L. Giuffra

Model Misspecification and Multipoint Linkage Analysis

Pairwise linkage analysis is robust to genetic model misspecification provided dominance is correctly specified, the primary effect being inflation of the recombination fraction. By contrast, we show that multipoint analysis under misspecified models is not robust when a putative disease locus is placed between close flanking markers, with potentially spuriously negative multipoint lod scores being produced. The problem is due to incorrect attribution of segregation of a disease allele and the consequent conclusion of (unlikely) double crossovers between flanking markers. As a possible solution, we propose the use of high disease allele frequencies, as this allows probabilistically for nonsegregation (through parental homozygosity or dual matings). We show analytically and through analysis of pedigree data simulated under a two-locus heterogeneity model that using a disease allele frequency of 0.05 in the dominant case and 0.25 in the recessive case is quite robust in producing positive multipoint lod scores with close flanking markers across a broad range of conditions including varying allele frequencies, epistasis, genetic heterogeneity and phenocopies.

The β subunit locus of the human fibronectin receptor: DNA restriction fragment length polymorphism and linkage mapping studies

SummaryThe beta subunit of the human fibronectin receptor (FNRB) is a transmembrane protein belonging to the VLA (very late antigens of activation) family. Using pGEM-32, a 2.5-kb partial cDNA clone corresponding to the 3′ portion of the human FNRB locus, multiple restriction fragment length polymorphisms (RFLPs) were revealed on DNAs from unrelated Caucasians. RFLPs detected by five enzymes, BanII, HinfI, KpnI, BglII, and SacI, are of the simple two-allele form, and pairwise linkage analyses of these RFLPs with numerous known DNA markers from the chromosome-10 pericentromeric region not only confirmed the chromosome-10 assignment of the functional FNRB gene but also supported its localization at p11.2 suggested by in situ hybridization. An infrequent MspI RFLP was detected by pB/R2, a 4.6-kb genomic clone from the FNRB locus. Another type of DNA polymorphism was also revealed by the cDNA clone and it was visualized on the Southern blot analyses as the presence or absence of an extra band (or a set of extra bands). It seems to stem from a stretch of DNA sequence present in some individuals at one single locus but absent in others, and is of non-chromosome-10 origin based on linkage analyses with known chromosome 10 markers. This “presence/absence” type of polymorphism could be revealed by all of the 25 restriction enzymes tested and is similar in nature to that previously reported with one of the human dihydrofolate reductase pseudogenes, DHFRP1. Dissection of the pGEM-32 clone demonstrated that the region revealing the non-chromosome-10 sequences is within a fragment about 1.7 kb in length extending from about 600 nucleotides preceding the stop codon down to the end of the cloned FNRB 3′ untranslated region. Due to its high polymorphism information content (PIC) value (0.71 for haplotypes of BanII, HinfI, and KpnI RFLPs) and proximity to the centromere, FNRB will prove to be a highly useful marker for genetic linkage studies of multiple endocrine neoplasia type 2A (MEN2A) as well as for chromosome-10 linkage studies in general.

Glucocorticoid receptor maps to the distal long arm of chromosome 5

Carte genetique du recepteur des glucocorticoides etudie par analyse de linkage avec des marqueurs RFLP dans 3 etudes familiales

The Na+/H+ antiporter : a melt polymorphism allows regional mapping to the short arm of chromosome 1

SummaryThe Na+/H+ antiporter is a ubiquitous membrane-associated protein that plays an important role in the regulation of intracellular pH. APNH, a gene encoding the antiporter, has been cloned and mapped to the short arm of chromosome 1 by in situ hybridization. Using the polymerase chain reaction, we have amplified a 376 base pair fragment corresponding to the 5′ end of APNH. We have detected a polymorphism within this fragment by denaturing gradient gel electrophoresis. Using polymorphisms at other 1p loci (ALPL, the gene for alkaline phosphatase, RH and D1S57), we have been able to map APNH telomeric to D1S57 and close to RH and ALPL by genetic linkage. APNH is a plausible candidate gene for human essential hypertension; the APNH polymorphism combined with a knowledge of its genetic map location allow this candidate to be tested in hypertensive kindreds and sib-pairs.

Linkage Analysis in Psychiatry

The success that linkage analysis is having in single-gene disorders (like cystic fibrosis and Duchenne muscular dystrophy) has prompted researchers in psychiatry to apply it to more complex traits (like schizophrenia and affective disorders). In the latter, twin and family studies strongly suggest the presence of a genetic component. However, this component may not act as a single-gene; thus, the lod scores resulting from applying linkage analysis (whether positive or negative) require a very cautious interpretation. We will discuss some of the problems encountered when using this method to study psychiatric disorders.

Clinical and Pathologic Features of Chromosome 21-Linked Familial Alzheimer's Disease

Many pedigrees have been described in which histologically proven Alzheimers disease (AD) is apparently inherited as an autosomal dominant disorder (Nee et al. 1983). Genetic analysis in such pedigrees indicates that some cases of early onset AD are linked to markers on chromosome 21 (St. George-Hyslop et al. 1987; Goate et al. 1989). However, the absence of proven linkage to chromosome 21 in families with late onset AD and in a group of families of Volga German origin suggests a genetic heterogeneity (Schellenberg et al. 1988). This possible genetic heterogeneity has not allowed us to ascribe a specific genetic etiology to any family with defined clinical or pathologic features. In this study, genetic data that demonstrate linkage in a single family between markers on chromosome 21 and AD are presented together with clinical features and neuropathologic findings in one case.

Genetic Linkage Analysis: Simple Solutions for Complex Traits?

Many human disorders are either partially or wholly determined by genetic factors. The identification of these genetic defects at the DNA level is a major goal with important implications. Such identification could greatly increase our understanding of diseases whose pathophysiology and clinical course are currently unknown. In turn, this could lead to logical improvements in the way the disorder is treated. Furthermore, antenatal diagnosis and the identification of carriers could provide the opportunity for more accurate genetic counseling.