Limits...
Dissecting genome-wide association signals for loss-of-function phenotypes in sorghum flavonoid pigmentation traits.

Morris GP, Rhodes DH, Brenton Z, Ramu P, Thayil VM, Deshpande S, Hash CT, Acharya C, Mitchell SE, Buckler ES, Yu J, Kresovich S - G3 (Bethesda) (2013)

Bottom Line: Genome-wide association studies are a powerful method to dissect the genetic basis of traits, although in practice the effects of complex genetic architecture and population structure remain poorly understood.Interestingly, a simple loss-of-function genome scan, for genotype-phenotype covariation only in the putative loss-of-function allele, is able to precisely identify the Tannin1 gene without considering relatedness.These findings highlight that complex association signals can emerge from even the simplest traits given epistasis and structured alleles, but that gene-resolution mapping of these traits is possible with high marker density and appropriate models.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208.

ABSTRACT
Genome-wide association studies are a powerful method to dissect the genetic basis of traits, although in practice the effects of complex genetic architecture and population structure remain poorly understood. To compare mapping strategies we dissected the genetic control of flavonoid pigmentation traits in the cereal grass sorghum by using high-resolution genotyping-by-sequencing single-nucleotide polymorphism markers. Studying the grain tannin trait, we find that general linear models (GLMs) are not able to precisely map tan1-a, a known loss-of-function allele of the Tannin1 gene, with either a small panel (n = 142) or large association panel (n = 336), and that indirect associations limit the mapping of the Tannin1 locus to Mb-resolution. A GLM that accounts for population structure (Q) or standard mixed linear model that accounts for kinship (K) can identify tan1-a, whereas a compressed mixed linear model performs worse than the naive GLM. Interestingly, a simple loss-of-function genome scan, for genotype-phenotype covariation only in the putative loss-of-function allele, is able to precisely identify the Tannin1 gene without considering relatedness. We also find that the tan1-a allele can be mapped with gene resolution in a biparental recombinant inbred line family (n = 263) using genotyping-by-sequencing markers but lower precision in the mapping of vegetative pigmentation traits suggest that consistent gene-level resolution will likely require larger families or multiple recombinant inbred lines. These findings highlight that complex association signals can emerge from even the simplest traits given epistasis and structured alleles, but that gene-resolution mapping of these traits is possible with high marker density and appropriate models.

Show MeSH

Related in: MedlinePlus

Genome-wide mapping of testa presence using a loss-of-function genome scan. (A) Allele counts for the tan1-a SNP and other SNPs near Tannin1 that are associated with a nontannin phenotype. The nominal P-value is from a binomial test on the putative loss-of-function allele at each SNP, (B) scanning genome-wide, and (C) a detailed view of the Tannin1 locus on chromosome 4, with Tannin1 indicated by the red bar. Other flavonoid-related genes are indicated by the blue bars, whereas all other annotated genes in the detailed view are indicated in green.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3815067&req=5

fig4: Genome-wide mapping of testa presence using a loss-of-function genome scan. (A) Allele counts for the tan1-a SNP and other SNPs near Tannin1 that are associated with a nontannin phenotype. The nominal P-value is from a binomial test on the putative loss-of-function allele at each SNP, (B) scanning genome-wide, and (C) a detailed view of the Tannin1 locus on chromosome 4, with Tannin1 indicated by the red bar. Other flavonoid-related genes are indicated by the blue bars, whereas all other annotated genes in the detailed view are indicated in green.

Mentions: Why did several of the linear models we tested fail to precisely identify the tan1-a allele in association panels, even though it is common and highly penetrant? A comparison of the 2 × 2 contingency tables for the tan1-a SNP vs. the more significant SNPs provides some insight here (Figure 4A). The loss-of-function tan1-a allele shows striking covariation with the testa phenotype (T allele: nontannin = 78 vs. tannin = 0) but little signal of covariation for the wild-type allele (G allele: nontannin = 112 vs. tannin = 139). Although this lack of covariation for the wild-type allele is to be expected (because there is no reason that accessions carrying the wild-type allele at Tannin1 cannot carry loss-of-function alleles at other loci), it reduces the significance of a linear model fitting the genotype-phenotype association. In contrast, the other more significant SNPs near Tannin1 show covariation for both alleles (in opposite directions), with the wild-type allele more often found with the wild-type phenotype (Figure 4A). This pattern of covariation increases the significance of the fit of a linear model or contingency test, even though the genotype-phenotype covariation for the wild-type allele is irrelevant when considering a loss-of-function polymorphism.


