Evolutionary conserved longevity genes and human cognitive abilities in elderly cohorts

Lopez, Lorna M.; Harris, Sarah E.; Luciano, Michelle; Liewald, D.C.M.; Davies, Gail; Gow, Alan J.; Tenesa, Albert; Payton, Antony; Ke, Xiayi; Whalley, Lawrence J.; Fox, Helen; Haggerty, Paul; Ollier, William; Pickles, Andrew; Porteous, David J.; Horan, Michael A.; Pendleton, Neil; Starr, John M.; Deary, Ian J.

doi:10.1038/ejhg.2011.201

Cited by 28 publications

(27 citation statements)

References 49 publications

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“…In addition to the 125 genes considered above, many of the genes identified as associated with domestication by only one of the four methods are potentially interesting and worthy of further research. These genes include synaptojanin 2 (SYNJ2), which has been detected with PAML [phylogenetic analysis by maximum likelihood; false discovery rate (FDR) = 5%] and represents a longevity gene candidate associated with variation in levels of agreeableness and cognitive abilities (60,61). Such changes could have been instrumental in the development of tameness and increased social interactions with humans.…”

Section: Resultsmentioning

confidence: 99%

Prehistoric genomes reveal the genetic foundation and cost of horse domestication

Schubert

Jónsson

Chang

et al. 2014

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

271

281

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The domestication of the horse ∼5.5 kya and the emergence of mounted riding, chariotry, and cavalry dramatically transformed human civilization. However, the genetics underlying horse domestication are difficult to reconstruct, given the near extinction of wild horses. We therefore sequenced two ancient horse genomes from Taymyr, Russia (at 7.4-and 24.3-fold coverage), both predating the earliest archeological evidence of domestication. We compared these genomes with genomes of domesticated horses and the wild Przewalski's horse and found genetic structure within Eurasia in the Late Pleistocene, with the ancient population contributing significantly to the genetic variation of domesticated breeds. We furthermore identified a conservative set of 125 potential domestication targets using four complementary scans for genes that have undergone positive selection. One group of genes is involved in muscular and limb development, articular junctions, and the cardiac system, and may represent physiological adaptations to human utilization. A second group consists of genes with cognitive functions, including social behavior, learning capabilities, fear response, and agreeableness, which may have been key for taming horses. We also found that domestication is associated with inbreeding and an excess of deleterious mutations. This genetic load is in line with the "cost of domestication" hypothesis also reported for rice, tomatoes, and dogs, and it is generally attributed to the relaxation of purifying selection resulting from the strong demographic bottlenecks accompanying domestication. Our work demonstrates the power of ancient genomes to reconstruct the complex genetic changes that transformed wild animals into their domesticated forms, and the population context in which this process took place.ancient DNA | horse domestication | Przewalski's horse | positive selection | cost of domestication T he domestication of the horse had a far-reaching impact on the sociopolitical and economic trajectories of human societies (1). It not only provided meat and milk (2) but also enabled the development of continent-sized nomadic empires, by transforming warfare and allowing for the rapid spread of goods and information over long distances. However, despite the characterization of the genome of modern horses (3), an understanding of the genetic processes underlying horse domestication is still lacking. In other organisms, such an understanding is usually achieved by comparing the genomes of domesticated species and their wild relatives (4-6), but this approach is not directly applicable to horses. Recent genome-wide analyses have shown that Przewalski's horse, the last truly wild horse population remaining today, is not the direct ancestor of domesticated SignificanceThe domestication of the horse revolutionized warfare, trade, and the exchange of people and ideas. This at least 5,500-ylong process, which ultimately transformed wild horses into the hundreds of breeds living today, is difficult to reconstruct from archeological data...

