Quantitative Trait Loci (QTL) analysis of longevity in C57BL/6J by DBA/2J (BXD) recombinant inbred mice

Lang, Dean H.; Gerhard, Glenn S.; Griffith, James W.; Vogler, George P.; Vandenbergh, David J.; Blizard, David A.; Stout, Joseph T.; Lakoski, Joan M.; McClearn, Gerald E.

doi:10.1007/bf03324809

Cited by 28 publications

(45 citation statements)

References 39 publications

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“…Fisher's exact test shows that the probability of the colocalization is not by chance (18). Among the three life-span QTL in the current report, Ls4 not only colocalizes with mouse longevity QTL previously mapped in the four-way cross, (BALB × B6) × (C3H × D2) and among B6 × D2 recombinant inbred strains (51,52), but also colocalizes with a GWAS peak for human longevity (rs8029244) (50). This is 1.5 Mb from a well-known longevity gene, insulin-like growth factor 1 receptor.…”

Section: Concordance Of Human and Mouse Locimentioning

confidence: 86%

Genetic Regulation of Female Sexual Maturation and Longevity Through Circulating IGF1

Yuan

Gatti

Krier

et al. 2014

The Journals of Gerontology: Series A

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We previously reported that insulin-like growth factor 1 (IGF1) was involved in coregulating female sexual maturation and longevity. To understand the underlying genetic mechanisms, based on the strain survey assays of development and aging traits, we crossed two mouse strains, KK/HIJ and PL/J, and produced 307 female F2 mice. We observed the age of vaginal patency (AVP) and the life span of these females. We also measured circulating IGF1 level at 7, 16, 24, 52, and 76 weeks. IGF1 level at 7 weeks significantly correlated with AVP. IGF1 levels at ages of 52 and 76 weeks negatively correlated with longevity (p ≤ .05). A gene mapping study found 22, 4 ,and 3 quantitative trait loci for IGF1, AVP, and life span, respectively. Importantly, the colocalization of IGF1, AVP, and life span quantitative trait loci in the distal region of chromosome 2 suggests this locus carries gene(s) that could regulate IGF1, AVP, and life span. In this region, proprotein convertase subtilisin/kexin type 2 has been found to be associated with female sexual maturation in a human genome-wide association study. We verified the roles of proprotein convertase subtilisin/kexin type 2 in regulating IGF1 and AVP by showing that depletion of proprotein convertase subtilisin/kexin type 2 significantly reduced IGF1 and delayed AVP in mice, suggesting that it also might be involved in the regulation of aging.Key Words: Female sexual maturation-Life span-Genetics-Mouse-Pcsk2. Decision Editor: Rafael de Cabo, PhDThe evolutionary theory of aging predicts the existence of pleiotropic genes that mediate female sexual maturation (FSM) and life span (1,2). Several lines of evidence support this hypothesis. In the invertebrates, researchers found that allowing only older female Drosophila to reproduce resulted in decreased female fecundity and increased life span in later generations (3,4). In wild mammalian species, ranging from mice to elephants show that the later the initial age of reproduction, the longer the life span (5). The tradeoff holds within species as well. For example, opossums living on a predator-free island in Virginia matured later and aged more slowly than opossums on the "more dangerous" mainland (6). Mice trapped in the wild had delayed FSM and greater female reproduction life span and longevity compared with laboratory mice (7,8). However, the underlying genetic and molecular mechanisms have yet to be clarified.Our previous studies systematically measured age of FSM and longevity in more than 30 mouse inbred strains (9,10). The age of

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Section: Concordance Of Human and Mouse Locimentioning

confidence: 86%

Genetic Regulation of Female Sexual Maturation and Longevity Through Circulating IGF1

Yuan

Gatti

Krier

et al. 2014

The Journals of Gerontology: Series A

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“…Lang et al [10] had previously searched for a genomewide significant peak in this region and found none. However, we predicted that there would be a small peak favoring longevity in the B6 strain exclusively between 35 and 80 megabases on Chr 13 (i.e.…”

Section: Independent Confirmation Of a Survival Effect In This Regionmentioning

confidence: 98%

“…We used WebQTL [18] to map loci associated with median lifespan in an RI panel on Chr 13 [10]. We excluded data for strains that showed very early mortality, as defined by the first quartile of age at death within strain earlier than 500 days of age (e.g.…”

Section: Independent Confirmation Of a Survival Effect In This Regionmentioning

confidence: 99%

“…Initial mapping approaches include quantitative trait locus (QTL) analysis that represents an unbiased association analysis to map genomic regions linked to variation of a phenotype. Previously we conducted QTL analyses of recombinant inbred mice derived from C57BL/ 6J (B6) and DBA/2J (D2) mice that replicated several previously identified longevity associated loci and identified 5 new QTLs [10], which built upon earlier work in these strains [11].…”

Section: Introductionmentioning

confidence: 97%

“…Since QTL for longevity in mice have shown strong sex specificity [10,12], we conducted sex-specific analyses. In addition, we also determined whether there were any change in pathology changes associated with the loci that showed frequency distortions with aging.…”

Section: Introductionmentioning

confidence: 99%

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A Chromosome 13 locus is associated with male-specific mortality in mice

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Complex Genetics of Behavior: BXDs in the Automated Home-Cage

Loos

Verhage

Spijker

et al. 2016

Methods in Molecular Biology

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This chapter describes a use case for the genetic dissection and automated analysis of complex behavioral traits using the genetically diverse panel of BXD mouse recombinant inbred strains. Strains of the BXD resource differ widely in terms of gene and protein expression in the brain, as well as in their behavioral repertoire. A large mouse resource opens the possibility for gene finding studies underlying distinct behavioral phenotypes, however, such a resource poses a challenge in behavioral phenotyping. To address the specifics of large-scale screening we describe how to investigate: (1) how to assess mouse behavior systematically in addressing a large genetic cohort, (2) how to dissect automation-derived longitudinal mouse behavior into quantitative parameters, and (3) how to map these quantitative traits to the genome, deriving loci underlying aspects of behavior.

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Quantitative Trait Loci (QTL) analysis of longevity in C57BL/6J by DBA/2J (BXD) recombinant inbred mice

Cited by 28 publications

References 39 publications

Genetic Regulation of Female Sexual Maturation and Longevity Through Circulating IGF1

Genetic Regulation of Female Sexual Maturation and Longevity Through Circulating IGF1

A Chromosome 13 locus is associated with male-specific mortality in mice

Complex Genetics of Behavior: BXDs in the Automated Home-Cage

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