title: Rec-8 dimorphism affects longevity, stress resistance and X-chromosome nondisjunction in C. elegans, and replicative lifespan in S. cerevisiae.
abstract: A quantitative trait locus (QTL) in the nematode C. elegans, "lsq4," was recently implicated by mapping longevity genes. QTLs for lifespan and three stress-resistance traits coincided within a span of <300 kbp, later narrowed to <200 kbp. A single gene in this interval is now shown to modulate all lsq4-associated traits. Full-genome analysis of transcript levels indicates that lsq4 contains a dimorphic gene governing the expression of many sperm-specific genes, suggesting an effect on spermatogenesis. Quantitative analysis of allele-specific transcripts encoded within the lsq4 interval revealed significant, 2- to 15-fold expression differences for 10 of 33 genes. Fourteen "dual-candidate" genes, implicated by both position and expression, were tested for RNA-interference effects on QTL-linked traits. In a strain carrying the shorter-lived allele, knockdown of rec-8 (encoding a meiotic cohesin) reduced its transcripts 4-fold, to a level similar to the longer-lived strain, while extending lifespan 25-26%, whether begun before fertilization or at maturity. The short-lived lsq4 allele also conferred sensitivity to oxidative and thermal stresses, and lower male frequency (reflecting X-chromosome non-disjunction), traits reversed uniquely by rec-8 knockdown. A strain bearing the longer-lived lsq4 allele, differing from the short-lived strain at <0.3% of its genome, derived no lifespan or stress-survival benefit from rec-8 knockdown. We consider two possible explanations: high rec-8 expression may include increased "leaky" expression in mitotic cells, leading to deleterious destabilization of somatic genomes; or REC-8 may act entirely in germ-line meiotic cells to reduce aberrations such as non-disjunction, thereby blunting a stress-resistance response mediated by innate immunity. Replicative lifespan was extended 20% in haploid S. cerevisiae (BY4741) by deletion of REC8, orthologous to nematode rec-8, implying that REC8 disruption of mitotic-cell survival is widespread, exemplifying antagonistic pleiotropy (opposing effects on lifespan vs. reproduction), and/or balancing selection wherein genomic disruption increases genetic variation under harsh conditions.
authors.affiliation: Central Arkansas Veterans Healthcare System, VA Medical Center Little Rock, AR, USA ; Department of Geriatrics, University of Arkansas for Medical Sciences Little Rock, AR, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ayyadevara
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences Little Rock, AR, USA.
authors.forename: Cagdas
authors.initials: C
authors.lastname: Tazearslan
authors.affiliation: Central Arkansas Veterans Healthcare System, VA Medical Center Little Rock, AR, USA ; Department of Geriatrics, University of Arkansas for Medical Sciences Little Rock, AR, USA.
authors.forename: Ramani
authors.initials: R
authors.lastname: Alla
authors.affiliation: Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center New Orleans, LA, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Jiang
authors.affiliation: Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center New Orleans, LA, USA.
authors.forename: S Michal
authors.initials: SM
authors.lastname: Jazwinski
authors.affiliation: Central Arkansas Veterans Healthcare System, VA Medical Center Little Rock, AR, USA ; Department of Geriatrics, University of Arkansas for Medical Sciences Little Rock, AR, USA ; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences Little Rock, AR, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Shmookler Reis
keywords: C. elegans; S. cerevisiae; genetics of aging; lifespan; longevity; meiotic cohesin; rec-8 or REC8; stress resistance