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Section: Resultsmentioning

confidence: 99%

Prehistoric genomes reveal the genetic foundation and cost of horse domestication

Schubert

Jónsson

Chang

et al. 2014

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

271

281

View full text Add to dashboard Cite

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“…It is differentially expressed in hippocampal sub-regions of the marmoset primate [47] and shows decreased expression in the human temporal cortex in persons with major depressive disorder [48]. SYNJ2 has been associated with cognitive abilities in two independent elderly cohorts [49]. Finally, haploinsufficiency of SYNJ2 due to a microdeletion on 6q is associated with a syndrome that presents with microencephaly, developmental delay and agenesis of the corpus callosum [50].…”

Section: Discussionmentioning

confidence: 99%

Genetic Interactions within Inositol-Related Pathways are Associated with Longitudinal Changes in Ventricle Size

Koran

Hohman

Meda

et al. 2013

JAD

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The genetic etiology of late onset Alzheimer disease (LOAD) has proven complex, involving clinical and genetic heterogeneity and gene-gene interactions. Recent genome wide association studies (GWAS) in LOAD have led to the discovery of novel genetic risk factors; however, the investigation of gene-gene interactions has been limited. Conventional genetic studies often use binary disease status as the primary phenotype, but for complex brain-based diseases, neuroimaging data can serve as quantitative endophenotypes that correlate with disease status and closely reflect pathological changes. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, we tested for association of genetic interactions with longitudinal MRI measurements of the inferior lateral ventricles (ILVs), which have repeatedly shown a relationship to LOAD status and progression. We performed linear regression to evaluate the ability of pathway-derived SNP-SNP pairs to predict the slope of change in volume of the ILVs. After Bonferroni correction, we identified four significant interactions in the right ILV (RILV) corresponding to gene-gene pairs SYNJ2-PI4KA, PARD3-MYH2, PDE3A-ABHD12B and OR2L13-PRKG1 and one significant interaction in the left ILV (LILV) corresponding to SYNJ2-PI4KA. The SNP-SNP interaction corresponding to SYNJ2-PI4KA was identical in the RILV and LILV and was the most significant interaction in each (RILV: p=9.10×10−12; LILV: p=8.20×10−13). Both genes belong to the inositol phosphate signaling pathway which has been previously associated with neurodegeneration in AD and we discuss the possibility that perturbation of this pathway results in a down-regulation of the Akt cell survival pathway and, thereby, decreased neuronal survival, as reflected by increased volume of the ventricles.

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“…Furthermore, deletions of other genes encoding mitoproteases, such as Afg3l2, Clpp and Parl, cause severe defects in mice, such as axonal degeneration, multisystem disorder and cachexia by general atrophy, respectively, which ultimately shorten their lifespan owing to impaired mitochondrial activities 41,106,117 . By contrast, another study suggested that single nucleotide polymorphisms (SNPs) in AGF3L2 are associated with longevity and enhanced cognitive abilities in elderly humans 118 .…”

Section: Mitochondrial Proteolysis and Ageingmentioning

confidence: 97%

New roles for mitochondrial proteases in health, ageing and disease

Quirós

Langer

López-Otı́n

2015

Nat Rev Mol Cell Biol

455

424

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Recent advances in mitochondrial biology have revealed the high diversity and complexity of proteolytic enzymes that regulate mitochondrial function. We have classified mitochondrial proteases, or mitoproteases, on the basis of their function and location, and defined the human mitochondrial degradome as the complete set of mitoproteases that are encoded by the human genome. In addition to their nonspecific degradative functions, mitoproteases perform highly regulated proteolytic reactions that are important in mitochondrial function, integrity and homeostasis. These include protein synthesis, quality control, mitochondrial biogenesis and dynamics, mitophagy and apoptosis. Impaired or dysregulated function of mitoproteases is associated with ageing and with many pathological conditions such as neurodegenerative disorders, metabolic syndromes and cancer. A better understanding of the mitochondrial proteolytic landscape and its modulation may contribute to improving human lifespan and 'healthspan'.

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Evolutionary conserved longevity genes and human cognitive abilities in elderly cohorts

Cited by 28 publications

References 49 publications

Prehistoric genomes reveal the genetic foundation and cost of horse domestication

Prehistoric genomes reveal the genetic foundation and cost of horse domestication

Genetic Interactions within Inositol-Related Pathways are Associated with Longitudinal Changes in Ventricle Size

New roles for mitochondrial proteases in health, ageing and disease

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