We did a journal club discussing the paper “Tightly-linked antagonistic-effect loci underlie polygenic demographic variation in C. elegans “ on bioRxiv.
Summary of the paper
In this paper Bernstein et al. used the experimental genetics to show most genomic regions carry variants with detectable effects on complex traits. They measured the fitness effects of Ceanorhabditis elegans under Nickel stress using a high-throughput phenotyping method that characterize demography as a multivariate trait in growing populations. They then focused on a 1.4-Mb region of the X chromosome using the near isogenic lines (NILs) that subdivide the region into fifteen intervals. They found that eleven of intervals have significant effects, indicating potential adjacent QTLs with antagonistic effects.
What are RILs and NILs
Before we get to the details of their result, it is worthwhile to understand two important concept in the C. elegans mapping field, that is RIL and NIL. In this bioRxiv paper, Bernstain et al. give a great introduction of these two terms. Here I just quote their introduction:
“The ability to identify loci associated with trait variation is dependent on the constitution of the mapping population and the number of measurements. Two of the most commonly used types of mapping populations are recombinant inbred lines (RILs) and near-isogenic lines (NILs). RILs leverage genotypic replication across random backgrounds, whereas NILs control for background by holding it constant (Doroszuk et al., 2009; Eshed and Zamir, 1995; Keurentjes et al., 2007; Koumproglou et al., 2002; Shao et al., 2010). RILs provide an efficient way to survey the whole genome for loci with significant marginal effects across multiple backgrounds, but those multiple backgrounds also contribute phenotypic variation. Thus, when comparing the phenotype distributions for two genotype classes at a given genetic marker, RILs have abundant variation within each class due to segregating genetic effects. With NILs, those background effects are eliminated, providing greater power to detect differences between focal genotypes. Moreover, when alleles have effects only in certain backgrounds, their marginal effects, detected in RILs, may be quite modest and hard to detect; in NILs, where the background is fixed, epistatic effects are converted to all or none, depending on the background. “
(figure from “Tightly-linked antagonistic-effect loci underlie polygenic demographic variation in C. elegans “)
Results in this paper
They used the N2 and CB4856 as the parental strains, and they identified significant difference between the parent strains in their demographies. N2 has more progeny and a greater proportion of the progeny were measured as adults, consistent with a developmental delay in CB4856 relative to N2. Then they performed multivariant QTL mapping in a RILs population, and identified 7 QTLs that influent the demography in the RILs. Given the discrepancy between the estimated broad-sense heritabilities and the heritability explained by the detected QTLs, they propose one possible genetic model for our traits ascribes the unexplained heritable variation to a large number of variants spread across the genome.
(figure from “Tightly-linked antagonistic-effect loci underlie polygenic demographic variation in C. elegans “)
They focused on a region on X chromosome, a chromosome that does not have detected QTL. They used a panel of 16 Near Isogenic Lines to test 15 consecutive intervals of 53-148 kb (that is, ~0.001 of the 100 Mb genome) spread along a 1.4 Mb region on the X chromosome, and they found that eleven of intervals have significant effects (or they called QTLs here). Their explanantion for this observation is in the RILs, the effects point in both directions for each trait, indicating that the NIL region harbors a mixture of antogonistic QTL. Each of these QTLs cancel out the effect of others.