Homozygosity Haplotype Allows a Genomewide Search for the Autosomal Segments Shared among Patients

Miyazawa, Hitoshi; Kato, Masaaki; Awata, Takuya; Kohda, Masakazu; Iwasa, Hiroyasu; Koyama, Nobuyuki; Tanaka, Tomoaki; Huqun,; Kyo, Shunei; Okazaki, Yasushi; Hagiwara, Koichi

doi:10.1086/518176

Cited by 61 publications

(87 citation statements)

References 10 publications

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“…(See [10] for a recent overview.) For genotype data, a simple approach is to search for shared chromosomal segments that are consistent with IBD and to infer IBD if the segment length exceeds a given threshold [38]. For phased data, haplotypes can be directly compared and IBD is inferred if shared segments are either sufficiently long or if the estimated frequency is sufficiently low [24,8].…”

Section: Discussionmentioning

confidence: 99%

On the use of dense SNP marker data for the identification of distant relative pairs

Sun

Jobling

Taliun

et al. 2016

Theoretical Population Biology

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There has been recent interest in the exploitation of readily available dense genome scan marker data for the identification of relatives. However, there are conflicting findings on how informative these data are in practical situations and, in particular, sets of thinned markers are often used with no concrete justification for the chosen spacing. We explore the potential usefulness of dense single nucleotide polymorphism (SNP) arrays for this application with a focus on inferring distant relative pairs. We distinguish between relationship estimation, as defined by a pedigree connecting the two individuals of interest, and estimation of general relatedness as would be provided by a kinship coefficient or a coefficient of relatedness. Since our primary interest is in the former case, we adopt a pedigree likelihood approach. We consider the effect of additional SNPs and data on an additional typed relative, together with choice of that relative, on relationship inference. We also consider the effect of linkage disequilibrium. When overall relatedness, rather than the specific relationship, would suffice, * Theoretical Population Biology. In Press. http://dx.doi.org/10.1016/j.tpb.2015.10 † Corresponding author. E-mail address: Nuala.Sheehan@leicester.ac.uk 1 we propose an approximate approach that is easy to implement and appears to compete well with a popular moment-based estimator and a recent maximum likelihood approach based on chromosomal sharing. We conclude that denser marker data are more informative for distant relatives. However, linkage disequilibrium cannot be ignored and will be the main limiting factor for applications to real data.

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Section: Discussionmentioning

confidence: 99%

On the use of dense SNP marker data for the identification of distant relative pairs

Sun

Jobling

Taliun

et al. 2016

Theoretical Population Biology

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“…Hence, the significance of the constitutive 'non-ROH' segmental UPD traits found in infant ALL patients and whether they could have a role in the leukemogenic progress still remain to be determined. Indeed, extended 'runs of homozygosity' in the Table 3 Recurrent UPD human genome have been found not only in patients [21][22][23] but also in healthy individuals; [23][24][25] therefore, UPDs could represent previously undetected new ROH, which are not involved in the pathogenesis of the disease. Conversely, it cannot be excluded that genomic background, characterized by constitutional stretches of homozygosity, might offer a permissive environment for the development of the disease, favoring the occurrence of the MLL rearrangement itself, although further work is required to explore this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…ROHs among unrelated patients lead to the identification of new genes or candidate loci responsible for the genetic basis of the disease. [23][24][25] In this study, we explored the genomic profile of infant ALL by SNP array to detect MLL-cooperating aberrations, hidden to conventional techniques. To further limit heterogeneity, we focused on patients carrying the t(4;11) translocation, which is the most frequent genetic abnormality in infant ALL.…”

Section: Introductionmentioning

confidence: 99%

DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4

et al. 2009

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The pathogenesis of infant acute lymphoblastic leukemia (ALL) is still not well defined. Short latency to leukemia and very high concordance rate for ALL in Mixed-Lineage Leukemia (MLL)-positive infant twins suggest that the MLL rearrangement itself could be sufficient for overt leukemia. Attempts to generate a suitable mouse model for MLL-AF4-positive ALL did not thoroughly resolve the issue of whether cooperating mutations are required to reduce latency and to generate overt leukemia in vivo. In this study, we applied single-nucleotide polymorphism array technology to perform genomic profiling of 28 infant ALL cases carrying t(4;11) to detect MLL-cooperating aberrations hidden to conventional techniques and to gain new insights into infant ALL pathogenesis. In contrast to pediatric, adolescent and adult ALL cases, the MLL rearrangement in infant ALL is associated with an exceptionally low frequency of copy-number abnormalities, thus confirming the unique nature of this disease. By contrast, additional genetic aberrations are acquired at disease relapse. Small-segmental uniparental disomy traits were frequently detected, mostly constitutional, and widely distributed throughout the genome. It can be argued that the MLL rearrangement as a first hit, rather than inducing the acquisition of additional genetic lesions, has a major role to drive and hasten the onset of leukemia.

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“…Our consideration of SNP streaks among subsets generalizes that of the very interesting work of Miyazawa, et al [Miyazawa, et al (2007)] which considers SNP streaks of homozygous loci (the so-called "homozygosity haplotype") in the sample genomes shared by pairs of samples. Our work differs in two ways.…”

Section: Relation To Previous Workmentioning

confidence: 90%

“…As has been pointed out by the referee, the streaks statistic introduced therein is identical to that contained herein. That said, there are differences between the two papers and we quote here from the (very thorough) referee report (suitably modified to incorporate our bibliographic style): "The innovation in this current paper is to extend the methods of [Miyazawa, et al (2007)] for homozygous sharing to evaluating statistical significance for heterozygous sharing. This has the advantage of being applicable when the pedigree structure is unsure, or has paths back to multiple common ancestors.…”

Section: Relation To Previous Workmentioning

confidence: 99%

A SNP Streak Model for the Identification of Genetic Regions Identical-by-descent

Leibon¹,

Rockmore²,

Pollak³

2008

Statistical Applications in Genetics and Molecular Biology

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The availability of very dense genetic maps is changing in a fundamental way the methods used to identify the genetic basis of both rare and common inherited traits. The ability to directly compare the genomes of two related individuals and quickly identify those regions that are inherited identical-by-descent (IBD) from a recent common ancestor would be of utility in a wide range of genetic mapping methods. Here, we describe a simple method for using dense SNP maps to identify regions of the genome likely to be inherited IBD by family members. This method is based on identifying obligate recombination events and examining the pattern of distribution of such events along the genetic map. Specifically, we use the length of a consecutive set of biallelic markers that have a high probability of having avoided such obligate recombination events. This "SNP streak" is derived from subsets of samples within a pedigree and allows us to make statistical inferences about the ancestry of the region(s) containing stretches of markers with these properties. We show that the use of subsets of more than two samples has the advantage of identifying shorter shared subsegments as significant. This mitigates the effects of errors in SNP calls. We provide specific examples of microarray-based SNP data, using a family with a complex pedigree and with a rare form of inherited kidney disease, to illustrate this approach.

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Homozygosity Haplotype Allows a Genomewide Search for the Autosomal Segments Shared among Patients

Cited by 61 publications

References 10 publications

On the use of dense SNP marker data for the identification of distant relative pairs

On the use of dense SNP marker data for the identification of distant relative pairs

DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4

A SNP Streak Model for the Identification of Genetic Regions Identical-by-descent

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