Detecting Genome-Wide Haplotype Polymorphism by Combined Use of Mendelian Constraints and Local Population Structure

Li, Xin; Chen, Yixuan; Li, Jing

doi:10.1142/9789814295291_0037

Cited by 5 publications

(8 citation statements)

References 18 publications

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“…nucleotide adjacent dependency [5]) may be used to address this problem. Although the recombination hotspots analyzed in this paper was obtained experimentally, our approach is not limited to this type of data and we can computationally estimate recombination rates from sequence polymorphism data in large scale, either based on LD structure [2], [13] or pedigree structure [14]. In addition, as our results of GO analysis suggested that epigenetic mechanism is shared by top candidate genes, we will follow up with studies of epigenetic interaction between histone and DNA as mediated by PRDM9 and other predicted proteins.…”

Section: Discussionmentioning

confidence: 99%

Prediction of Trans-regulators of Recombination Hotspots in Mouse Genome

Kwoh

Przytycka³

et al. 2011

2011 IEEE International Conference on Bioinformatics and Biomedicine

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The regulatory mechanism of recombination is a fundamental problem in genomics, with wide applications in genome wide association studies, birth-defect diseases, molecular evolution, cancer research, etc. In mammalian genomes, recombination events cluster into short genomic regions called "recombination hotspots". Recently, a 13-mer motif enriched in hotspots is identified as a candidate cis-regulatory element of human recombination hotspots; moreover, a zinc finger protein, PRDM9, binds to this motif and is associated with variation of recombination phenotype in human and mouse genomes, thus is a trans-acting regulator of recombination hotspots. However, this pair of cis and trans-regulators covers only a fraction of hotspots, thus other regulators of recombination hotspots remain to be discovered. In this paper, we propose an approach to predicting additional trans-regulators from DNAbinding proteins by comparing their enrichment of binding sites in hotspots. Applying this approach on newly mapped mouse hotspots genome-wide, we confirmed that PRDM9 is a major trans-regulator of hotspots. In addition, a list of top candidate trans-regulators of mouse hotspots is reported. Using GO analysis we observed that the top genes are enriched with function of histone modification, highlighting the epigenetic regulatory mechanisms of recombination hotspots.

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Section: Discussionmentioning

confidence: 99%

Prediction of Trans-regulators of Recombination Hotspots in Mouse Genome

Kwoh

Przytycka³

et al. 2011

2011 IEEE International Conference on Bioinformatics and Biomedicine

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“…We assume that the genotypes of both parents are not available and infer the IBD status for each pair of siblings. We then compare the results of IBD changing breakpoints with the recombination breakpoints inferred by our previous algorithm Mendelian constrained maximum likelihood (MML) (Li et al , 2010) using genotypes of both parents and children. The second dataset is a pedigree of size 15, among which only seven members are typed.…”

Section: Resultsmentioning

confidence: 99%

“…To systematically evaluate the correctness of inferred IBD sharing regions of all sibling pairs, we compare our result with that inferred by our previous algorithm MML (Li et al , 2010), which is a Mendelian law-based method and use genotypes of both parents and children. MML infers the inheritance pattern by using Mendelian constraints between parents and children.…”

Section: Resultsmentioning

confidence: 99%

“…However, their method is mainly for nuclear family data with two offsprings. Recently, we have demonstrated that with high-density SNP data, (i) we can infer recombination breakpoints with high precision (Li et al , 2010); (ii) our algorithm (Li and Li, 2009) can efficiently infer haplotypes and inheritance patterns for large pedigrees; and (iii) in most cases, inheritance can be uniquely determined for large pedigrees with large number of SNPs. Experimental results show that our approach is highly efficient and can also tolerate high missing rates.…”

Section: Introductionmentioning

confidence: 99%

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Efficient identification of identical-by-descent status in pedigrees with many untyped individuals

Yin

2010

Bioinformatics

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Motivation: Inference of identical-by-descent (IBD) probabilities is the key in family-based linkage analysis. Using high-density single nucleotide polymorphism (SNP) markers, one can almost always infer haplotype configurations of each member in a family given all individuals being typed. Consequently, the IBD status can be obtained directly from haplotype configurations. However, in reality, many family members are not typed due to practical reasons. The problem of IBD/haplotype inference is much harder when treating untyped individuals as missing.Results: We present a novel hidden Markov model (HMM) approach to infer the IBD status in a pedigree with many untyped members using high-density SNP markers. We introduce the concept of inheritance-generating function, defined for any pair of alleles in a descent graph based on a pedigree structure. We derive a recursive formula for efficient calculation of the inheritance-generating function. By aggregating all possible inheritance patterns via an explicit representation of the number and lengths of all possible paths between two alleles, the inheritance-generating function provides a convenient way to theoretically derive the transition probabilities of the HMM. We further extend the basic HMM to incorporate population linkage disequilibrium (LD). Pedigree-wise IBD sharing can be constructed based on pair-wise IBD relationships. Compared with traditional approaches for linkage analysis, our new model can efficiently infer IBD status without enumerating all possible genotypes and transmission patterns of untyped members in a family. Our approach can be reliably applied on large pedigrees with many untyped members, and the inferred IBD status can be used for non-parametric genome-wide linkage analysis.Availability: The algorithm is implemented in Matlab and is freely available upon request.Contact: jingli@cwru.eduSupplementary information: Supplementary data are available on Bioinformatics online.

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“…A description of the Beagle software is available at http://faculty.washington.edu/browning/beagle/beagle.html. [The method proposed by Li et al (23) can be used to infer the haplotypes for sibpair data. ]…”

Section: Methodsmentioning

confidence: 99%

Detecting Rare Variants

Feng

Zhu

2011

Methods in Molecular Biology

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Summary The limitations of genome-wide association (GWA) studies that are based on the common disease common variants (CDCV) hypothesis have motivated geneticists to test the hypothesis that rare variants contribute to the variation of common diseases, i.e., common disease rare variants (CDRV). The newly developed high-throughput sequencing technologies have made the studies of rare variants practicable. Statistical approaches to test associations between a phenotype and rare variants are quickly developing. The central idea of these methods is to test a set of rare variants in a defined region or regions by collapsing or aggregating rare variants, thereby improving the statistical power. In this chapter, we introduce these methods as well as their applications in practice.

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Detecting Genome-Wide Haplotype Polymorphism by Combined Use of Mendelian Constraints and Local Population Structure

Cited by 5 publications

References 18 publications

Prediction of Trans-regulators of Recombination Hotspots in Mouse Genome

Prediction of Trans-regulators of Recombination Hotspots in Mouse Genome

Efficient identification of identical-by-descent status in pedigrees with many untyped individuals

Detecting Rare Variants

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