Linkage analysis, kinship, and the short-term evolution of chromosomes

Schork, Nicholas J.; Thiel, Bonnie; Jean, Pamela St.

doi:10.1002/(sici)1097-010x(199809/10)282:1/2<133::aid-jez15>3.0.co;2-v

Cited by 9 publications

(4 citation statements)

References 71 publications

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“…To further localize PSORS1, we turned to recombinant ancestral haplotype analysis. Use of a dense marker map to identify recombinants of an ancestral haplotype known to carry a disease gene is a powerful analytical tool, since comparison of recombinant haplotypes in unrelated individuals with psoriasis permits the study of a much larger number of informative recombinants than would typically be identified by a family study (Xiong and Guo 1997;Schork et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Localization of Psoriasis-Susceptibility Locus PSORS1 to a 60-kb Interval Telomeric to HLA-C

Nair

Stuart

Henseler

et al. 2000

The American Journal of Human Genetics

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Recent genome scans have established the presence of a major psoriasis-susceptibility locus in the human leukocyte antigen (HLA) complex on chromosome 6p21.3. To narrow the interval for candidate gene testing, we performed a linkage-disequilibrium analysis of 339 families, with the use of 62 physically mapped microsatellite markers spanning the major histocompatibility complex (MHC). As detected by use of the transmission/disequilibrium test (TDT), individual markers yielded significant linkage disequilibrium across most of the MHC. However, the strongest evidence for marker-trait disequilibrium was found in an ∼300-kb region extending from the MICA gene to the corneodesmosin gene. Maximum-likelihood haplotypes were constructed across the entire MHC in the original sample and across a 1.2-Mb region of the central MHC in an expanded sample containing 139 additional families. Short (two-to five-marker) haplotypes were subjected to the TDT using a "moving-window" strategy that reduced the variability of TDT P values relative to the single-locus results. Furthermore, the expanded sample yielded a sharp peak of evidence for linkage disequilibrium that spanned ∼170 kb and that was centered 100 kb telomeric to HLA-C. The 1.2-Mb interval was further dissected by means of recombinant ancestral haplotype analysis. This analysis identified risk haplotype 1 (RH1), which is a 60-kb fragment of ancestral haplotype 57.1, on all identifiable HLA risk haplotypes. One of these haplotypes exhibits significant linkage disequilibrium with psoriasis but does not carry Cw6, which is the HLA allele most strongly associated with the disease. These results demonstrate that RH1 is highly likely to carry the disease allele at PSORS1, and they exclude HLA-C and corneodesmosin with a high degree of confidence.

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Section: Discussionmentioning

confidence: 99%

Localization of Psoriasis-Susceptibility Locus PSORS1 to a 60-kb Interval Telomeric to HLA-C

Nair

Stuart

Henseler

et al. 2000

The American Journal of Human Genetics

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241

223

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“…For example, one can consider the evolution or phylogeny of the chromosomes harboring disease-causing variations within the human species. 65 Such analyses can shed light on groups of haplotypes or chromosomes that should be analyzed together in, eg, an association analysis setting. 66,67…”

Section: Evolutionary Analysismentioning

confidence: 99%

Statistical Genetics Concepts and Approaches in Schizophrenia and Related Neuropsychiatric Research

Schork

Greenwood

Braff

2006

Schizophrenia Bulletin

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Statistical genetics is a research field that focuses on mathematical models and statistical inference methodologies that relate genetic variations (ie, naturally occurring human DNA sequence variations or "polymorphisms") to particular traits or diseases (phenotypes) usually from data collected on large samples of families or individuals. The ultimate goal of such analysis is the identification of genes and genetic variations that influence disease susceptibility. Although of extreme interest and importance, the fact that many genes and environmental factors contribute to neuropsychiatric diseases of public health importance (eg, schizophrenia, bipolar disorder, and depression) complicates relevant studies and suggests that very sophisticated mathematical and statistical modeling may be required. In addition, large-scale contemporary human DNA sequencing and related projects, such as the Human Genome Project and the International HapMap Project, as well as the development of high-throughput DNA sequencing and genotyping technologies have provided statistical geneticists with a great deal of very relevant and appropriate information and resources. Unfortunately, the use of these resources and their interpretation are not straightforward when applied to complex, multifactorial diseases such as schizophrenia. In this brief and largely nonmathematical review of the field of statistical genetics, we describe many of the main concepts, definitions, and issues that motivate contemporary research. We also provide a discussion of the most pressing contemporary problems that demand further research if progress is to be made in the identification of genes and genetic variations that predispose to complex neuropsychiatric diseases.

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“…Given that the shared haplotype in the carriers is composed of a long string of markers, it is highly unlikely that the observed sharing represents identity by state (IBS) rather than identity by descent (IBD) (Schork et al 1998). Two distantly related families showed large haplotype sharing for 9p21 among p16-Leiden carriers.…”

Section: Discussionmentioning

confidence: 99%

A Locus Linked to p16 Modifies Melanoma Risk in Dutch Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome Families

Velden¹,

Sandkuijl²,

Bergman³

et al. 1999

Genome Res.

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The CDKN2A gene that encodes the cell cycle inhibitor p16 shows mutations in many but not all 9p21-linked melanoma families. Most Dutch melanoma families segregate for a unique founder mutation (p16-Leiden), encoding a truncated nonfunctional p16 protein. The highly variable risk for p16-Leiden carriers to develop melanoma suggests a role for other genetic and/or environmental factors. We hypothesized that a 9p21 gene other than CDKN2A may be relevant in the remaining 9p21-linked melanoma families without p16 mutations but may also act as a risk modifier in p16-Leiden carriers. Haplotype analysis for 9p21 was performed using microsatellite markers in six p16-Leiden families originating from a founder population. p16-Leiden carriers in two families shared an unexpectedly large founder haplotype (∼20-cM) around CDKN2A, mostly in proximal direction. Melanoma-positive p16-Leiden carriers from these families showed this extensive proximal haplotype compared with melanoma-negative p16-Leiden carriers from the same families. Additional p16-Leiden families less heavily affected with melanoma showed shorter haplotypes sharing, excluding the region proximally of CDKN2A. The presence of a gene involved in melanoma susceptibility proximal of CDKN2A is corroborated by somatic deletions of 9p in tumors, which frequently do not include CDKN2A but a more proximal chromosomal area instead. Our results provide a candidate region for further gene mapping in p16-negative 9p21-linked melanoma families and guide the search for risk modifiers in melanoma development.

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Linkage analysis, kinship, and the short-term evolution of chromosomes

Cited by 9 publications

References 71 publications

Localization of Psoriasis-Susceptibility Locus PSORS1 to a 60-kb Interval Telomeric to HLA-C

Localization of Psoriasis-Susceptibility Locus PSORS1 to a 60-kb Interval Telomeric to HLA-C

Statistical Genetics Concepts and Approaches in Schizophrenia and Related Neuropsychiatric Research

A Locus Linked to p16 Modifies Melanoma Risk in Dutch Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome Families

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