Archaic adaptive introgression in
            <i>TBX15/WARS2</i>

Racimo, Fernando; Gokhman, David; Fumagalli, Matteo; Ko, Amy J.; Hansen, Torben; Moltke, Ida; Albrechtsen, Anders; Carmel, Liran; Huerta‐Sánchez, Emilia; Nielsen, Rasmus

doi:10.1093/molbev/msw283

Cited by 94 publications

(88 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our analysis of GWAS data highlighting TBX15 as both an osteoporosis-and obesity-related gene harboring risk SNPs is consistent with the importance to bone development of TBX15 (25) and the relationships of this TF to adipose biology (20,22,23,34,66,67). It is also in accord with the interrelationships in the development of bone and adipose tissue (68) and the preferential expression of TBX15 in both adult-derived ostb and SAT.…”

Section: Discussionsupporting

confidence: 82%

“…It is also preferentially expressed in MSC (which can give rise to ostb) and chond (which are in an alternative pathway to bone formation) (23,66,69). There is also evidence for the involvement of TBX15 in modulating white and brown/brite adipocyte differentiation; mitochondrial function and oxidative or glycolytic metabolism in adipose cells; and cold-adapted adipose metabolism among the Inuit (22,23,34,66,67). In addition, this TF has a well-established role in the embryonic development of many parts of the skeleton (25,26).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Osteoporosis- and obesity-risk interrelationships: An epigenetic analysis of GWAS-derived SNPs at the developmental geneTBX15

Zhang

Ehrlich

et al. 2019

Preprint

View full text Add to dashboard Cite

A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighborhood to prioritize this region's best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15. Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.Recently, whole-genome profiles of epigenetics features, such as promoter-type or enhancer-type chromatin, have been used to help discriminate likely causal variants from bystander SNPs in high LD with them (15,17,18).GWAS SNPs, including those for obesity-related traits (9), are generally enriched in enhancer chromatin or promoter regions (14,15,19,20). In GWAS of (mostly) individuals of European ancestry (EUR) (13, 21) or of East Asians (6, 11), SNPs linked to TBX15 were identified as significantly associated with BMI, WHRadjBMI or WCadjBMI in mixed sex populations, or separately in women or men (Supplementary Material, Table S1). TBX15 codes for a Tbox transcription factor (TF) that may be involved in various aspects of adipose development and maintenance (22)(23)(24) and is known to be important in formation of the skeletal system (25,26). SNPs in or near TBX15 are significantly associated not only with obesity traits but also with estimated heel bone mineral density (eBMD), a useful indicator of hip and non-spine fractures that is used as a proxy for osteoporosis risk (27).Our study of the relationships in GWAS of TBX15 to both adipose and bone biology provides novel insights into the developmental relationships between two related tissue lineages converging on one gene. Both adipocytes and oste...

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Osteoporosis- and obesity-risk interrelationships: An epigenetic analysis of GWAS-derived SNPs at the developmental geneTBX15

Zhang

Ehrlich

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…This hypothesis becomes particularly interesting in the light of previously reported cases of adaptive introgression at LEPR (MIM: 601007) and WARS2/TBX15 (MIM: 604733/604127), both involved in the regulation of adipose tissue differentiation and body-fat distribution. 23,55 Further studies aiming to functionally characterize the regulatory effects of Neanderthal variants on adipocyte differentiation and fat distribution are now warranted, as these archaic variants may have contributed to the adaptation of early Eurasians to colder climates.…”

Section: Discussionmentioning

confidence: 99%

“…6,17,18 Natural selection in Neanderthals would thus have been less efficient to purge deleterious mutations, 19,20 a large proportion of which were removed from the genome of modern humans following their admixture with Neanderthals. 21 However, archaic variants have also contributed, in some cases, to human adaptation, 15,[22][23][24][25][26] shortly after their introduction into modern humans or after an initial period of neutral evolution. 27,28 Given the rapid evolution of regulatory regions and their potential adaptive nature, 29,30 the evolutionary dynamics of Neanderthal introgression at regulatory elements needs to be explored in further detail.…”

Section: Introductionmentioning

confidence: 99%

Impact and evolutionary determinants of Neanderthal introgression on transcriptional and post-transcriptional regulation

