Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22

Puffenberger, Erik G.; Kauffman, Erick; Bolk, Stacey; Matise, Tara C.; Washington, Sarah S.; Angrist, Misha; Weissenbach, Jean; Garver, Kenneth L.; Mascari, Maria J.; Ladda, Roger L.; A.SIaugenhaupt, Susan; Chakravarti, Aravinda

doi:10.1093/hmg/3.8.1217

Cited by 227 publications

(116 citation statements)

References 0 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…This demonstrated that shared segment mapping can be used to assign a gene by using only a limited number of markers, whenever a suitable population is available. The same principle has been used for the mapping of other monogenic disorders too, in both humans (Puffenberger et al 1994;Carlton et al 1995;Kalaydjieva et al 1996;Newport et al 1996) and cattle (Charlier et al 1996). Byler disease, a form of PFIC, was mapped to the BRIC region on chromosome 18q21, by studying two distantly related patients, both descendants of Jacob Byler (Carlton et al 1995).…”

Section: Discussionmentioning

confidence: 99%

Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64

Sinke

Carlton

et al. 1997

Human Genetics

View full text Add to dashboard Cite

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. The gene was previously assigned to chromosome 18q21, using a shared segment analysis in three families from the Netherlands. In the present study we report the linkage analysis of an expanded sample of 14 BRIC families, using 15 microsatellite markers from the 18q21 region. Obligate recombinants in two families place the gene in a 7-cM interval, between markers D18S69 and D18S64. All intervening markers had significant LOD scores in two-point linkage analysis. Moreover, we identified one family in which the BRIC gene seems to be unlinked to the 18q21 region, or that represents incomplete penetrance of the BRIC genotype. IntroductionBenign recurrent intrahepatic cholerstasis (BRIC) is a rare autosomal recessive liver disease (De Koning et al. 1995) characterized by intermittent attacks of cholestasis without extrahepatic bile duct obstruction (Summerskil and Walshe 1959;Brenard et al. 1989). Each cholestatic attack starts with rising serum bile acid levels, usually followed by hyperbilirubinemia and overt cholestasis (Bijleveld et al. 1989;Brenard et al. 1989). The attacks vary in duration (weeks to months) and resolve spontaneously. No biochemical abnormalities are found in patients between attacks. The initial episode can occur at any age from infancy to adulthood, although most patients present before the age of 25 years. The frequency of attacks varies from several times a year to less than once per decade (Brenard et al. 1989). Progression to chronic liver disease has not been observed, but cholestatic episodes result in substantial morbidity, including pronounced weight loss and deficiency of fat-soluble vitamins. No established treatment is available, although cholestyramine may alleviate symptoms in some patients. Development of an effective therapy is hampered because the basic defect in BRIC is unknown.The gene for BRIC was originally mapped to chromosome 18q21 through the identification of a shared chromosomal segment in three distantly related patients from an isolated community in the Netherlands (Houwen et al. 1994). The region shared in these patients extended from D18S363 to D18S55, a genetic distance of more than 20 cM. To facilitate future molecular genetic studies we subsequently started to delimit the region of interest by studying additional BRIC families with a more densly spaced set of markers. We now present an analysis of 14 BRIC families from different ethnic sources with microsatellites selected primarily from the Généthon map, with the addi- Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64

show abstract

Section: Discussionmentioning

confidence: 99%

Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64

Sinke

Carlton

et al. 1997

Human Genetics

View full text Add to dashboard Cite

show abstract

“…For many species, however, the lack of a genomic map leads to an inability to separate background LD from other types of LD. Furthermore, events other than admixture, such as population bottlenecks (Lynch and Walsh, 1998) or important demographic changes, could also generate strong LD and increase the occurrence of background LD (Jorde, 2000;Peltonen, 2000;Puffenberger et al, 1994). In this situation, users should not rely on the genomic map alone to decide which loci to use or not.…”

Section: Introductionmentioning

confidence: 99%

Detecting population structure using STRUCTURE software: effect of background linkage disequilibrium

