The majority of the variants have a functional classification of non-pathogenic (79 variants; fClass 1 and 2), with only four variants falling in the uncertain category (L1404P, F1571S, R1699P, and H1746Y; fClass 3; Supplementary Table S4).
We counted how many variants fell in each window and plotted these values against the genomic coordinates to generate a map of variant density for the parental genomes.
For low-ROH individuals, the mean proportion of non-deleterious homozygote variants falling in ROH marginally exceeded the nonsense or loss of function variants.
In addition to SIFT predictions, VEP identifies variants falling in noncoding and potentially regulatory regions that may impact a gene's expression.
Sequence variants falling in the first three bp or last three bp of an exon, plus intronic variants detected in the vicinity of the splice junction sequences, with allele frequencies <1%, were scored for their potential impact on splicing using MaxEntScan (MES), which computes the maximum entropy score of a given sequence using splice site models trained on human data [ 37].
We have highlighted variants falling in a QTL on chromosome 13 associated with basal glucose levels and a QTL on chromosome 6 associated with tibia length to illustrate how all of these data – whole genome sequence variants, IBD regions, QTL, and functional predictions – can be integrated with each other and with other public datasets to identify and prioritize QTG and QTN.
Accordingly, we carried out an analysis of MRN gene rMS limited to these key functional domains, largely as described in a recent review of MRN protein structure and function [ 4] with the exception that we excluded from the analysis variants falling in the second DNA binding domain of MRE11A because this domain is required for DSB formation during meiosis but not for repair of DSBs [ 46].
Finally, we include an indicator variable for when a variant falls in a Caltech RNA seq bin with zero signal.
As the variant falls in an area of weak genetic linkage, FBAT empirical variance estimates were used to control for correlation amongst sibling genotypes within pedigrees.
These results were confirmed by the DH analysis (fig. 4 A): The variant fell in a local valley of DH, in line with this statistic having maximum power for high-frequency sweeps (Zeng et al. 2006) (table 4).
