Dataset Information

Turning Observed Founder Alleles into Expected Relationships in an Intercross Population.

ABSTRACT: Pedigree-derived relationships for individuals from an intercross of several lines cannot easily account for the segregation variance that is mainly caused by loci with alternative alleles fixed in different lines. However, when all founders are genotyped for a large number of markers, such relationships can be derived for descendants as expected genomic relationships conditional on the observed founder allele frequencies. A tabular method was derived in detail for autosomes and the X-chromosome. As a case study, we analyzed litter size and body weights at three different ages in an advanced mouse intercross (29 generations, total pedigree size 19,266) between a line selected for high litter size (FL1) and a highly inbred control line (DUKsi). Approximately 60% of the total genetic variance was due to segregation variance. Estimated heritability values were 0.20 (0.03), 0.34 (0.04), 0.23 (0.03), 0.41 (0.03) and 0.47 (0.02) for litter size, litter weight and body weight at ages of 21, 42 and 63 days, respectively (standard errors in brackets). These values were between 12% and 65% higher than observed in analyses that treated founders as unrelated. Fields of applications include experimental populations (selection experiments or advanced intercross lines) with a limited number of founders, which can be genotyped at a reasonable cost. In principle any number of founder lines can be treated. Additional genotypes from individuals in later generations can be combined into a joint relationship matrix by capitalizing on previously published approaches.

SUBMITTER: Meng J

PROVIDER: S-EPMC6404597 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Turning Observed Founder Alleles into Expected Relationships in an Intercross Population.

Meng Jilun J Mayer Manfred M Wytrwat Erika E Langhammer Martina M Reinsch Norbert N

G3 (Bethesda, Md.) 20190307 3

Pedigree-derived relationships for individuals from an intercross of several lines cannot easily account for the segregation variance that is mainly caused by loci with alternative alleles fixed in different lines. However, when all founders are genotyped for a large number of markers, such relationships can be derived for descendants as expected genomic relationships conditional on the observed founder allele frequencies. A tabular method was derived in detail for autosomes and the X-chromosome ...[more]

PMID: 30718274

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Project description:While direct additive and dominance effects on complex traits have been mapped repeatedly, additional genetic factors contributing to the heterogeneity of complex traits have been scarcely investigated. To assess genetic background effects, we investigated transmission ratio distortions (TRDs) of alleles from parent to offspring using an advanced intercross line (AIL) of an initial cross between the mouse inbred strains C57BL/6NCrl (B6N) and BFMI860-12 [Berlin Fat Mouse Inbred (BFMI)]. A total of 341 males of generation 28 and their respective 61 parents and 66 grandparents were genotyped using Mega Mouse Universal Genotyping Arrays. TRDs were investigated using allele transmission asymmetry tests, and pathway overrepresentation analysis was performed. Sequencing data were used to test for overrepresentation of nonsynonymous SNPs (nsSNPs) in TRD regions. Genetic incompatibilities were tested using the Bateson-Dobzhansky-Muller two-locus model. A total of 62 TRD regions were detected, many in close proximity to the telocentric centromere. TRD regions contained 44.5% more nsSNPs than randomly selected regions (182 vs 125.9 ± 17.0, P < 1 × 10-4). Testing for genetic incompatibilities between TRD regions identified 29 genome-wide significant incompatibilities between TRD regions [P(BF) < 0.05]. Pathway overrepresentation analysis of genes in TRD regions showed that DNA methylation, epigenetic regulation of RNA, and meiotic/meiosis regulation pathways were affected independent of the parental origin of the TRD. Paternal BFMI TRD regions showed overrepresentation in the small interfering RNA biogenesis and in the metabolism of lipids and lipoproteins. Maternal B6N TRD regions harbored genes involved in meiotic recombination, cell death, and apoptosis pathways. The analysis of genes in TRD regions suggests the potential distortion of protein-protein interactions influencing obesity and diabetic retinopathy as a result of disadvantageous combinations of allelic variants in Aass, Pgx6, and Nme8. Using an AIL significantly improves the resolution at which we can investigate TRD. Our analysis implicates distortion of protein-protein interactions as well as meiotic drive as the underlying mechanisms leading to the observed TRD in our AIL. Furthermore, genes with large amounts of nsSNPs located in TRD regions are more likely to be involved in pathways that are related to the phenotypic differences between the parental strains. Genes in these TRD regions provide new targets for investigating genetic adaptation, protein-protein interactions, and determinants of complex traits such as obesity.

Dataset Information

Turning Observed Founder Alleles into Expected Relationships in an Intercross Population.

Publications

Turning Observed Founder Alleles into Expected Relationships in an Intercross Population.

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