Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/061333

Imputation-based fine-mapping suggests that most QTL in an outbred chicken Advanced Intercross Line are due to multiple, linked loci

Monika Brandt·Muhammad Ahsan·Christa F Honaker·Paul B Siegel·Orjan Carlborg
View original source ↗Export metadata ↓

Abstract

AO_SCPLOWBSTRACTC_SCPLOWThe Virginia chicken lines have been divergently selected for juvenile body-weight for more than 50 generations. Today, the high-and low-weight lines show a 12-fold difference for the selected trait, 56-day body-weight. These lines provide unique opportunities to study the genetic architecture of long-term, single-trait selection. Previously, several Quantitative Trait Loci (QTL) contributing to weight differences between the lines were mapped in an F2-cross between them, and these were later replicated and fine-mapped in a nine-generation advanced intercross of them. Here, we explore the possibility to further increase the fine-mapping resolution of these QTL via a pedigree-based imputation strategy that aims to better capture the haplotype-diversity in the divergently selected, but outbred, founder lines. The founders of the intercross were high-density genotyped, and then pedigree-based imputation was used to assign genotypes throughout the pedigree. Imputation increased the marker-density 20-fold in the selected QTL, providing 6911 markers for the subsequent analysis. Both single-marker association and multi-marker backward-elimination analyses were used to detect associations to 56-day body-weight. The approach revealed several statistically and population-structure independent associations and increased the resolution of most QTL. Further, most QTL were also found to contain multiple independent associations, implying a complex underlying architecture due to the combined effects of multiple, linked loci on independent haplotypes that still segregate in the selected lines.\n\nArticle summaryAfter 50 generations of bi-directional selection, the Virginia chicken lines display a 12-fold difference in bodyweight at 56 days of age. Birds from the high and low selected lines were crossed to found an Advanced Intercross Line, which has been maintained for 9 generations. Using high-density genotypes of the founders, we imputed genotypes in intercross birds that were only genotyped for a sparse set of markers. Using single and multi-marker association analyses, we replicated nine known body-weight QTL. Multiple statistically independent associations were revealed in eight of the QTL, suggesting that most are caused by multiple linked loci.

Source connections

Explore related subjects

GeneticsPreprint

Keep this discovery

BibTeXRIS

Monika Brandt, Muhammad Ahsan, Christa F Honaker, Paul B Siegel, Orjan Carlborg. 2016-06-29. Imputation-based fine-mapping suggests that most QTL in an outbred chicken Advanced Intercross Line are due to multiple, linked loci. https://doi.org/10.1101/061333

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2016

Rapid evolution of primate type 2 immune response factors linked to asthma susceptibility

Host immunity pathways evolve rapidly in response to antagonism by pathogens. Microbial infections can also trigger excessive inflammation that contributes to diverse autoimmune disorders including asthma, lupus, diabetes, and arthritis. Definitive links between immune system evolution and human autoimmune disease remain unclear. Here we provide evidence that several components of the type 2 immune response pathway have been subject to recurrent positive selection in the primate lineage. Notably, rapid evolution of the central immune regulator IL13 corresponds to a polymorphism linked to asthma susceptibility in humans. We also find evidence of accelerated amino acid substitutions as well as repeated gene gain and loss events among eosinophil granule proteins, which act as toxic antimicrobial effectors that promote asthma pathology by damaging airway tissues. These results support the hypothesis that evolutionary conflicts with pathogens promote tradeoffs for increasingly robust immune responses during animal evolution. Our findings are also consistent with the view that natural selection has contributed to the spread of autoimmune disease alleles in humans.

Genetics↗
bioRxiv2016

Single Cell Expression Data Reveal Human Genes that Escape X-Chromosome Inactivation

Sex chromosomes pose an inherent genetic imbalance between genders. In mammals, one of the females X-chromosomes undergoes inactivation (Xi). Indirect measurements estimate that about 20% of Xi genes completely or partially escape inactivation. The identity of these escapee genes and their propensity to escape inactivation remain unsolved. A direct method for identifying escapees was applied by quantifying differential allelic expression from single cells. RNA-Seq fragments were assigned to informative SNPs which were labeled by the appropriate parental haplotype. This method was applied for measuring allelic specific expression from Chromosome-X (ChrX) and an autosomal chromosome as a control. We applied the protocol for measuring biallelic expression from ChrX to 104 primary fibroblasts. Out of 215 genes that were considered, only 13 genes (6%) were associated with biallelic expression. The sensitivity of escapees' identification was increased by combining SNP mapping for parental diploid genomes together with RNA-Seq from clonal single cells (25 lymphoblasts). Using complementary protocols, referred to as strict and relaxed, we confidently identified 25 and 31escapee genes, respectively. When pooled versions of 30 and 100 cells were used, <50% of these genes were revealed. We assessed the generality of our protocols in view of an escapee catalog compiled from indirect methods. The overlap between the escapee catalog and the genes list from this study is statistically significant (P-value of E-07). We conclude that single cells expression data are instrumental for studying X-inactivation with an improved sensitivity. Finally, our results support the emerging notion of the non-deterministic nature of genes that escape X-chromosome inactivation.

Genetics↗
bioRxiv2016

Frequency of mosaicism points towards mutation-prone early cleavage cell divisions.

It has recently become possible to directly estimate the germ-line de novo mutation (dnm) rate by sequencing the whole genome of father-mother-offspring trios, and this has been conducted in human1-5, chimpanzee6, mice7, birds8 and fish9. In these studies dnms are typically defined as variants that are heterozygous in the offspring while being absent in both parents. They are assumed to have occurred in the germ-line of one of the parents and to have been transmitted to the offspring via the sperm cell or oocyte. This definition assumes that detectable mosaicism in the parent in which the mutation occurred is negligible. However, instances of detectable mosaicism or premeiotic clusters are well documented in humans and other organisms, including ruminants10-12. We herein take advantage of cattle pedigrees to show that as much as [~]30% to [~]50% of dnms present in a gamete may occur during the early cleavage cell divisions in males and females, respectively, resulting in frequent detectable mosaicism and a high rate of sharing of multiple dnms between siblings. This should be taken into account to accurately estimate the mutation rate in cattle and other species.

Genetics↗