Academic journal article Genetics

The Genetic Basis of Natural Variation in Caenorhabditis Elegans Telomere Length

Academic journal article Genetics

The Genetic Basis of Natural Variation in Caenorhabditis Elegans Telomere Length

Article excerpt

GENOME-WIDE association (GWA) studies, in which phenotypic differences are correlated with genome-wide variation in populations, offer a powerful approach to understand the genetic basis of complex traits (McCarthy et al. 2008). GWA requires accurate and quantitative measurement of traits for a large number of individuals. Even in organisms that are studied easily in the laboratory, the measurement of quantitative traits is difficult and expensive. By contrast, the rapid decrease in sequencing costs has made the collection of genome-wide variation accessible. From Drosophila (Mackay et al. 2012; Lack et al. 2015) to Arabidopsis (Weigel and Mott 2009) to humans (The 1000 Genomes Project Consortium 2012), the whole genomes from large populations of individuals can be analyzed to identify natural variation that is correlated with quantitative traits. Because the genome itself can vary across populations, whole-genome sequence data sets can be mined for traits without measuring the physical organism. Specifically, large numbers of sequence reads generated from individuals in a species can be analyzed to determine attributes of genomes, including mitochondrial- or ribosomal-DNA copy numbers. Another such trait is the length of the highly repetitive structures at the ends of linear chromosomes called telomeres (Blackburn 1991).

Telomeres are nucleoprotein complexes that serve as protective capping structures to prevent chromosomal degradation and fusion (O'Sullivan and Karlseder 2010). The DNA component of telomeres in most organisms consists of long stretches of nucleotide repeats that terminate in a single-stranded 39 overhang (McEachern et al. 2000). The addition of telomeric repeats is necessary becauseDNApolymerase isunable to completely replicate the lagging strand (Watson 1972; Levy et al. 1992). The length of telomeres can differ among cell populations (Samassekou et al. 2010), from organism to organism (Fulcher et al. 2014), and within proliferating cellular lineages (Frenck et al. 1998). Two antagonistic pathways regulate telomere length. In the first pathway, the reverse transcriptase telomerase adds de novo telomeric repeats to the 39 ends of chromosomes. In the second, telomere lengthening is inhibited by the shelterin complex. Shelterin forms a protective cap at telomere ends, presumably through the formation of lariat structures known as t-loops (Griffith et al. 1999). The t-loops are hypothesized to inhibit telomerase activity by preventing access to the 39 tail. Additionally, because uncapped telomeres resemble double-stranded DNA breaks, shelterin association with telomeric DNA represses endogenous DNA-damage repair pathways, preventing chromosomal fusion events, and preserving genome integrity (De Lange 2010).

Variation in telomere length has important biological implications. In cells lacking telomerase, chromosome ends become shorter with every cell division, which eventually triggers cell-cycle arrest (Harley et al. 1992). In this way, telomere length sets the replicative potential of cells and acts as an important tumor-suppressor mechanism (Harley et al. 1992; Deng et al. 2008). In populations of nonclonal human leukocytes, telomere lengths have been shown to be highly heritable (Broer et al. 2013). Quantitative trait loci (QTL) identified from human GWA studies of telomere length implicate telomere-associated genes, including telomerase (TERT), its RNA template (TERC), and OBFC1 (Levy et al. 2010; Jones et al. 2012; Codd et al. 2013). QTL underlying variation in telomere length have been identified in Arabidopsis thaliana, Saccharomyces paradoxus, and S. cerevisiae using both linkage and association approaches (Gatbonton et al. 2006; Liti et al. 2009; Kwan et al. 2011; Fulcher et al. 2014). In S. paradoxus, natural variation in telomere lengths is mediated by differences in telomerase complex components. In S. cerevisiae, natural telomere lengthening is caused by a loss of an amino acid permease gene. …

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