Recovery of trait heritability from whole genome sequence data, bioRxiv, 2019-03-26

AbstractHeritability, the proportion of phenotypic variance explained by genetic factors, can be estimated from pedigree data 1, but such estimates are uninformative with respect to the underlying genetic architecture. Analyses of data from genome-wide association studies (GWAS) on unrelated individuals have shown that for human traits and disease, approximately one-third to two-thirds of heritability is captured by common SNPs 2–5. It is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular if the causal variants are rare, or other reasons such as over-estimation of heritability from pedigree data. Here we show that pedigree heritability for height and body mass index (BMI) appears to be fully recovered from whole-genome sequence (WGS) data on 21,620 unrelated individuals of European ancestry. We assigned 47.1 million genetic variants to groups based upon their minor allele frequencies (MAF) and linkage disequilibrium (LD) with variants nearby, and estimated and partitioned variation accordingly. The estimated heritability was 0.79 (SE 0.09) for height and 0.40 (SE 0.09) for BMI, consistent with pedigree estimates. Low-MAF variants in low LD with neighbouring variants were enriched for heritability, to a greater extent for protein altering variants, consistent with negative selection thereon. Cumulatively variants in the MAF range of 0.0001 to 0.1 explained 0.54 (SE 0.05) and 0.51 (SE 0.11) of heritability for height and BMI, respectively. Our results imply that the still missing heritability of complex traits and disease is accounted for by rare variants, in particular those in regions of low LD.

biorxiv genetics 500+-users 2019

Extraordinary claims require extraordinary evidence in the case of asserted mtDNA biparental inheritance, bioRxiv, 2019-03-25

AbstractA breakthrough article published in PNAS by Luo et al. (2018) challenges a central dogma in biology which states that the mitochondrial DNA (mtDNA) is inherited exclusively from the mother. By sequencing the mitogenomes of several members of three independent families, the authors inferred an unprecedented pattern of biparental inheritance that requires the participation of an autosomal nuclear factor in the molecular process. However, a comprehensive analysis of their data reveals a number of issues that must be carefully addressed before challenging the current paradigm. Unfortunately, the methods section lacks any description of sample management, validation of their results in independent laboratories was deficient, and the reported findings have been observed at a frequency at complete variance with established evidence. Moreover, the remarkably high (and unusually homogeneous) levels of heteroplasmy reported can be readily detected using classical techniques for DNA sequencing. By reassessing the raw sequencing data with an alternative computational pipeline, we report strong correlation to the NextGENe results provided by the authors on a per sample base. However, the sequencing replicates from the same donors show aberrations in the variants detected that need further investigation to exclude contributions from other sources or methodological artifacts. Finally, applying the principle of reductio ad absurdum, we demonstrate that the nuclear factor invoked by the authors would need to be extraordinarily complex and precise in order to preclude linear accumulation of mtDNA lineages across generations. We discuss alternate scenarios that explain findings of the same nature as reported by Luo et al., in the context of in-vitro fertilization and therapeutic mtDNA replacement ooplasmic transplantation.

biorxiv genetics 100-200-users 2019

 

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