Application of Homozygosity Haplotype Analysis to Genetic Mapping with High-Density SNP Genotype Data

BACKGROUND: In families segregating a monogenic genetic disorder with a single disease gene introduction, patients share a mutation-carrying chromosomal interval with identity-by-descent (IBD). Such a shared chromosomal interval or haplotype, surrounding the actual pathogenic mutation, is typically detected and defined by multipoint linkage and phased haplotype analysis using microsatellite or SNP genotype data. High-density SNP genotype data presents a computational challenge for conventional genetic analyses. A novel non-parametric method termed Homozygosity Haplotype (HH) was recently proposed for the genome-wide search of the autosomal segments shared among patients using high density SNP genotype data. METHODOLOGY/PRINCIPAL FINDINGS: The applicability and the effectiveness of HH in identifying the potential linkage of disease causative gene with high-density SNP genotype data were studied with a series of monogenic disorders ascertained in eastern Canadian populations. The HH approach was validated using the genotypes of patients from a family affected with a rare autosomal dominant disease Schnyder crystalline corneal dystrophy. HH accurately detected the approximately 1 Mb genomic interval encompassing the causative gene UBIAD1 using the genotypes of only four affected subjects. The successful application of HH to identify the potential linkage for a family with pericentral retinal disorder indicates that HH can be applied to perform family-based association analysis by treating affected and unaffected family members as cases and controls respectively. A new strategy for the genome-wide screening of known causative genes or loci with HH was proposed, as shown the applications to a myoclonus dystonia and a renal failure cohort. CONCLUSIONS/SIGNIFICANCE: Our study of the HH approach demonstrates that HH is very efficient and effective in identifying potential disease linked region. HH has the potential to be used as an efficient alternative approach to sequencing or microsatellite-based fine mapping for screening the known causative genes in genetic disease study

Fzd4 Haploinsufficiency Delays Retinal Revascularization in the Mouse Model of Oxygen Induced Retinopathy.

Mutations in genes that code for components of the Norrin-FZD4 ligand-receptor complex cause the inherited childhood blinding disorder familial exudative vitreoretinopathy (FEVR). Statistical evidence from studies of patients at risk for the acquired disease retinopathy of prematurity (ROP) suggest that rare polymorphisms in these same genes increase the risk of developing severe ROP, implying that decreased Norrin-FZD4 activity predisposes patients to more severe ROP. To test this hypothesis, we measured the development and recovery of retinopathy in wild type and Fzd4 heterozygous mice in the absence or presence of ocular ischemic retinopathy (OIR) treatment. Avascular and total retinal vascular areas and patterning were determined, and vessel number and caliber were quantified. In room air, there was a small delay in retinal vascularization in Fzd4 heterozygous mice that resolved as mice reached maturity suggestive of a slight defect in retinal vascular development. Subsequent to OIR treatment there was no difference between wild type and Fzd4 heterozygous mice in the vaso-obliterated area following exposure to high oxygen. Importantly, after return of Fzd4 heterozygous mice to room air subsequent to OIR treatment, there was a substantial delay in retinal revascularization of the avascular area surrounding the optic nerve, as well as delayed vascularization toward the periphery of the retina. Our study demonstrates that a small decrease in Norrin-Fzd4 dependent retinal vascular development lengthens the period during which complications from OIR could occur

Histogram distribution of the dhSNPs introduced by genotyping error.

<p>Error simulation was performed on the genotype data of Myoclonus dystonia patients in region Chr11:111,851,211–113,785,527 including DRD2 gene. The curve is the fitted Poisson distribution curve with λ = 8.98 (σ = 0.03). Genotyping error was simulated using error model 1 with an error ratio 0.01. Monte Carlo error simulation was run 10,000 times.</p

The error possibilities calculated using genotyping error simulation method in screening known causative genes PKD1 and PKD2 for a family with renal failure with the genotype data of patient s1 and s4.

<p>The error possibilities calculated using genotyping error simulation method in screening known causative genes PKD1 and PKD2 for a family with renal failure with the genotype data of patient s1 and s4.</p

The effect of using subsets of the affected individuals (s1, s2, s3 and s4) and different cutoff values in the screening of the known causative genes PKD1 and PKD2 for a family with renal failure.

<p>‘+’ indicates no RCHH shared by patients is found flanking the gene, and suggests the gene is excludable; ‘−’ indicates an RCHH is found flanking the gene. <i>m</i> and <i>n</i> are the number of generations of the two patients descended from their common ancestor.</p

The error possibilities calculated using genotyping error simulation method in the screening of the known causative genes for a family with myoclonus dystonia with the genotype data of four affected individuals.

<p>The error possibilities calculated using genotyping error simulation method in the screening of the known causative genes for a family with myoclonus dystonia with the genotype data of four affected individuals.</p