancy and robustness to variation. However, we do not understand how attributes of a gene's distal CRE landscape-the CREs that contribute to its regulation-relate to its expression and function. Here, we integrate three-dimensional chromatin conformation and functional genomics data to quantify the CRE landscape composition genome-wide across ten human tissues and relate their attributes to the function, constraint, and expression patterns of genes. Within each tissue, we find that expressed genes have larger CRE landscapes than nonexpressed genes and that genes with tissue-specific CREs are more likely to have tissue-specific expression. Controlling for the association between expression level and CRE landscape size, we also find that CRE landscapes around genes under strong constraint (e.g., loss-of-function intolerant and housekeeping genes) are not significantly smaller than other expressed genes as previously proposed; however, they do have more evolutionarily conserved sequences than CREs of expressed genes overall. We also show that CRE landscape size does not associate with expression variability across individuals; nonetheless, genes with larger CRE landscapes have a relative depletion for variants that influence expression levels (expression quantitative trait loci). Overall, this work illustrates how differences in gene function, expression, and evolutionary constraint are reflected in features of CRE landscapes. Thus, considering the CRE landscape of a gene is vital for understanding gene expression dynamics across biological contexts and interpreting the effects of noncoding genetic variants.
MeSH term(s)	Humans ; Organ Specificity ; Regulatory Sequences, Nucleic Acid ; Genomics ; Genome ; Phenotype
Language	English
Publishing date	2023-07-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2495328-3
ISSN	1759-6653 ; 1759-6653
ISSN (online)	1759-6653
ISSN	1759-6653
DOI	10.1093/gbe/evad126
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Article ; Online: Resurrecting the alternative splicing landscape of archaic hominins using machine learning.

Brand, Colin M / Colbran, Laura L / Capra, John A

Nature ecology & evolution

2023 Volume 7, Issue 6, Page(s) 939–953

Abstract: Alternative splicing contributes to adaptation and divergence in many species. However, it has not been possible to directly compare splicing between modern and archaic hominins. Here, we unmask the recent evolution of this previously unobservable ... ...

Abstract	Alternative splicing contributes to adaptation and divergence in many species. However, it has not been possible to directly compare splicing between modern and archaic hominins. Here, we unmask the recent evolution of this previously unobservable regulatory mechanism by applying SpliceAI, a machine-learning algorithm that identifies splice-altering variants (SAVs), to high-coverage genomes from three Neanderthals and a Denisovan. We discover 5,950 putative archaic SAVs, of which 2,186 are archaic-specific and 3,607 also occur in modern humans via introgression (244) or shared ancestry (3,520). Archaic-specific SAVs are enriched in genes that contribute to traits potentially relevant to hominin phenotypic divergence, such as the epidermis, respiration and spinal rigidity. Compared to shared SAVs, archaic-specific SAVs occur in sites under weaker selection and are more common in genes with tissue-specific expression. Further underscoring the importance of negative selection on SAVs, Neanderthal lineages with low effective population sizes are enriched for SAVs compared to Denisovan and shared SAVs. Finally, we find that nearly all introgressed SAVs in humans were shared across the three Neanderthals, suggesting that older SAVs were more tolerated in human genomes. Our results reveal the splicing landscape of archaic hominins and identify potential contributions of splicing to phenotypic differences among hominins.
MeSH term(s)	Animals ; Humans ; Hominidae/genetics ; Neanderthals/genetics ; Alternative Splicing ; Genome, Human ; Population Density
Language	English
Publishing date	2023-05-04
Publishing country	England
Document type	Journal Article
ISSN	2397-334X
ISSN (online)	2397-334X
DOI	10.1038/s41559-023-02053-5
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Article ; Online: Modeling the Evolutionary Architectures of Transcribed Human Enhancer Sequences Reveals Distinct Origins, Functions, and Associations with Human Trait Variation.

Fong, Sarah L / Capra, John A

Molecular biology and evolution

2021 Volume 38, Issue 9, Page(s) 3681–3696

Abstract: Despite the importance of gene regulatory enhancers in human biology and evolution, we lack a comprehensive model of enhancer evolution and function. This substantially limits our understanding of the genetic basis of species divergence and our ability ... ...

