Adaptive sequence divergence forged new neurodevelopmental enhancers in humans

Mangan, Riley J.; Alsina, Fernando C.; Mosti, Federica; Sotelo-Fonseca, Jesús Emiliano; Snellings, Daniel A.; Au, Eric H.; Carvalho, Juliana Lott; Sathyan, Laya; Johnson, Graham D.; Reddy, Timothy E.; Silver, Debra L.; Lowe, Craig B.

doi:10.1016/j.cell.2022.10.016

Cited by 62 publications

(45 citation statements)

References 115 publications

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“…[4][5][6] Humanlineage-specific genomic sequences have been shown to be enriched for brain-specific elements and risk loci for neurodegenerative disorders. 7 Thus, while positive natural selection may have driven a proportion of human-specific adaptive evolution, 8,9 it may be possible that the same selected variants also influence the risk of neurodegenerative disease.…”

Section: Introductionmentioning

confidence: 99%

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

Chen

Reynolds

Pardiñas

et al. 2022

Preprint

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BackgroundHumans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions.MethodsWe used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.ResultsWe found a significant depletion of positively-selected SNPs in the heritability of Parkinson’s disease, raising the possibility that these variants may modulate disease risk, in addition to conferring an evolutionary advantage. For Alzheimer’s disease and amyotrophic lateral sclerosis, common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk.ConclusionsThese findings provide insight into the origins of neurodegenerative disorders within the evolution of Homo sapiens and addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans.

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Section: Introductionmentioning

confidence: 99%

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

Chen

Reynolds

Pardiñas

et al. 2022

Preprint

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“…This is consistent with the fact that enhancer sequences are largely species-specific, being conserved only between close phyla, in sharp contrast to genes (74, 187, 232). Simple repeats may also be involved (47, 108, 109). Any young TE is subjected to repression upon insertion and can seemingly behave as a ProB element.…”

Section: Discussionmentioning

confidence: 99%

“…A growing body of literature shows that, in all tissues where this has been investigated, a significant proportion of DHS/enhancers active in a given cell type are in fact RepSeqs (26,(104)(105)(106)(107). Mounting evidence further suggests that all DHS/enhancers are of RepSeq origin, deriving either from TE or non-TE sequences, which may essentially have become undetectable due to sequence drift across evolutionary times (see Box1) (47,74,(108)(109)(110).…”

Section: Dhs/enhancers Are Of Repseq Originmentioning

confidence: 99%

ProA and ProB repeat sequences shape genome organization, and enhancers open domains

Bonnet,

Hulo,

Mourad

et al. 2023

Preprint

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SUMMARYThere is a growing awareness that repeat sequences (RepSeq) - the main constituents of the human genome - are also prime players in its organization. Here we propose that the genome should be envisioned as a supersystem with three main subsystems, each composed of functionally redundant, cooperating elements. We define herein ProA and ProB RepSeqs as sequences that promote either the A/euchromatin or the B/heterochromatin compartment. ProA and ProB RepSeqs shape A/B partitioning, such that the relative proportions of ProA and ProB RepSeqs determine the propensity of a chromosome segment to adopt either an A or a B configuration. In human, core ProA RepSeqs are essentially made of Alu elements, whereas core ProB RepSeqs consist of young L1 and some Endogenous Retroviruses (ERVs) as well as a panel of AT-rich microsatellites and pericentromeric and telomeric satellites. Additionally, RepSeqs with more indefinite character and, importantly, their derivatives known as “transcriptional enhancers”, can shift between ProA and ProB functions and thus act to open or close specific chromatin domains depending on the cellular context. In this framework, genes and their promoters appear as a special class of RepSeqs that, in their active, transcribed state, reinforce the openness of their surroundings. Molecular mechanisms involve cooperativity between ProB elements, presumably underpinned by the condensate-like properties of heterochromatin, which ProA elements oppose in several ways. We provide strong arguments that altered CpG methylation patterns in cancer including a marked loss in the B compartment, result primarily from a global imbalance in the process of CpG methylation and its erasure. Our results suggest that the resulting altered methylation and impaired function of ProB RepSeqs globally weaken the B compartment, rendering it more plastic, which in turn may confer fate plasticity to the cancer cell.

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“…Conservation-based analyses have focused on the modification of existing functional elements; however, the origin of novel functional elements from neutrally evolving DNA could provide an even greater reduction in pleiotropic effects. Indeed, the most divergent regions of the human genome are enriched for bivalent chromatin marks indicative of gene regulatory potential across diverse cell types and anatomical locations, including a few regions where the human sequence functions as a neurodevelopmental enhancer but the sequence from the inferred human–chimpanzee ancestor does not 78 . Future analyses are required to reveal more examples of evolutionary changes that generate novel human-specific functional elements.…”

Section: Comparative Great Ape Genomicsmentioning

confidence: 99%

Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution

et al. 2023

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Our ancestors acquired morphological, cognitive and metabolic modifications that enabled humans to colonize diverse habitats, develop extraordinary technologies and reshape the biosphere. Understanding the genetic, developmental and molecular bases for these changes will provide insights into how we became human. Connecting human-specific genetic changes to species differences has been challenging owing to an abundance of low-effect size genetic changes, limited descriptions of phenotypic differences across development at the level of cell types and lack of experimental models. Emerging approaches for single-cell sequencing, genetic manipulation and stem cell culture now support descriptive and functional studies in defined cell types with a human or ape genetic background. In this Review, we describe how the sequencing of genomes from modern and archaic hominins, great apes and other primates is revealing human-specific genetic changes and how new molecular and cellular approaches — including cell atlases and organoids — are enabling exploration of the candidate causal factors that underlie human-specific traits.

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Adaptive sequence divergence forged new neurodevelopmental enhancers in humans

Cited by 62 publications

References 115 publications

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

ProA and ProB repeat sequences shape genome organization, and enhancers open domains

Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution

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