A B S T R A C T Using isoelectric focusing in polyacrylamide gel and a hemolytic assay for development of patterns, extensive structural polymorphism in human C8 has been delineated. Two C8 allotypes have been determined for two previously studied familes, each with a homozygous C8-deficient propositus. This study suggests that C8 deficiency is a silent or null allele of the C8 structural locus, and that half normal levels of C8 cannot be used as a single criterion for the establishment of heterozygous C8 deficiency. C8 allotypes, as well as 18 other autosomal markers, were also determined for 24 familes. The C8 structural locus is not closely linked to these markers, including the human histocompatibility loci complex.
Eleven extended pedigrees segregating autosomal dominant Huntington disease (HD) were analyzed for linkage with 15 gene markers. A straight-line age correction (STLN), fitted roughly t o published age-of-onset data but excluding the oldest and youngest ages, was used. The results failed t o confirm a positive lod score reported by Brackenridge e t a1 [ 19781 between HD and haptoglobin (Hp); our lod scores, taken alone, would rule out this linkage. No lod score in our study exceeded 0.40.Three informative markers, adenosine deaminase (ADA), Hp, and MNSs, were used t o compare results obtained by employing different age corrections during lod score calculation. In addition t o STLN, a least-squares line (LSQR) and a cumulative normal curve (CUMN) were used. CUMN was assumed to be the most accurate, since it fitted the data most closely. For comparison, two methods involving n o age correction were also examined: one in which all unaffected persons were uniformly assigned a 50% penetrance (NONE) and one in which all younger at-risk persons were removed from the analysis (REMV). NONE and REMV distorted lod scores, in some cases strikingly. More importantly, they also sometimes biased the estimate of the recombination fraction. In contrast, STLN and LSQR gave results generally very similar to those found using CUMN. Thus, it was concluded that the exact shape of the age correction used is not critical to linkage analyses, but that failure t o use any correction may lead t o unacceptable results.
A genetic linkage study, performed on a large family with autosomal dominant retinitis pigmentosa (RP), demonstrated that the RP gene may be linked to the Rh locus, known to be on the short arm of human chromosome 1. Linkage studies on RP along with other studies, can help to more accurately classify these disease entities. Localizing the RP gene locus has the potential for allowing the early diagnosis of individuals at risk.
Recently it has been suggested that multiple sclerosis may be a multifactorial disorder. We found in British Columbia 364 families (sibship size greater than or equal to 2) in which at least on sibling was diagnosed as having "clinically definite" multiple sclerosis. The data were tested for goodness-of-fit to the multifactorial model using an analysis that considers various parameters including ascertainment probability heritability, and sex-dependent prevalence rates. The results suggest that multiple sclerosis does not fit the multifactorial model. As an alternative genetic model we propose that a major gene could be responsible for at least a portion of the cases of multiple sclerosis.
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