Dissecting genome-wide association signals for loss-of-function phenotypes in sorghum flavonoid pigmentation traits.

Morris GP, Rhodes DH, Brenton Z, Ramu P, Thayil VM, Deshpande S, Hash CT, Acharya C, Mitchell SE, Buckler ES, Yu J, Kresovich S - G3 (Bethesda) (2013)

Genome-wide mapping of testa presence using a loss-of-function genome scan. (A) Allele counts for the tan1-a SNP and other SNPs near Tannin1 that are associated with a nontannin phenotype. The nominal P-value is from a binomial test on the putative loss-of-function allele at each SNP, (B) scanning genome-wide, and (C) a detailed view of the Tannin1 locus on chromosome 4, with Tannin1 indicated by the red bar. Other flavonoid-related genes are indicated by the blue bars, whereas all other annotated genes in the detailed view are indicated in green.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3815067&req=5

fig4: Genome-wide mapping of testa presence using a loss-of-function genome scan. (A) Allele counts for the tan1-a SNP and other SNPs near Tannin1 that are associated with a nontannin phenotype. The nominal P-value is from a binomial test on the putative loss-of-function allele at each SNP, (B) scanning genome-wide, and (C) a detailed view of the Tannin1 locus on chromosome 4, with Tannin1 indicated by the red bar. Other flavonoid-related genes are indicated by the blue bars, whereas all other annotated genes in the detailed view are indicated in green.
Mentions: Why did several of the linear models we tested fail to precisely identify the tan1-a allele in association panels, even though it is common and highly penetrant? A comparison of the 2 × 2 contingency tables for the tan1-a SNP vs. the more significant SNPs provides some insight here (Figure 4A). The loss-of-function tan1-a allele shows striking covariation with the testa phenotype (T allele: nontannin = 78 vs. tannin = 0) but little signal of covariation for the wild-type allele (G allele: nontannin = 112 vs. tannin = 139). Although this lack of covariation for the wild-type allele is to be expected (because there is no reason that accessions carrying the wild-type allele at Tannin1 cannot carry loss-of-function alleles at other loci), it reduces the significance of a linear model fitting the genotype-phenotype association. In contrast, the other more significant SNPs near Tannin1 show covariation for both alleles (in opposite directions), with the wild-type allele more often found with the wild-type phenotype (Figure 4A). This pattern of covariation increases the significance of the fit of a linear model or contingency test, even though the genotype-phenotype covariation for the wild-type allele is irrelevant when considering a loss-of-function polymorphism.

Bottom Line: Genome-wide association studies are a powerful method to dissect the genetic basis of traits, although in practice the effects of complex genetic architecture and population structure remain poorly understood.Interestingly, a simple loss-of-function genome scan, for genotype-phenotype covariation only in the putative loss-of-function allele, is able to precisely identify the Tannin1 gene without considering relatedness.These findings highlight that complex association signals can emerge from even the simplest traits given epistasis and structured alleles, but that gene-resolution mapping of these traits is possible with high marker density and appropriate models.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208.

ABSTRACT
Genome-wide association studies are a powerful method to dissect the genetic basis of traits, although in practice the effects of complex genetic architecture and population structure remain poorly understood. To compare mapping strategies we dissected the genetic control of flavonoid pigmentation traits in the cereal grass sorghum by using high-resolution genotyping-by-sequencing single-nucleotide polymorphism markers. Studying the grain tannin trait, we find that general linear models (GLMs) are not able to precisely map tan1-a, a known loss-of-function allele of the Tannin1 gene, with either a small panel (n = 142) or large association panel (n = 336), and that indirect associations limit the mapping of the Tannin1 locus to Mb-resolution. A GLM that accounts for population structure (Q) or standard mixed linear model that accounts for kinship (K) can identify tan1-a, whereas a compressed mixed linear model performs worse than the naive GLM. Interestingly, a simple loss-of-function genome scan, for genotype-phenotype covariation only in the putative loss-of-function allele, is able to precisely identify the Tannin1 gene without considering relatedness. We also find that the tan1-a allele can be mapped with gene resolution in a biparental recombinant inbred line family (n = 263) using genotyping-by-sequencing markers but lower precision in the mapping of vegetative pigmentation traits suggest that consistent gene-level resolution will likely require larger families or multiple recombinant inbred lines. These findings highlight that complex association signals can emerge from even the simplest traits given epistasis and structured alleles, but that gene-resolution mapping of these traits is possible with high marker density and appropriate models.

Show MeSH
Related in: MedlinePlus