Kaeuffer¹,

Réale²,

Coltman³

et al. 2007

Heredity

107

View full text Add to dashboard Cite

STRUCTURE is the most widely used clustering software to detect population genetic structure. The last version of this software (STRUCTURE 2.1) has been enhanced recently to take into account the occurrence of linkage disequilibrium (LD) caused by admixture between populations. This last version, however, still does not consider the effects of strong background LD caused by genetic drift, and which may cause spurious results. STRUCTURE authors have, therefore, suggested a rough threshold value of the distance (1.0 cM) between two loci below which the pair of loci should not be used. Because of the sensitiveness of LD to demographic events, the distance between loci is not always a good indicator of the strength of LD. In this study, we examine the link between genomic distance and the strength of the correlation between loci (r LD ) in a free-ranging population of mouflon (Ovis aries), and we present an empirical test of effect of r LD on the clustering results provided by the linkage model in STRUCTURE. We showed that a high r LD value increases the probability of detecting spurious clustering. We propose to use r LD as an index to base a decision on whether or not to use a pair of loci in a clustering analysis. Keywords: STRUCTURE software; linkage disequilibrium; population structure; clustering Introduction STRUCTURE (Pritchard et al., 2000) is the most widely used clustering software applied to detect population genetic structure, with more than 1000 citations for its first version (Pritchard et al., 2000) and more than 170 citations for its recent enhanced version (Falush et al., 2003) (source: ISI Web of Science database). STRUCTURE generates clusters based on both transient HardyWeinberg disequilibrium (HWD) and linkage disequilibrium (LD) caused by admixture between populations. The program works by clustering individuals in groups, where both linkage and HWD are minimized, and therefore, the presence of LD in the data improves clustering results (Falush et al., 2003). On the other hand, 'strong' LD or departure from Hardy-Weinberg equilibrium could lead to an overestimation of the number of clusters detected (Falush et al., 2003).STRUCTURE deals with two kinds of LD: the first is mixture LD, which occurs across loci even if they are unlinked due to the correlation of allele frequencies 'because individuals with a large component of ancestry in population k have an excess of alleles that are common in k' (Falush et al., 2003). The second is admixture LD, which is 'the correlation that arises between linked markers in recently admixed populations ' (Pritchard and Wen, 2004). This LD occurs because markers are on the same 'chunk' of chromosome that derives from an ancestral population. The 'admixture model' implemented in the latest version of STRUCTURE (STRUCTURE 2.1;Falush et al., 2003) combines admixture LD with map distances between markers to improve clustering results. Falush et al. (2003) defined a third kind of LD: the background LD measured between syntenous loci separated by few cM. Background...

show abstract

“…35 Puffenberger et al 35 ascertained a large, inbred, Mennonite pedigree (depicted in Figure 1 in Puffenberger et al 35 ), exhibiting high incidence of Hirschsprung disease. Genealogical analysis of all members of the Mennonite pedigree identified a single common ancestral couple for all parents of the affected offspring.…”

Section: Chromosome Segment Sharing O Libiger and Nj Schorkmentioning

confidence: 99%

“…Figure 2 The probability of sharing a 10 Mb IBD segment when IBS sharing is observed with markers 2 Mb apart (chromosome 13). The conditional probability that affected members of the Mennonite pedigree (depicted in Figure 1 in Puffenberger et al 35 ) share a 10 Mb IBD segment on chromosome 13 (ie, five markers), given the observed IBS sharing. The solid lines correspond to IBS sharing using five markers in linkage equilibrium with five equifrequent alleles (full black line), vs one common allele with frequency equal to 0.6 and four rare alleles with frequency equal to 0.1 (full gray line).…”

Section: Chromosome Segment Sharing O Libiger and Nj Schorkmentioning

confidence: 99%

A simulation-based analysis of chromosome segment sharing among a group of arbitrarily related individuals

Libiger

Schork

2007

Eur J Hum Genet

View full text Add to dashboard Cite

A fundamental set of issues in human genetics research concerns the statistical properties of the DNA sequence or chromosomal segments that are shared between related individuals. Although wellestablished mathematical formulations exist that consider such sharing via measures such as the kinship coefficient, many of these formulations are derived for entire genomes, individual sequence variations, or small stretches of DNA, and hence, do not consider either the actual size or the number of the genomewide chromosomal segments that are shared between two or more arbitrarily related individuals. In this paper, we employ a flexible gene-dropping simulation-based approach for estimating the distribution of the size and the number of chromosomal segments shared by any number of arbitrarily related individuals. The approach takes advantage of chromosome-and sex-specific recombination rates adopted from integrated genetic and physical maps, and considers the genome as a whole, rather than specific genomic regions or loci. In addition, our analysis considers the effects of linkage disequilibrium and crossover interference on segment sharing. Our proposed analysis and computational strategy can be used to provide compelling answers to questions concerning variation in the kinship coefficient as well as the distribution of chromosomal sharing over individual chromosomes. We present results that showcase possible application of assessing genomic sharing in gene mapping and apply our analysis to data available from published gene mapping studies.

show abstract

Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22

Cited by 227 publications

References 0 publications

Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64

Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64

Detecting population structure using STRUCTURE software: effect of background linkage disequilibrium

A simulation-based analysis of chromosome segment sharing among a group of arbitrarily related individuals

Contact Info

Product

Resources

About