Abstract	Despite the importance of gene regulatory enhancers in human biology and evolution, we lack a comprehensive model of enhancer evolution and function. This substantially limits our understanding of the genetic basis of species divergence and our ability to interpret the effects of noncoding variants on human traits. To explore enhancer sequence evolution and its relationship to regulatory function, we traced the evolutionary origins of transcribed human enhancer sequences with activity across diverse tissues and cellular contexts from the FANTOM5 consortium. The transcribed enhancers are enriched for sequences of a single evolutionary age ("simple" evolutionary architectures) compared with enhancers that are composites of sequences of multiple evolutionary ages ("complex" evolutionary architectures), likely indicating constraint against genomic rearrangements. Complex enhancers are older, more pleiotropic, and more active across species than simple enhancers. Genetic variants within complex enhancers are also less likely to associate with human traits and biochemical activity. Transposable-element-derived sequences (TEDS) have made diverse contributions to enhancers of both architectures; the majority of TEDS are found in enhancers with simple architectures, while a minority have remodeled older sequences to create complex architectures. Finally, we compare the evolutionary architectures of transcribed enhancers with histone-mark-defined enhancers. Our results reveal that most human transcribed enhancers are ancient sequences of a single age, and thus the evolution of most human enhancers was not driven by increases in evolutionary complexity over time. Our analyses further suggest that considering enhancer evolutionary histories provides context that can aid interpretation of the effects of variants on enhancer function. Based on these results, we propose a framework for analyzing enhancer evolutionary architecture.
MeSH term(s)	DNA Transposable Elements ; Enhancer Elements, Genetic ; Gene Expression Regulation ; Genomics ; Humans ; Phenotype
Chemical Substances	DNA Transposable Elements
Language	English
Publishing date	2021-04-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	998579-7
ISSN	1537-1719 ; 0737-4038
ISSN (online)	1537-1719
ISSN	0737-4038
DOI	10.1093/molbev/msab138
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Article ; Online: GSEL: a fast, flexible python package for detecting signatures of diverse evolutionary forces on genomic regions.

Abraham, Abin / Labella, Abigail L / Benton, Mary Lauren / Rokas, Antonis / Capra, John A

Bioinformatics (Oxford, England)

2024 Volume 39, Issue 1

Abstract: Summary: GSEL is a computational framework for calculating the enrichment of signatures of diverse evolutionary forces in a set of genomic regions. GSEL can flexibly integrate any sequence-based evolutionary metric and analyze sets of human genomic ... ...

Abstract	Summary: GSEL is a computational framework for calculating the enrichment of signatures of diverse evolutionary forces in a set of genomic regions. GSEL can flexibly integrate any sequence-based evolutionary metric and analyze sets of human genomic regions identified by genome-wide assays (e.g. GWAS, eQTL, -seq). The core of GSEL's approach is the generation of empirical null distributions tailored to the allele frequency and linkage disequilibrium structure of the regions of interest. We illustrate the application of GSEL to variants identified from a GWAS of body mass index, a highly polygenic trait. Availability and implementation:* GSEL is implemented as a fast, flexible and user-friendly python package. It is available with demonstration data at https://github.com/abraham-abin13/gsel_vec. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Humans ; Gene Frequency ; Genome, Human ; Genome-Wide Association Study ; Genomics ; Software ; Body Mass Index
Language	English
Publishing date	2024-02-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btad037
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Article ; Online: Human gene regulatory evolution is driven by the divergence of regulatory element function in both cis and trans.

Hansen, Tyler J / Fong, Sarah L / Day, Jessica K / Capra, John A / Hodges, Emily

Cell genomics

2024 Volume 4, Issue 4, Page(s) 100536

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Humans ; Macaca mulatta/genetics ; Regulatory Sequences, Nucleic Acid/genetics ; Gene Expression Regulation/genetics ; Transcription Factors/genetics ; Chromatin/genetics
Chemical Substances	Transcription Factors ; Chromatin
Language	English
Publishing date	2024-04-09
Publishing country	United States
Document type	Journal Article
ISSN	2666-979X
ISSN (online)	2666-979X
DOI	10.1016/j.xgen.2024.100536
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Article: Human gene regulatory evolution is driven by the divergence of regulatory element function in both

Hansen, Tyler / Fong, Sarah / Capra, John A / Hodges, Emily

bioRxiv : the preprint server for biology

2023

Abstract: Gene regulatory divergence between species can result ... ...