Silvert

Rotival

2019

Preprint

View full text Add to dashboard Cite

Archaic admixture is increasingly recognized as an important source of diversity in modern humans, with Neanderthal haplotypes covering 1-3% of the genome of present-day Eurasians. Recent work has shown that archaic introgression has contributed to human phenotypic diversity, mostly through the regulation of gene expression. Yet, the mechanisms through which archaic variants alter gene expression, and the forces driving the introgression landscape at regulatory regions remain elusive. Here, we explored the impact of archaic introgression on transcriptional and post-transcriptional regulation, focusing on promoters and enhancers across 127 different tissues as well as microRNA-mediated regulation.Although miRNAs themselves harbor few archaic variants, we found that some of these variants may have a strong impact on miRNA-mediated gene regulation. Enhancers were by far the regulatory elements most affected by archaic introgression, with one third of the tissues tested presenting significant enrichments. Specifically, we found strong enrichments of archaic variants in adipose-related tissues and primary T cells, even after accounting for various genomic and evolutionary confounders such as recombination rate and background selection. Interestingly, we identified signatures of adaptive introgression at enhancers of some key regulators of adipogenesis, raising the interesting hypothesis of a possible adaptation of early Eurasians to colder climates. Collectively, this study sheds new light onto the mechanisms through which archaic admixture have impacted gene regulation in Eurasians and, more generally, increases our understanding of the contribution of Neanderthals to the regulation of acquired immunity and adipose homeostasis in modern humans.

show abstract

“…Populations in southern Asia contain smaller traces of comparable Denisovan-like DNA, while those in eastern Asia contain traces more similar to the actual Denisova Cave genomes (Browning et al, 2018). Specific Denisovan-like genes linked with high-altitude adaptation and storage of fats have been recognized in Tibetans and Inuit, respectively (Huerta-Sánchez et al, 2014;Racimo et al, 2017). Recent research suggests that the apparent effects of archaic introgression may also be evident in the unusual morphology of late Pleistocene fossils from Dushan Cave, China (Liao et al, 2019), and a primitivelooking mandible from Xiahe has provided the first physical evidence of a Denisovan in China, based on its large and complex molars and proteomic affinities with the material from Denisova Cave (Chen et al, 2019).…”

Section: The Impact Of Adna From Neanderthals and Denisovansmentioning

confidence: 99%

Aspects of human physical and behavioural evolution during the last 1 million years

Galway‐Witham

Cole

Stringer

2019

J Quaternary Science

104

View full text Add to dashboard Cite

This paper reviews some of the main advances in our understanding of human evolution over the last 1 million years, presenting a holistic overview of a field defined by interdisciplinary approaches to studying the origins of our species. We begin by briefly summarizing the climatic context across the Old World for the last 1 million years before directly addressing the fossil and archaeological records. The main themes in this work explore (i) recent discoveries in the fossil record over the last 15 years, such as Homo naledi and Homo floresiensis; (ii) the implications of palaeogenetics for understanding the evolutionary history of, and relationships between, Neanderthals, Denisovans and Homo sapiens; (iii) the interplay between physiology and metabolic demand, landscape use, and behavioural adaptations in the evolution of morphological and behavioural innovation; and (iv) recent advances in archaeological understanding for the behavioural record, in particular that of the Neanderthals. This paper seeks to provide a broad‐scale, holistic perspective of our current understanding of human evolution for the last 1 Ma, providing a reference point for researchers that can be built upon as new discoveries continue to develop the landscapes of human evolution. © 2019 The Authors. Journal of Quaternary Science Published by Wiley Periodicals, Inc.

show abstract

Archaic adaptive introgression in TBX15/WARS2

Cited by 94 publications

References 63 publications

Osteoporosis- and obesity-risk interrelationships: An epigenetic analysis of GWAS-derived SNPs at the developmental geneTBX15

Osteoporosis- and obesity-risk interrelationships: An epigenetic analysis of GWAS-derived SNPs at the developmental geneTBX15

Impact and evolutionary determinants of Neanderthal introgression on transcriptional and post-transcriptional regulation

Aspects of human physical and behavioural evolution during the last 1 million years

Contact Info

Product

Resources

About