Dataset Information

Congruence as a measurement of extended haplotype structure across the genome.

ABSTRACT:

Background

Historically, extended haplotypes have been defined using only a few data points, such as alleles for several HLA genes in the MHC. High-density SNP data, and the increasing affordability of whole genome SNP typing, creates the opportunity to define higher resolution extended haplotypes. This drives the need for new tools that support quantification and visualization of extended haplotypes as defined by as many as 2000 SNPs. Confronted with high-density SNP data across the major histocompatibility complex (MHC) for 2,300 complete families, compiled by the Type 1 Diabetes Genetics Consortium (T1DGC), we developed software for studying extended haplotypes.

Methods

The software, called ExHap (Extended Haplotype), uses a similarity measurement we term congruence to identify and quantify long-range allele identity. Using ExHap, we analyzed congruence in both the T1DGC data and family-phased data from the International HapMap Project.

Results

Congruent chromosomes from the T1DGC data have between 96.5% and 99.9% allele identity over 1,818 SNPs spanning 2.64 megabases of the MHC (HLA-DRB1 to HLA-A). Thirty-three of 132 DQ-DR-B-A defined haplotype groups have > 50% congruent chromosomes in this region. For example, 92% of chromosomes within the DR3-B8-A1 haplotype are congruent from HLA-DRB1 to HLA-A (99.8% allele identity). We also applied ExHap to all 22 autosomes for both CEU and YRI cohorts from the International HapMap Project, identifying multiple candidate extended haplotypes.

Conclusions

Long-range congruence is not unique to the MHC region. Patterns of allele identity on phased chromosomes provide a simple, straightforward approach to visually and quantitatively inspect complex long-range structural patterns in the genome. Such patterns aid the biologist in appreciating genetic similarities and differences across cohorts, and can lead to hypothesis generation for subsequent studies.

SUBMITTER: Baschal EE

PROVIDER: S-EPMC3310717 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Publications

Congruence as a measurement of extended haplotype structure across the genome.

Baschal Erin E EE Jasinski Jean M JM Boyle Theresa A TA Fain Pamela R PR Eisenbarth George S GS Siebert Janet C JC

Journal of translational medicine 20120227

<h4>Background</h4>Historically, extended haplotypes have been defined using only a few data points, such as alleles for several HLA genes in the MHC. High-density SNP data, and the increasing affordability of whole genome SNP typing, creates the opportunity to define higher resolution extended haplotypes. This drives the need for new tools that support quantification and visualization of extended haplotypes as defined by as many as 2000 SNPs. Confronted with high-density SNP data across the maj ...[more]

PMID: 22369243

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Project description:The structures of RNA molecules are often important for their function and regulation, yet there are no experimental techniques for genome-scale measurement of RNA structure. Here, we describe a novel strategy termed Parallel Analysis of RNA Structure (PARS), which is based on deep sequencing fragments of RNAs that were treated with structure-specific enzymes, thus providing simultaneous in-vitro profiling of the secondary structure of thousands of RNA species at single nucleotide resolution. We apply PARS to profile the secondary structure of the mRNAs of the budding yeast S. cerevisiae and obtain structural profiles for over 3000 distinct transcripts. Analysis of these profiles reveals several RNA structural properties of yeast transcripts, including the existence of more secondary structure over coding regions compared to untranslated regions, a three-nucleotide periodicity of secondary structure across coding regions, and a relationship between the efficiency with which an mRNA is translated and the lack of structure over its translation start site. PARS is readily applicable to other organisms and to profiling RNA structure in diverse conditions, thus enabling studies of the dynamics of secondary structure at a genomic scale. RNA sample was treated with one of two structure-specific enzymes (RNase V1 or RNase S1). Four independent V1 experiments and three independent S1 experiments were carried out. Processed data file linked below. Data processing involves merging (or rather log-ratio-ing) the 7 lanes of SOLiD sequencing data against each other. Also linked below are the genome and transcriptome FASTA files used for mapping, and the annotation file having the format: gene_ID, chromosome, start, end, feature. Start and end are 1-based; feature is "Transcript" for the entire transcript (including introns), "Intron", "Exon", "5UTR" or "3UTR". Genome-wide measurement of RNA secondary structure in yeast, Kertesz et al., Nature Volume:467, Pages:103-107, Date published:(02 September 2010) http://www.nature.com/nature/journal/v467/n7311/abs/nature09322.html

Project description:BackgroundThe Bovine HapMap Consortium has generated assay panels to genotype ~30,000 single nucleotide polymorphisms (SNPs) from 501 animals sampled from 19 worldwide taurine and indicine breeds, plus two outgroup species (Anoa and Water Buffalo). Within the larger set of SNPs we targeted 101 high density regions spanning up to 7.6 Mb with an average density of approximately one SNP per 4 kb, and characterized the linkage disequilibrium (LD) and haplotype block structure within individual breeds and groups of breeds in relation to their geographic origin and use.ResultsFrom the 101 targeted high-density regions on bovine chromosomes 6, 14, and 25, between 57 and 95% of the SNPs were informative in the individual breeds. The regions of high LD extend up to ~100 kb and the size of haplotype blocks ranges between 30 bases and 75 kb (10.3 kb average). On the scale from 1-100 kb the extent of LD and haplotype block structure in cattle has high similarity to humans. The estimation of effective population sizes over the previous 10,000 generations conforms to two main events in cattle history: the initiation of cattle domestication (~12,000 years ago), and the intensification of population isolation and current population bottleneck that breeds have experienced worldwide within the last ~700 years. Haplotype block density correlation, block boundary discordances, and haplotype sharing analyses were consistent in revealing unexpected similarities between some beef and dairy breeds, making them non-differentiable. Clustering techniques permitted grouping of breeds into different clades given their similarities and dissimilarities in genetic structure.ConclusionThis work presents the first high-resolution analysis of haplotype block structure in worldwide cattle samples. Several novel results were obtained. First, cattle and human share a high similarity in LD and haplotype block structure on the scale of 1-100 kb. Second, unexpected similarities in haplotype block structure between dairy and beef breeds make them non-differentiable. Finally, our findings suggest that ~30,000 uniformly distributed SNPs would be necessary to construct a complete genome LD map in Bos taurus breeds, and ~580,000 SNPs would be necessary to characterize the haplotype block structure across the complete cattle genome.

Dataset Information

Congruence as a measurement of extended haplotype structure across the genome.

Background

Methods

Results

Conclusions

Publications

Congruence as a measurement of extended haplotype structure across the genome.

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