Targeted, haplotype-resolved resequencing of long segments of the human genome

Raymond, Christopher K.; Subramanian, Sandhya; Paddock, Marcia N.; Qiu, Ruolan; Deodato, Chloe R.; Palmieri, Anthony; Chang, Jean L.; Radke, Tana; Haugen, Eric; Kas, Arnie; Waring, David; Bovee, Donald; Stacy, Robin; Kaul, Rajinder; Olson, Maynard V.

doi:10.1016/j.ygeno.2005.08.013

Cited by 24 publications

(16 citation statements)

References 19 publications

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“…An additional possibility would be to use a set of "known" haplotypes as 'predefined haplotypes' to help phasing genotype population data. These could be obtained from HapMap data (for CEPH and Yoruban), from sequence or genotyping of monosomic cell lines for candidate loci, or from the application of novel techniques to obtain phase information of long genomic regions [Kukita et al, 2005;Raymond et al, 2005].…”

Section: Discussionmentioning

confidence: 99%

Understanding the accuracy of statistical haplotype inference with sequence data of known phase

Andrés

Clark

Shimmin

et al. 2007

Genetic Epidemiology

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Statistical methods for haplotype inference from multi-site genotypes of unrelated individuals have important application in association studies and population genetics. Understanding the factors that affect the accuracy of this inference is important, but their assessment has been restricted by the limited availability of biological data with known phase. We created hybrid cell lines monosomic for human chromosome 19 and produced single-chromosome complete sequences of a 48 kb genomic region in 39 individuals of African American (AA) and European American (EA) origin. We employ these phase-known genotypes and coalescent simulations to assess the accuracy of statistical haplotype reconstruction by several algorithms. Accuracy of phase inference was considerably low in our biological data even for regions as short as 25-50 kb, suggesting that caution is needed when analyzing reconstructed haplotypes. Moreover, the reliability of estimated confidence in phase inference is not high enough to allow for a reliable incorporation of site-specific uncertainty information in subsequent analyses. We show that, in samples of certain mixed ancestry (AA and EA populations), the most accurate haplotypes are probably obtained when increasing sample size by considering the largest, pooled sample, despite the hypothetical problems associated with pooling across those heterogeneous samples. Strategies to improve confidence in reconstructed haplotypes, and realistic alternatives to the analysis of inferred haplotypes, are discussed.

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Section: Discussionmentioning

confidence: 99%

Understanding the accuracy of statistical haplotype inference with sequence data of known phase

Andrés

Clark

Shimmin

et al. 2007

Genetic Epidemiology

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“…In this case, the signal of hitchhiking emerges because recombination between epistatic loci produces relatively unfit haplotypes that are eliminated by selection (55). Selection against recombinants has been proposed to explain the strong, longrange linkage disequilibrium between neutral and selected sites in 100-kb haplotypes of the human MHC class II region (56). Examples of epistatic interactions between cis-regulatory variants and coding polymorphisms were quite common in a recent survey of human cis-regulatory evolution (47).…”

Section: Discussionmentioning

confidence: 99%

Ancient polymorphism and functional variation in the primate MHC-DQA15′ cis-regulatory region

Loisel

Rockman

Wray

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Precise regulation of MHC gene expression is critical to vertebrate immune surveillance and response. Polymorphisms in the 5 proximal promoter region of the human class II gene HLA-DQA1 have been shown to influence its transcriptional regulation and may contribute to the pathogenesis of autoimmune diseases. We investigated the evolutionary history of this cis-regulatory region by sequencing the DQA1 5 proximal promoter region in eight nonhuman primate species. We observed unexpectedly high levels of sequence variation and multiple strong signatures of balancing selection in this region. Specifically, the considerable DQA1 promoter region diversity was characterized by abundant shared (or trans-species) polymorphism and a pronounced lack of fixed differences between species. The majority of transcription factor binding sites in the DQA1 promoter region were polymorphic within species, and these binding site polymorphisms were commonly shared among multiple species despite evidence for negative selection eliminating a significant fraction of binding site mutations. We assessed the functional consequences of intraspecific promoter region diversity using a cell line-based reporter assay and detected significant differences among baboon DQA1 promoter haplotypes in their ability to drive transcription in vitro. The functional differentiation of baboon promoter haplotypes, together with the significant deviations from neutral sequence evolution, suggests a role for balancing selection in the evolution of DQA1 transcriptional regulation in primates.balancing selection ͉ cis-regulatory evolution ͉ major histocompatibility complex ͉ primate molecular evolution

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“…We sequenced additional individuals (NA01814, NA10471, NA10540, NA10543, NA10975, NA10976, NA11321, NA11521, NA13838, NA14663) to identify three samples from each of the two haplotypes defined as described above. For each candidate locus, we isolated the six haplotypes from fosmid libraries constructed from the identified individuals, using PCR assays targeted 10 kbp upstream and downstream from the site of the original read to identify fosmids sharing at least 20 kbp of overlapping sequence (Raymond et al 2005b). Isolated fosmids were then sequenced by standard shotgun-sequencing and finishing methods to an estimated error rate of ,10 À5 (the sequences have been deposited in GenBank with accession nos.…”

Section: Methodsmentioning

confidence: 99%

Scan of Human Genome Reveals No New Loci Under Ancient Balancing Selection

Bubb¹,

et al. 2006

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There has been much speculation as to what role balancing selection has played in evolution. In an attempt to identify regions, such as HLA, at which polymorphism has been maintained in the human population for millions of years, we scanned the human genome for regions of high SNP density. We found 16 regions that, outside of HLA and ABO, are the most highly polymorphic regions yet described; however, evidence for balancing selection at these sites is notably lacking-indeed, whole-genome simulations indicate that our findings are expected under neutrality. We propose that (i) because it is rarely stable, longterm balancing selection is an evolutionary oddity, and (ii) when a balanced polymorphism is ancient in origin, the requirements for detection by means of SNP data alone will rarely be met.

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Targeted, haplotype-resolved resequencing of long segments of the human genome

Cited by 24 publications

References 19 publications

Understanding the accuracy of statistical haplotype inference with sequence data of known phase

Understanding the accuracy of statistical haplotype inference with sequence data of known phase

Ancient polymorphism and functional variation in the primate MHC-DQA15′ cis-regulatory region

Scan of Human Genome Reveals No New Loci Under Ancient Balancing Selection

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