Abstract	Gene regulatory divergence between species can result from
Language	English
Publishing date	2023-02-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.14.528376
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Article ; Online: Diverse functions associate with non-coding polymorphisms shared between humans and chimpanzees.

Velazquez-Arcelay, Keila / Benton, Mary Lauren / Capra, John A

BMC ecology and evolution

2022 Volume 22, Issue 1, Page(s) 68

Abstract: Background: Long-term balancing selection (LTBS) can maintain allelic variation at a locus over millions of years and through speciation events. Variants shared between species in the state of identity-by-descent, hereafter "trans-species polymorphisms", ...

Abstract	Background: Long-term balancing selection (LTBS) can maintain allelic variation at a locus over millions of years and through speciation events. Variants shared between species in the state of identity-by-descent, hereafter "trans-species polymorphisms", can result from LTBS, often due to host-pathogen interactions. For instance, the major histocompatibility complex (MHC) locus contains TSPs present across primates. Several hundred candidate LTBS regions have been identified in humans and chimpanzees; however, because many are in non-protein-coding regions of the genome, the functions and potential adaptive roles for most remain unknown. Results: We integrated diverse genomic annotations to explore the functions of 60 previously identified regions with multiple shared polymorphisms (SPs) between humans and chimpanzees, including 19 with strong evidence of LTBS. We analyzed genome-wide functional assays, expression quantitative trait loci (eQTL), genome-wide association studies (GWAS), and phenome-wide association studies (PheWAS) for all the regions. We identify functional annotations for 59 regions, including 58 with evidence of gene regulatory function from GTEx or functional genomics data and 19 with evidence of trait association from GWAS or PheWAS. As expected, the SPs associate in humans with many immune system phenotypes, including response to pathogens, but we also find associations with a range of other phenotypes, including body size, alcohol intake, cognitive performance, risk-taking behavior, and urate levels. Conclusions: The diversity of traits associated with non-coding regions with multiple SPs support previous hypotheses that functions beyond the immune system are likely subject to LTBS. Furthermore, several of these trait associations provide support and candidate genetic loci for previous hypothesis about behavioral diversity in human and chimpanzee populations, such as the importance of variation in risk sensitivity.
MeSH term(s)	Animals ; Genome-Wide Association Study ; Genomics ; Humans ; Pan troglodytes/genetics ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci/genetics
Language	English
Publishing date	2022-05-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2730-7182
ISSN (online)	2730-7182
DOI	10.1186/s12862-022-02020-x
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Article ; Online: Predicting Archaic Hominin Phenotypes from Genomic Data.

Brand, Colin M / Colbran, Laura L / Capra, John A

Annual review of genomics and human genetics

2022 Volume 23, Page(s) 591–612

Abstract: Ancient DNA provides a powerful window into the biology of extant and extinct species, including humans' closest relatives: Denisovans and Neanderthals. Here, we review what is known about archaic hominin phenotypes from genomic data and how those ... ...

Abstract	Ancient DNA provides a powerful window into the biology of extant and extinct species, including humans' closest relatives: Denisovans and Neanderthals. Here, we review what is known about archaic hominin phenotypes from genomic data and how those inferences have been made. We contend that understanding the influence of variants on lower-level molecular phenotypes-such as gene expression and protein function-is a promising approach to using ancient DNA to learn about archaic hominin traits. Molecular phenotypes have simpler genetic architectures than organism-level complex phenotypes, and this approach enables moving beyond association studies by proposing hypotheses about the effects of archaic variants that are testable in model systems. The major challenge to understanding archaic hominin phenotypes is broadening our ability to accurately map genotypes to phenotypes, but ongoing advances ensure that there will be much more to learn about archaic hominin phenotypes from their genomes.
MeSH term(s)	Animals ; DNA, Ancient ; Genome, Human ; Genomics ; Hominidae/genetics ; Humans ; Neanderthals/genetics ; Phenotype
Chemical Substances	DNA, Ancient
Language	English
Publishing date	2022-04-19
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2037670-4
ISSN	1545-293X ; 1527-8204
ISSN (online)	1545-293X
ISSN	1527-8204
DOI	10.1146/annurev-genom-111521-121903
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