Reduction of physical assignments to a standard lod table: Chromosome 1

Summary A method for reducing physical assignments of markers to a lod score table is described, and these tables are added to those from family data to provide a consistent genetic map of chromosome 1. Various chiasma maps are considered, and the results suggest that terminalization of chiasmata does occur. Chiasmata appear to be significantly less localized in oocytes than spermatocytes, and crossing-over in the vicinity of the centromere is more common in females than in males.This work was supported by Grants GM 23021, GM 24941, and NF 1-475 from the U.S. National Institutes of Health and National Foundation, PGL Paper No. 228     

Likely linkage: Inv with Jk

Summary In a data base consisting of 1665 pairs of loci linkage between Inv and Jk is significant . Recombination is nearly the same in the two sexes . The reason why this linkage was not noticed earlier is discussed.     

A multivariate method for detecting genetic linkage, with application to a pedigree with an adverse lipoprotein phenotype.

The robust or model-free method for detecting linkage developed by Haseman and Elston for data from sib pairs is extended to incorporate observations of multiple traits on each individual. A method is proposed that estimates the linear function that results in the strongest correlation between the squared pair differences in the trait measurements and identity by descent at a marker locus. The method is illustrated by the study of apolipoprotein and cholesterol levels in individuals from a large family that had many members diagnosed with coronary heart disease.     

Another elliptocytosis locus on chromosome 1?

Summary Analysis of pedigrees given in the literature suggests that a second elliptocytosis locus (not linked to Rh) may be linked to Duffy (=1.97 at ) and therefore on chromosome 1. Significant heterogeneity is found between the El₁ and El₂ total lod scores with Fy.     

A role for Alström syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence

Premature truncation alleles in the ALMS1 gene are a frequent cause of human Alstr?m syndrome. Alstr?m syndrome is a rare disorder characterized by early obesity and sensory impairment, symptoms shared with other genetic diseases affecting proteins of the primary cilium. ALMS1 localizes to centrosomes and ciliary basal bodies, but truncation mutations in Alms1/ALMS1 do not preclude formation of cilia. Here, we show that in vitro knockdown of Alms1 in mice causes stunted cilia on kidney epithelial cells and prevents these cells from increasing calcium influx in response to mechanical stimuli. The stunted-cilium phenotype can be rescued with a 5' fragment of the Alms1 cDNA, which resembles disease-associated alleles. In a mouse model of Alstr?m syndrome, Alms1 protein can be stably expressed from the mutant allele and is required for cilia formation in primary cells. Aged mice developed specific loss of cilia from the kidney proximal tubules, which is associated with foci of apoptosis or proliferation. As renal failure is a common cause of mortality in Alstr?m syndrome patients, we conclude that this disease should be considered as a further example of the class of renal ciliopathies: wild-type or mutant alleles of the Alstr?m syndrome gene can support normal kidney ciliogenesis in vitro and in vivo, but mutant alleles are associated with age-dependent loss of kidney primary cilia.     

Replication-mediated instability of the GAA triplet repeat mutation in Friedreich ataxia

Friedreich ataxia is caused by the expansion of a polymorphic and unstable GAA triplet repeat in the FRDA gene, but the mechanisms for its instability are poorly understood. Replication of (GAA•TTC)_n sequences (9–105 triplets) in plasmids propagated in Escherichia coli displayed length- and orientation-dependent instability. There were small length variations upon replication in both orientations, but large contractions were frequently observed when GAA was the lagging strand template. DNA replication was also significantly slower in this orientation. To evaluate the physiological relevance of our findings, we analyzed peripheral leukocytes from human subjects carrying repeats of similar length (8–107 triplets). Analysis of 9400 somatic FRDA molecules using small-pool PCR revealed a similar mutational spectrum, including large contractions. The threshold length for the initiation of somatic instability in vivo was between 40 and 44 triplets, corresponding to the length of a eukaryotic Okazaki fragment. Consistent with the stabilization of premutation alleles during germline transmission, we also found that instability of somatic cells in vivo and repeats propagated in E.coli were abrogated by (GAGGAA)_n hexanucleotide interruptions. Our data demonstrate that the GAA triplet repeat mutation in Friedreich ataxia is destabilized, frequently undergoing large contractions, during DNA replication.     

The USH1C 216G→A mutation and the 9-repeat VNTR(t,t) allele are in complete linkage disequilibrium in the Acadian population

Recently, mutations in USH1C were shown to be associated with Usher syndrome type IC, and a mutation (216G-->A) in exon 3 was identified in an Acadian family. In addition, a 45-bp variable number of tandem repeat (VNTR) polymorphism was found in intron 5 of USH1C. Polymerase chain reaction amplification of the VNTR region and restriction enzyme analysis of exon 3 of USH1C showed that, of 44 Acadian patients, 43 were homozygous for both the 216G-->A mutation and nine repeats of the VNTR, with a "t" nucleotide replacing a "g" nucleotide at the 8th position of both the eighth and ninth copies of the repeat, viz., 9VNTR(t,t). The remaining Acadian patient was reported to be a compound heterozygote for 216G-->A/9VNTR(t,t) and 238-239insC, a USH1C mutation that has been found in other populations. These data demonstrate that the 9VNTR(t,t) allele is in complete linkage disequilibrium with the 216G-->A mutation in the Acadian population. Among 82 Acadian controls, one was heterozygous for 216G-->A/9VNTR(t,t). The 238-239insC mutation was not found in Acadian controls. Analysis of 340 non-Acadian normal samples showed the presence of a 9-repeat VNTR allele in one Hispanic sample. This individual had neither the 216G-->A mutation nor the Acadian VNTR(t,t) structure. These results suggest that the 216G-->A mutation and the 9VNTR(t,t) allele are restricted to the Acadians and are in complete linkage disequilibrium.